Publications by year
In Press
Min JL, Hemani G, Hannon E, Dekkers KF, Castillo-Fernandez J, Luijk R, Carnero-Montoro E, Lawson DJ, Burrows K, Suderman M, et al (In Press). Genomic and phenomic insights from an atlas of genetic effects on DNA methylation.
Abstract:
Genomic and phenomic insights from an atlas of genetic effects on DNA methylation
AbstractCharacterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.
Abstract.
2023
Clarke SLN, Mitchell RE, Sharp GC, Ramanan AV, Relton CL (2023). Vitamin D Levels and Risk of Juvenile Idiopathic Arthritis: a Mendelian Randomization Study.
Arthritis Care Res (Hoboken),
75(3), 674-681.
Abstract:
Vitamin D Levels and Risk of Juvenile Idiopathic Arthritis: a Mendelian Randomization Study.
OBJECTIVES: Observational studies report mixed findings regarding the association between vitamin D and juvenile idiopathic arthritis (JIA) incidence or activity; however, such studies are susceptible to considerable bias. Because low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation, we examined the causal effect of the major circulating form of vitamin D, 25-hydroxy vitamin D (25-[OH]D), on JIA incidence using Mendelian randomization (MR). METHODS: in this 2-sample MR analysis, we used summary level data from the largest and most recent genome-wide association study of 25-(OH)D levels (sample size 443,734), alongside summary data from 2 JIA genetic studies (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy, we employed multiple MR methods and sensitivity analyses. RESULTS: We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (odds ratio 1.00 [95% confidence interval (95% CI) 0.76, 1.33] per SD increase in standardized natural-log transformed 25-[OH]D levels). This estimate was consistent across all methods tested. Additionally, there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 SD change in standardized natural-log transformed 25-[OH]D levels per doubling odds in genetically predicted JIA [95% CI -0.006, 0.002]). CONCLUSION: Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.
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Author URL.
2022
Clarke SLN, Richmond RC, Zheng J, Spiller W, Ramanan AV, Sharp GC, Relton CL (2022). Examining Health Outcomes in Juvenile Idiopathic Arthritis: a Genetic Epidemiology Study.
ACR Open Rheumatol,
4(4), 363-370.
Abstract:
Examining Health Outcomes in Juvenile Idiopathic Arthritis: a Genetic Epidemiology Study.
OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease; however, little is known about its wider health impacts. This study explores health outcomes associated with JIA genetic liability. METHODS: We used publicly available genetic data sets to interrogate the genetic correlation between JIA and 832 other health-related traits using linkage disequilibrium score regression. Two-sample Mendelian randomization (2SMR) was used to examine four genetic correlates for evidence of causality. RESULTS: We found robust evidence (adjusted P [Padj ]
Abstract.
Author URL.
Juvinao-Quintero D, Sharp G, Sanderson E, Relton C, Elliott H (2022). Investigating causality in the association between DNA methylation and prevalent T2D using a bidirectional two-sample Mendelian Randomization.
Abstract:
Investigating causality in the association between DNA methylation and prevalent T2D using a bidirectional two-sample Mendelian Randomization
ABSTRACT Aim Several studies have identified associations between type 2 diabetes (T2D) and DNA methylation (DNAm). However, the causal role of these associations remains unclear. This study aims to provide evidence for a causal relationship between DNA methylation and T2D. Methods We implemented a bidirectional two-sample Mendelian randomization (2SMR) to evaluate causality at 58 CpG sites previously detected in a meta-analysis of epigenome-wide association studies (meta-EWAS) of prevalent T2D in Europeans. We retrieved genetic proxies for T2D and DNAm from the largest GWAS available. We also used data from the Avon Longitudinal Study of Parents and Children (ALSPAC, UK) when associations of interest were not available in the larger datasets. We identified 62 independent SNPs as proxies for T2D, and 39 methylation quantitative trait loci or mQTL as proxies for 30 of the 58 T2D-related CpGs. We applied correction for multiple testing using Bonferroni and inferred causality based on a P < 1.0×10 −3 or P < 2.0×10 −3 for the T2D⟶ DNAm direction, and the opposing DNAm ⟶ T2D direction of the 2SMR, respectively. Results We found strong evidence of causality of DNAm at cg25536676 ( DHCR24 ) on T2D, where an increase in transformed residuals of DNAm at this site were associated with 43% (OR=1.43, 95%CI=1.15-1.78, P =0.001) higher risk of T2D. We infer a likely causal direction for the remaining CpG sites assessed. In silico analyses showed that CpGs analyzed were enriched for eQTMs, and for specific traits dependent on the direction of causality predicted by 2SMR. Conclusions We identified one CpG mapping to a gene related with the metabolism of lipids ( DHCR24 ), as a novel causal biomarker for the risk of T2D. CpGs within the same gene-region have previously been associated with T2D-related traits in observational studies (BMI, waist circumference, HDL-cholesterol, insulin) and in MR analyses (LDL-cholesterol). Thus, we hypothesize that our candidate CpG in DHCR24 may be a causal mediator of the association between known modifiable risk factors and T2D. Formal causal mediation analysis should be implemented to further validate this assumption.
Abstract.
Sammallahti S, Koopman-Verhoeff ME, Binter A-C, Mulder RH, Cabré-Riera A, Kvist T, Malmberg ALK, Pesce G, Plancoulaine S, Heiss JA, et al (2022). Longitudinal associations of DNA methylation and sleep in children: a meta-analysis.
Clin Epigenetics,
14(1).
Abstract:
Longitudinal associations of DNA methylation and sleep in children: a meta-analysis.
BACKGROUND: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children. METHODS: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration. RESULTS: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10-8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10-8, n = 577) and sleep onset latency (p = 8.8 × 10-9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539). CONCLUSION: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.
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Author URL.
Küpers LK, Fernández-Barrés S, Mancano G, Johnson L, Ott R, Vioque J, Colombo M, Landgraf K, Tobi EW, Körner A, et al (2022). Maternal Dietary Glycemic Index and Glycemic Load in Pregnancy and Offspring Cord Blood DNA Methylation.
Diabetes Care,
45(8), 1822-1832.
Abstract:
Maternal Dietary Glycemic Index and Glycemic Load in Pregnancy and Offspring Cord Blood DNA Methylation.
OBJECTIVE: Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWAS) of maternal dietary glycemic index and load with cord blood DNA methylation. RESEARCH DESIGN AND METHODS: We calculated maternal glycemic index and load from food frequency questionnaires and ran EWAS on cord blood DNA methylation in 2,003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWAS of maternal glycemic traits and BMI as well as in EWAS of birth weight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalog and in 223 adipose tissue samples. RESULTS: Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, P < 1.17 × 10-7), mostly in mothers with overweight/obesity. We did not observe overlap with CpGs associated with maternal glycemic traits, BMI, or child birth weight or BMI. Only DNA methylation at cg24458009 and cg23347399 was associated with expression of PCED1B and PCDHG, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of TFAP4, ZNF500, PPL, and ANKS3 in child subcutaneous adipose tissue. CONCLUSIONS: We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.
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Author URL.
Küpers LK, Fernández-Barrés S, Nounu A, Friedman C, Fore R, Mancano G, Dabelea D, Rifas-Shiman SL, Mulder RH, Oken E, et al (2022). Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium.
Epigenetics,
17(11), 1419-1431.
Abstract:
Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium
Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation. We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother–child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0–18 and an adjusted rMED excluding alcohol (rMEDp, range 0–16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5–7.8 y). rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011, P = 2.41 × 10−8). This cytosine–phosphate–guanine (CpG) site maps to WNT5B, associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood. In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.
Abstract.
Tran C, Crawford AA, Hamilton A, French CE, Wren Y, Sandy J, Sharp G (2022). Maternal Stressful Life Events During the Periconceptional Period and Orofacial Clefts: a Systematic Review and Meta-Analysis.
Cleft Palate Craniofac J,
59(10), 1253-1263.
Abstract:
Maternal Stressful Life Events During the Periconceptional Period and Orofacial Clefts: a Systematic Review and Meta-Analysis.
OBJECTIVE: to assess whether women who experience stressful life events during the periconceptional period are at higher risk of giving birth to a baby with an orofacial cleft (OFC). DESIGN: Systematic review and meta-analysis of studies reporting the proportion of babies born with OFC to mothers exposed and unexposed to population-level or personal-level stressful life events during the periconceptional period. Six electronic databases were searched from inception to August 2020. Risk of bias was assessed using the Newcastle-Ottawa scale. Odds ratios (ORs) for the odds of OFC in babies of exposed mothers relative to unexposed controls were extracted and/or calculated. Random effects meta-analysis was undertaken, stratified by cleft subtype. RESULTS: of 12 eligible studies, 8 examined experience of personal events and 4 examined population-level events. Studies demonstrated low-moderate risk of bias and there was indication of publication bias. There was some evidence that personal stressful life events were associated with greater odds of cleft lip and/or palate (six studies, OR 1.63, 95% confidence interval (CI) 1.16, 2.30, P = 0.001) and cleft palate only (six studies, OR 1.45, 95% CI 1.02, 2.06, P = 0.04). Population-level events were associated with higher odds of OFC in studies that did not specify subtype (three studies, OR 1.64, 95% CI 1.19, 2.25, P = 0.002), but subtype stratified analyses were underpowered. Heterogeneity was high. CONCLUSIONS: Limited evidence indicated a weak positive association between maternal stressful life events during the periconceptional period and risk of OFC in the offspring, but further studies with greater consistency in research design are needed.
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Taeubert MJ, de Prado-Bert P, Geurtsen ML, Mancano G, Vermeulen MJ, Reiss IKM, Caramaschi D, Sunyer J, Sharp GC, Julvez J, et al (2022). Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis.
CLINICAL EPIGENETICS,
14(1).
Author URL.
Solomon O, Huen K, Yousefi P, Küpers LK, González JR, Suderman M, Reese SE, Page CM, Gruzieva O, Rzehak P, et al (2022). Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.
Mutation Research - Reviews in Mutation Research,
789Abstract:
Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation
Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy and Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: in newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.
Abstract.
Caramaschi D, Neumann A, Cardenas A, Tindula G, Alemany S, Zillich L, Pesce G, Lahti JMT, Havdahl A, Mulder R, et al (2022). Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.
Molecular Psychiatry,
27(4), 2126-2135.
Abstract:
Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills
Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy and Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.
Abstract.
Clarke SLN, Mageean KS, Maccora I, Harrison S, Simonini G, Sharp GC, Relton CL, Ramanan AV (2022). Moving from nature to nurture: a systematic review and meta-analysis of environmental factors associated with juvenile idiopathic arthritis.
Rheumatology (United Kingdom),
61(2), 514-530.
Abstract:
Moving from nature to nurture: a systematic review and meta-analysis of environmental factors associated with juvenile idiopathic arthritis
Objectives: JIA is the most common paediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanism and ultimately benefit patients. This review aimed to collate and synthesize the current evidence of environmental factors associated with JIA. Methods: Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to January 2020. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesized in narrative form. Results: This review includes 66 environmental factors from 39 studies (11 cohort and 28 case-control studies) over 45 years. Study sample sizes ranged from 41 to 1.9 million participants. Eight environmental factors from ten studies were meta-analysed. Caesarean section delivery was associated with increased JIA risk [pooled odds ratio (OR) 1.11, 95% CI: 1.01, 1.22]. Conversely, presence (vs absence) of siblings (pooled OR 0.60, 95% CI: 0.44, 0.81) and maternal prenatal smoking (pooled OR 0.70, 95% CI: 0.58, 0.84) were associated with decreased JIA risk. Conclusion: This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research undertaken over five decades. We also highlight the challenges of combining data collected over this period due to limited between study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies.
Abstract.
Sharp GC, Fraser A, Sawyer G, Kountourides G, Easey KE, Ford G, Olszewska Z, Howe LD, Lawlor DA, Alvergne A, et al (2022). The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities.
Int J Epidemiol,
51(3), 691-700.
Author URL.
Battram T, Yousefi P, Crawford G, Prince C, Sheikhali Babaei M, Sharp G, Hatcher C, Vega-Salas MJ, Khodabakhsh S, Whitehurst O, et al (2022). The EWAS Catalog: a database of epigenome-wide association studies.
Wellcome Open Research,
7Abstract:
The EWAS Catalog: a database of epigenome-wide association studies
Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p
Abstract.
Battram T, Yousefi P, Crawford G, Prince C, Sheikhali Babaei M, Sharp G, Hatcher C, Vega-Salas MJ, Khodabakhsh S, Whitehurst O, et al (2022). The EWAS Catalog: a database of epigenome-wide association studies.
Wellcome Open Res,
7Abstract:
The EWAS Catalog: a database of epigenome-wide association studies.
Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p
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Author URL.
Prince C, Sharp GC, Howe LD, Fraser A, Richmond RC (2022). The relationships between women’s reproductive factors: a Mendelian randomisation analysis.
BMC Medicine,
20(1).
Abstract:
The relationships between women’s reproductive factors: a Mendelian randomisation analysis
Background: Women’s reproductive factors include their age at menarche and menopause, the age at which they start and stop having children and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors. Methods: We used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomisation (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap. Results: LDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06–0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (beta (B) = 0.09 SD, 95% confidence intervals (CI) = 0.06,0.11), age at first birth (B = 0.07 SD, CI = 0.04,0.10), age at last birth (B = 0.06 SD, CI = 0.04,0.09) and age at menopause (B = 0.06 SD, CI = 0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B = 0.21 SD, CI = 0.13,0.29), age at last birth (B = 0.72 SD, CI = 0.67, 0.77) and a lower number of births (B = −0.38 SD, CI = −0.44, −0.32). Conclusion: This study presents evidence that women’s reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman’s entire reproductive history, including the causal interplay between reproductive factors.
Abstract.
2021
Alvergne A, Kountourides G, Argentieri A, Agyen L, Rogers N, Knight D, Sharp G, Maybin J, Olszewska Z (2021). COVID-19 vaccination and menstrual cycle changes: a United Kingdom (UK) retrospective case-control study.
Abstract:
COVID-19 vaccination and menstrual cycle changes: a United Kingdom (UK) retrospective case-control study
Background There has been increasing public concern that COVID-19 vaccines cause menstrual cycle disturbances, yet there is currently limited data to evaluate the impact of vaccination on menstrual health. Our objectives were (1) to evaluate the prevalence of menstrual changes following vaccination against COVID-19, (2) to test potential risk factors for any such changes, and (3) to identify patterns of symptoms in participants’ written accounts. Methods We performed a secondary analysis of a retrospective online survey titled “The Covid-19 Pandemic and Women’s Reproductive Health”, conducted in March 2021 in the UK before widespread media attention regarding potential impacts of SARS-CoV-2 vaccination on menstruation. Participants were recruited via a Facebook ad campaign in the UK and eligibility criteria for survey completion were age greater than 18 years, having ever menstruated and currently living in the UK. In total, 26,710 people gave consent and completed the survey. For this analysis we selected 4,989 participants who were pre-menopausal and vaccinated. These participants were aged 28 to 43, predominantly from England (81%), of white background (95%) and not using hormonal contraception (58%). Findings Among pre-menopausal vaccinated individuals (n=4,989), 80% did not report any menstrual cycle changes up to 4 months after their first COVID-19 vaccine injection. Current use of combined oral contraceptives was associated with lower odds of reporting any changes by 48% (OR = 0.52, 95CI = [0.34 to 0.78], P
Abstract.
Juvinao-Quintero DL, Marioni RE, Ochoa-Rosales C, Russ TC, Deary IJ, van Meurs JBJ, Voortman T, Hivert MF, Sharp GC, Relton CL, et al (2021). DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.
Clinical Epigenetics,
13(1).
Abstract:
DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts
Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. Results: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). Conclusions: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.
Abstract.
Min JL, Hemani G, Hannon E, Dekkers KF, Castillo-Fernandez J, Luijk R, Carnero-Montoro E, Lawson DJ, Burrows K, Suderman M, et al (2021). Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.
Nat Genet,
53(9), 1311-1321.
Abstract:
Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
Abstract.
Author URL.
Prince C, Sharp GC, Howe LD, Fraser A, Richmond RC (2021). INVESTIGATING CAUSALITY BETWEEN ADIPOSITY AND WOMEN'S REPRODUCTIVE FACTORS: a MENDELIAN RANDOMIZATION ANALYSIS.
Author URL.
Richmond R, Rejon CS, Khouja J, Prince C, Board A, Sharp G, Suderman M, Relton C, Munafò M, Gage S, et al (2021). Investigating the DNA methylation profile of e-cigarette use.
Abstract:
Investigating the DNA methylation profile of e-cigarette use
Rationale and objectives Little evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use. Methods Among 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. We tested associations between e-cigarette use and methylation scores known to predict smoking and smoking-related disease. We assessed the ability of a methylation score for predicting e-cigarette use and for discriminating lung cancer. Measurements and Main Results 7 CpGs were identified in relation to e-cigarette use at p
Abstract.
Richmond RC, Sillero-Rejon C, Khouja JN, Prince C, Board A, Sharp G, Suderman M, Relton CL, Munafò M, Gage SH, et al (2021). Investigating the DNA methylation profile of e-cigarette use.
Clin Epigenetics,
13(1).
Abstract:
Investigating the DNA methylation profile of e-cigarette use.
BACKGROUND: Little evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use. RESULTS: Among 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. DNA methylation at 7 cytosine-phosphate-guanine sites (CpGs) was associated with e-cigarette use at p
Abstract.
Author URL.
Schellhas L, Haan E, Easey KE, Wootton RE, Sallis HM, Sharp GC, Munafò MR, Zuccolo L (2021). Maternal and child genetic liability for smoking and caffeine consumption and child mental health: an intergenerational genetic risk score analysis in the ALSPAC cohort.
Addiction,
116(11), 3153-3166.
Abstract:
Maternal and child genetic liability for smoking and caffeine consumption and child mental health: an intergenerational genetic risk score analysis in the ALSPAC cohort
Background and aims: Previous studies suggest an association between maternal tobacco and caffeine consumption during and outside of pregnancy and offspring mental health. We aimed to separate effects of the maternal environment (intrauterine or postnatal) from pleiotropic genetic effects. Design: Secondary analysis of a longitudinal study. We (i) validated smoking and caffeine genetic risk scores (GRS) derived from published genome-wide association study (GWAS) for use during pregnancy, (ii) compared estimated effects of maternal and offspring GRS on childhood mental health outcomes and (iii) tested associations between maternal and offspring GRS on their respective outcomes. Setting: We used data from a longitudinal birth cohort study from England, the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants: Our sample included 7921 mothers and 7964 offspring. Measurements: Mental health and non-mental health phenotypes were derived from questionnaires and clinical assessments: 79 maternal phenotypes assessed during and outside of pregnancy and 71 offspring phenotypes assessed in childhood (
Abstract.
Sammallahti S, Cortes Hidalgo AP, Tuominen S, Malmberg A, Mulder RH, Brunst KJ, Alemany S, McBride NS, Yousefi P, Heiss JA, et al (2021). Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.
MOLECULAR PSYCHIATRY,
26(6), 1832-1845.
Author URL.
Martin FZ, Easey KE, Howe LD, Lawlor DA, Fraser A, Relton CL, Sharp GC (2021). NOVEL RISK FACTORS FOR MENORRHAGIA AND DYSMENORRHEA IN ADOLESCENCE USING THE ALSPAC COHORT.
Author URL.
Sharp GC, Alfano R, Ghantous A, Urquiza J, Rifas-Shiman SL, Page CM, Jin J, Fernández-Barrés S, Santorelli G, Tindula G, et al (2021). Paternal body mass index and offspring DNA methylation: Findings from the PACE consortium.
International Journal of Epidemiology,
50(4), 1297-1315.
Abstract:
Paternal body mass index and offspring DNA methylation: Findings from the PACE consortium
Background: Accumulating evidence links paternal adiposity in the periconceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans. Methods: in the Pregnancy and Childhood Epigenetics (PACE) consortium, we conducted a meta-Analysis of coordinated epigenome-wide association studies (EWAS) of paternal prenatal body mass index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 data sets; total n = 4894) and in childhood (6 data sets; total n = 1982). Results: We found little evidence of an association at either time point: at all CpGs, the false-discovery-rate-Adjusted P-values were >0.05. In secondary sex-stratified analyses, we found just four CpGs for which there was robust evidence of an association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes. Conclusion: Our findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring-blood DNA methylation, even at imprinted regions.
Abstract.
Berman S, Sharp G, Lewis S, Blakey R, Davies A, Humphries K, Wren Y, Sandy J, Stergiakouli E (2021). Prevalence and Factors Associated with Behavioural Problems in 5-year-old Children Born with Cleft Lip and/or Palate from the Cleft Collective.
Abstract:
Prevalence and Factors Associated with Behavioural Problems in 5-year-old Children Born with Cleft Lip and/or Palate from the Cleft Collective
Objectives We determined the prevalence of behavioural problems in 5-year-old children born with Cleft Lip and/or Palate (CL/P) and compared it to the prevalence in general population samples. We also identified risk factors for behavioural problems in children with CL/P. Design Observational study using questionnaire data from the Cleft Collective (CC) 5-Year-Old cohort study and three general population samples. Main Outcome Measure the Strengths and Difficulties Questionnaire (SDQ) was used to measure behavioural problems. Participants a total of 340 children born with CL/P whose mothers had completed the SDQ when their child was 5 years old. Published estimates from three large cohorts were used to approximate general population SDQ scores in the UK and these were used as comparison groups; Millennium Cohort Study (MCS) (n=12,511), Office of National Statistics (ONS) normative school-age SDQ data (n=5,855) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=9,386). Results an estimated 14.3% of 5-year-old children born with CL/P experienced behavioural problems. There was strong evidence to suggest children with CL/P were more likely to experience difficulties than children in the general population, as measured by SDQ total difficulties scores from all three population cohorts: MCS (OR = 2.07 [95% CI = 1.50-2.85]; P
Abstract.
Sharp G, Fraser A, Sawyer G, Kountourides G, Easey K, Ford G, Olszewska Z, Howe LD, Lawlor DA, Alvergne A, et al (2021). The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities.
Battram T, Yousefi P, Crawford G, Prince C, Babei MS, Sharp G, Hatcher C, Vega-Salas MJ, Khodabakhsh S, Whitehurst O, et al (2021). The EWAS Catalog: a database of epigenome-wide association studies.
Easey K, Sharp G (2021). The impact of paternal alcohol, tobacco, caffeine use and physical activity on offspring mental health: a systematic review and meta-analysis.
Abstract:
The impact of paternal alcohol, tobacco, caffeine use and physical activity on offspring mental health: a systematic review and meta-analysis
Background There is some evidence that paternal health behaviours during and around pregnancy could be associated with offspring health outcomes. However, the impact that paternal health behaviours during pregnancy can have on offspring mental health is understudied and remains unclear. Methods We conducted a systematic review and meta-analysis of articles in PubMed describing studies of potentially modifiable paternal health behaviours (tobacco smoking, alcohol consumption, caffeine consumption and physical activity) in the prenatal period in relation to offspring mental health. Results Ten studies were included and categorized by paternal health behaviour and offspring mental health outcome investigated. The narrative synthesis provided evidence of association between paternal health behaviours around pregnancy and offspring mental health problems, with the strongest evidence shown for tobacco use. Grouped by analysis type, two separate meta-analyses showed evidence of paternal smoking during pregnancy being associated with greater odds of ADHD in offspring (OR 1.42, 95% CI 1.02 to 1.99; HR 1.28, 95% CI 1.19 to 1.39). Conclusions Our review suggests that paternal tobacco smoking and alcohol consumption in the prenatal period are associated with poorer offspring mental health, particularly hyperactivity/ADHD. Future investigation using methods that allow stronger causal inference is needed to further investigate if these associations are causal.
Abstract.
Easey KE, Sharp GC (2021). The impact of paternal alcohol, tobacco, caffeine use and physical activity on offspring mental health: a systematic review and meta-analysis.
Reproductive Health,
18(1).
Abstract:
The impact of paternal alcohol, tobacco, caffeine use and physical activity on offspring mental health: a systematic review and meta-analysis
Background: There is some evidence that paternal health behaviours during and around pregnancy could be associated with offspring health outcomes. However, the impact that paternal health behaviours during pregnancy can have on offspring mental health is understudied and remains unclear. Methods: We conducted a systematic review and meta-analysis of articles in PubMed describing studies of potentially modifiable paternal health behaviours (tobacco smoking, alcohol consumption, caffeine consumption and physical activity) in the prenatal period in relation to offspring mental health. GRADE was used to measure risk of bias. Results: Eight studies were included and categorized by paternal health behaviour and offspring mental health outcome investigated. The narrative synthesis provided evidence of association between paternal health behaviours around pregnancy and offspring mental health problems, with the strongest evidence shown for tobacco use. Grouped by analysis type, two separate meta-analyses showed evidence of paternal smoking during pregnancy being associated with greater odds of ADHD in offspring (OR 1.42, 95% CI 1.02–1.99; HR 1.28, 95% CI 1.19–1.39). Conclusions: the small number of studies that have investigated paternal prenatal effects on offspring mental health, and the limited sample sizes of those studies, makes it challenging to draw firm conclusions. Although existing studies suggest that paternal tobacco smoking and alcohol consumption in the prenatal period are associated with poorer offspring mental health, (particularly hyperactivity/ADHD), further investigation of potential paternal effects is required, using methods that allow stronger inference to determine whether associations are causal.
Abstract.
Prince C, Sharp G, Howe L, Fraser A, Richmond R (2021). The relationships between women’s reproductive factors: a Mendelian randomization analysis.
Abstract:
The relationships between women’s reproductive factors: a Mendelian randomization analysis
Background Women’s reproductive factors include their age at menarche and menopause, the age at which they start and stop having children, and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors. Methods We used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age at first sex and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomization (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap. Results LDSC indicated that most reproductive factors are genetically correlated (r g range: |0.06 – 0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (r g < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (Beta (B)=0.09 SD, 95% confidence intervals (CI)=0.06,0.11), age at first birth (B=0.07 SD, CI=0.04,0.10), age at last birth (B=0.06 SD, CI=0.04,0.09) and age at menopause (B=0.06 SD, CI=0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B=0.21 SD, CI=0.13,0.29), age at last birth (B=0.72 SD, CI=0.67,0.77) and a lower number of births (B=-0.38 SD, CI=-0.44,-0.32). Conclusion This study presents evidence that women’s reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman’s entire reproductive history, including the causal interplay between reproductive factors.
Abstract.
Easey K, Sharp G (2021). USING DATA ON FATHERS/PARTNERS TO STUDY PRENATAL PARENTAL EXPOSURES AND CHILD HEALTH: CHALLENGES INTRODUCED BY MISSING DATA AND SELECTION BIAS.
Author URL.
Clarke SLN, Mageean KS, Carlton H, Simonini G, Sharp GC, Relton CL, Ramanan AV (2021). “Environmental risk factors associated with juvenile idiopathic arthritis associated uveitis: a systematic review of the literature”.
Journal of Ophthalmic Inflammation and Infection,
11(1).
Abstract:
“Environmental risk factors associated with juvenile idiopathic arthritis associated uveitis: a systematic review of the literature”
Background: Juvenile idiopathic arthritis associated uveitis (JIA-U) is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and carries considerable risk to vision. The aim of this systematic review was to synthesise evidence of environmental risk factors for JIA-U and identify risk factors which may be modifiable or used to stratify JIA patients. Methods: This systematic review was carried out in accordance with PRISMA guidelines. Four online databases - Cumulative Index of Nursing and Allied Health Literature, Web of Science, MEDLINE and Embase - were searched from database inception to 12th August 2020. Identified studies were screened by two independent reviewers against pre-defined inclusion and exclusion criteria. Data was extracted from all primary studies meeting inclusion criteria and independently checked. Results: We identified three studies from 895 unique records which met the inclusion criteria, each examining a different environmental risk factor. This systematic review includes 973, predominantly female, participants with JIA across these three studies. The use of allergy medication or documentation of “allergy”/“allergic” in the medical records was associated with an increased risk of JIA-U in all models presented. Vitamin D sufficiency was associated with reduced risk of JIA-U. There was insufficient evidence to support an association between seasonality and JIA-U. Conclusions: This review identifies a potential role for allergy and vitamin D in JIA-U. It also illustrates the paucity of data regarding environmental risk factors for JIA-U and highlights the need for further research to both identify additional risk factors and replicate existing findings.
Abstract.
2020
Neumann A, Walton E, Alemany S, Cecil C, Gonzalez JR, Jima DD, Lahti J, Tuominen ST, Barker ED, Binder E, et al (2020). Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.
TRANSLATIONAL PSYCHIATRY,
10(1).
Author URL.
Dardani C, Howe LJ, Mukhopadhyay N, Stergiakouli E, Wren Y, Humphries K, Davies A, Ho K, Weinberg SM, Marazita ML, et al (2020). Cleft lip/palate and educational attainment: Cause, consequence or correlation? a Mendelian randomization study.
International Journal of Epidemiology,
49(4), 1282-1293.
Abstract:
Cleft lip/palate and educational attainment: Cause, consequence or correlation? a Mendelian randomization study
Background: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. Methods: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. Results: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (βMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; βMR -0.009, 95% CI -0.02 to 0.002, P 0.11). Conclusions: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.
Abstract.
Griffith GJ, Morris TT, Tudball MJ, Herbert A, Mancano G, Pike L, Sharp GC, Sterne J, Palmer TM, Davey Smith G, et al (2020). Collider bias undermines our understanding of COVID-19 disease risk and severity.
Nature Communications,
11(1).
Abstract:
Collider bias undermines our understanding of COVID-19 disease risk and severity
Numerous observational studies have attempted to identify risk factors for infection with SARS-CoV-2 and COVID-19 disease outcomes. Studies have used datasets sampled from patients admitted to hospital, people tested for active infection, or people who volunteered to participate. Here, we highlight the challenge of interpreting observational evidence from such non-representative samples. Collider bias can induce associations between two or more variables which affect the likelihood of an individual being sampled, distorting associations between these variables in the sample. Analysing UK Biobank data, compared to the wider cohort the participants tested for COVID-19 were highly selected for a range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the mechanisms inducing these problems, and approaches that could help mitigate them. While collider bias should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.
Abstract.
Griffith G, Morris T, Tudball M, Herbert A, Mancano G, Pike L, Sharp G, Palmer T, Smith GD, Tilling K, et al (2020). Collider bias undermines our understanding of COVID-19 disease risk and severity.
Abstract:
Collider bias undermines our understanding of COVID-19 disease risk and severity
Observational data on COVID-19 including hypothesised risk factors for infection and progression are accruing rapidly, often from non-random sampling such as hospital admissions, targeted testing or voluntary participation. Here, we highlight the challenge of interpreting observational evidence from such samples of the population, which may be affected by collider bias. We illustrate these issues using data from the UK Biobank in which individuals tested for COVID-19 are highly selected for a wide range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the sampling mechanisms that leave aetiological studies of COVID-19 infection and progression particularly susceptible to collider bias. We also describe several tools and strategies that could help mitigate the effects of collider bias in extant studies of COVID-19 and make available a web app for performing sensitivity analyses. While bias due to non-random sampling should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.
Abstract.
Vehmeijer FOL, Küpers LK, Sharp GC, Salas LA, Lent S, Jima DD, Tindula G, Reese S, Qi C, Gruzieva O, et al (2020). DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.
Genome Medicine,
12(1).
Abstract:
DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies
Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10−7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions: There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
Abstract.
Merid SK, Novoloaca A, Sharp GC, Küpers LK, Kho AT, Roy R, Gao L, Annesi-Maesano I, Jain P, Plusquin M, et al (2020). Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.
Genome Medicine,
12(1).
Abstract:
Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: Fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10-7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
Abstract.
Schellhas L, Haan E, Easey K, Wootton R, Sallis H, Sharp G, Munafò M, Zuccolo L (2020). Maternal and child genetic liability for smoking and caffeine consumption and. child mental health: an intergenerational genetic risk score analysis in the. ALSPAC cohort.
Abstract:
Maternal and child genetic liability for smoking and caffeine consumption and. child mental health: an intergenerational genetic risk score analysis in the. ALSPAC cohort
ABSTRACT. Background and aims. Previous studies suggest an association between maternal tobacco and. caffeine consumption during and outside of pregnancy and offspring mental. health. We aimed to separate effects of the maternal environment. (intrauterine or postnatal) from pleiotropic genetic effects. Design. Secondary analysis of a longitudinal study. We 1) validated smoking and. caffeine genetic risk scores (GRS) derived from published GWAS for use. during pregnancy, 2) compared estimated effects of maternal and offspring. GRS on childhood mental health outcomes, and 3) tested associations between. maternal and offspring GRS on their respective outcomes. Setting. We used data from a longitudinal birth cohort study from England, the. Avon Longitudinal Study of Parents and Children (ALSPAC). Participants. Our sample included 7921 mothers and 7964 offspring. Measurements. Mental health and non-mental health phenotypes were derived from. questionnaires and clinical assessments: 79 maternal phenotypes assessed. during and outside of pregnancy, and 71 offspring phenotypes assessed in. childhood (
Abstract.
Howe CG, Cox B, Fore R, Jungius J, Kvist T, Lent S, Miles HE, Salas LA, Rifas-Shiman S, Starling AP, et al (2020). Maternal gestational diabetes mellitus and newborn DNA Methylation: Findings from the pregnancy and childhood epigenetics consortium.
Diabetes Care,
43(1), 98-105.
Abstract:
Maternal gestational diabetes mellitus and newborn DNA Methylation: Findings from the pregnancy and childhood epigenetics consortium
OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-Analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, usingDNAmethylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations betweenGDMandDNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-Analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene bodyof CYP2E1. IndividualCpGanalyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS MaternalGDMwas associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.
Abstract.
Caramaschi D, Neumann A, Cardenas A, Tindula G, Alemany S, Zillich L, Pesce G, Lahti JMT, Havdahl A, Mulder R, et al (2020). Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.
Sharp G, Alfano R, Ghantous A, Urquiza J, Rifas-Shiman S, Page C, Jin J, Fernández-Barrés S, Santorelli G, Tindula G, et al (2020). Paternal body mass index and offspring DNA methylation: findings from the PACE consortium.
Abstract:
Paternal body mass index and offspring DNA methylation: findings from the PACE consortium
Background Accumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans. Methods and findings in the Pregnancy and Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 datasets; total n= 4,894) and in childhood (six datasets; total n = 1,982). We found little evidence of association at either time point: for all CpGs, the False Discovery Rate-adjusted P-values were >0.05. In sex-stratified analyses, we found just four CpGs where there was robust evidence of association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes. Conclusion Our findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring blood DNA methylation, even at imprinted regions. Author Summary Previous small, mostly candidate gene studies have shown associations between paternal pre-pregnancy BMI and offspring blood DNA methylation. However, in our large meta-analysis of co-ordinated EWAS results from a total of 19 datasets across two timepoints, we found little evidence to support these findings, even at imprinted regions. This does not rule out the possibility of a paternal epigenetic effect in different tissues, at regions not covered by the 450k array, via different mechanisms, or in populations with greater extremes of paternal BMI. More research is warranted to help understand the size and nature of contributions of paternal adiposity to offspring epigenetics and health outcomes.
Abstract.
Schellhas L, Lou M, Monasso G, Fernandez Barres S, Pesce G, Maesano IA, Page C, London S, Cecil C, Felix J, et al (2020). The epigenome as a biological pathway of the effects of prenatal exposure to tobacco, alcohol, and caffeine on childhood internalising problems in offspring: two large multi-cohort epigenome-wide association studies.
Author URL.
Sharp G, Schellhas L, Richardson S, Lawlor D (2020). Time to cut the cord: recognizing and addressing the imbalance of DOHaD research towards the study of maternal pregnancy exposures - CORRIGENDUM.
J Dev Orig Health Dis,
11(1).
Author URL.
2019
Richardson TG, Richmond RC, North TL, Hemani G, Davey Smith G, Sharp GC, Relton CL (2019). An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility.
International Journal of Epidemiology,
48(3), 887-898.
Abstract:
An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility
Background: There is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation. It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence in this regard has been challenging to uncover. Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNA methylation levels on disease susceptibility. Methods: to illustrate our approach, we identified 412 CpG sites where DNA methylation was associated with prenatal smoking. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits using findings from large-scale genome-wide association studies. To strengthen evidence of mediatory mechanisms, we used multiple-trait colocalization to assess whether DNA methylation, nearby gene expression and complex trait variation were all influenced by the same causal genetic variant. Results: We identified 22 associations that survived multiple testing (P < 1.89 × 10-7). In-depth follow-up analyses of particular note suggested that the associations between DNA methylation at the ASPSCR1 and REST/POL2RB gene regions, both linked with reduced lung function, may be mediated by changes in gene expression. We validated associations between DNA methylation and traits using independent samples from different stages across the life course. Conclusion: Our approach should prove valuable in prioritizing CpG sites that may mediate the effect of causal risk factors on disease. In-depth evaluations of findings are necessary to robustly disentangle causality from alternative explanations such as horizontal pleiotropy.
Abstract.
Neumann A, Walton E, Alemany S, Cecil C, González JR, Jima DD, Lahti J, Tuominen ST, Barker ED, Binder E, et al (2019). Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.
Juvinao-Quintero DL, Hivert M-F, Sharp GC, Relton CL, Elliott HR (2019). DNA Methylation and Type 2 Diabetes: the Use of Mendelian Randomization to Assess Causality.
Curr Genet Med Rep,
7(4), 191-207.
Abstract:
DNA Methylation and Type 2 Diabetes: the Use of Mendelian Randomization to Assess Causality.
PURPOSE OF REVIEW: This review summarises recent advances in the field of epigenetics in order to understand the aetiology of type 2 diabetes (T2D). RECENT FINDINGS: DNA methylation at a number of loci has been shown to be robustly associated with T2D, including TXNIP, ABCG1, CPT1A, and SREBF1. However, due to the cross-sectional nature of many epidemiological studies and predominant analysis in samples derived from blood rather than disease relevant tissues, inferring causality is difficult. We therefore outline the use of Mendelian randomisation (MR) as one method able to assess causality in epigenetic studies of T2D. SUMMARY: Epidemiological studies have been fruitful in identifying epigenetic markers of T2D. Triangulation of evidence including utilisation of MR is essential to delineate causal from non-causal biomarkers of disease. Understanding the causality of epigenetic markers in T2D more fully will aid prioritisation of CpG sites as early biomarkers to detect disease or in drug development to target epigenetic mechanisms in order to treat patients.
Abstract.
Author URL.
Staunstrup N, Viuff A-C, Sharp G, Pedersen L, Kyng K, Rai D, Relton C, Henriksen T (2019). EPIGENETIC DIFFERENCES IN CORD BLOOD OF NEWBORNS EXPOSED TO ANTIDEPRESSANT MEDICATION DURING PREGNANCY - a STUDY IN THE AARHUS BIRTH COHORT.
Author URL.
Elliott HR, Sharp GC, Relton CL, Lawlor DA (2019). Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction.
Diabetologia,
62(12), 2171-2178.
Abstract:
Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction
Epigenetics encapsulates a group of molecular mechanisms including DNA methylation, histone modification and microRNAs (miRNAs). Gestational diabetes (GDM) increases the risk of adverse perinatal outcomes and is associated with future offspring risk of obesity and type 2 diabetes. It has been hypothesised that epigenetic mechanisms mediate an effect of GDM on offspring adiposity and type 2 diabetes and this could provide a modifiable mechanism to reduce type 2 diabetes in the next generation. Evidence for this hypothesis is lacking. Epigenetic epidemiology could also contribute to reducing type 2 diabetes by identifying biomarkers that accurately predict risk of GDM and its associated future adverse outcomes. We reviewed published human studies that explored associations between any of maternal GDM, type 2 diabetes, gestational fasting or post-load glucose and any epigenetic marker (DNA methylation, histone modification or miRNA). of the 81 relevant studies we identified, most focused on the potential role of epigenetic mechanisms in mediating intrauterine effects of GDM on offspring outcomes. Studies were small (median total number of participants 58; median number of GDM cases 27) and most did not attempt replication. The most common epigenetic measure analysed was DNA methylation. Most studies that aimed to explore epigenetic mediation examined associations of in utero exposure to GDM with offspring cord or infant blood/placenta DNA methylation. Exploration of any causal effect, or effect on downstream offspring outcomes, was lacking. There is a need for more robust methods to explore the role of epigenetic mechanisms as possible mediators of effects of exposure to GDM on future risk of obesity and type 2 diabetes. Research to identify epigenetic biomarkers to improve identification of women at risk of GDM and its associated adverse (maternal and offspring) outcomes is currently rare but could contribute to future tools for accurate risk stratification.
Abstract.
Everson TM, Zhang H, Lockett GA, Kaushal A, Forthofer M, Ewart SL, Burrows K, Relton CL, Sharp GC, Henderson AJ, et al (2019). Epigenome-wide association study of asthma and wheeze characterizes loci within HK1.
Allergy, Asthma and Clinical Immunology,
15(1), 1-12.
Abstract:
Epigenome-wide association study of asthma and wheeze characterizes loci within HK1
Background: to identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood. Methods: We performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC and followed-up our top finding with children of the IOW cohort. Results: We identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n = 370), five of which exhibited evidence of associations in the replication study (ALSPAC, n = 720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (ORIOW = 0.17, 95% CI 0.04–0.57) (ORALSPAC = 0.57, 95% CI 0.38–0.87). Additionally, higher expression of HK1 (OR = 3.81, 95% CI 1.41–11.77) in cord blood was predictive of wheezing in infancy (n = 82). Conclusion: We identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze.
Abstract.
Imboden M, Wielscher M, Rezwan FI, Amaral AFS, Schaffner E, Jeong A, Beckmeyer-Borowko A, Harris SE, Starr JM, Deary IJ, et al (2019). Epigenome-wide association study of lung function level and its change.
European Respiratory Journal,
54(1).
Abstract:
Epigenome-wide association study of lung function level and its change
Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults. In a discovery–replication EWAS design, DNAme in blood and spirometry were measured twice, 6–15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p
Abstract.
Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, Merid SK, Rezwan FI, Page CM, Ullemar V, et al (2019). Epigenome-wide meta-analysis of DNA methylation and childhood asthma.
Journal of Allergy and Clinical Immunology,
143(6), 2062-2074.
Abstract:
Epigenome-wide meta-analysis of DNA methylation and childhood asthma
Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy and Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: in newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.
Abstract.
Howe LJ, Richardson TG, Arathimos R, Alvizi L, Passos-Bueno MR, Stanier P, Nohr E, Ludwig KU, Mangold E, Knapp M, et al (2019). Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate.
Epigenomics,
11(2), 133-145.
Abstract:
Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate
Aim: to determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Materials & methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. Results & conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.
Abstract.
Timms JA, Relton CL, Sharp GC, Rankin J, Strathdee G, McKay JA (2019). Exploring a potential mechanistic role of DNA methylation in the relationship between in utero and post-natal environmental exposures and risk of childhood acute lymphoblastic leukaemia.
International Journal of Cancer,
145(11), 2933-2943.
Abstract:
Exploring a potential mechanistic role of DNA methylation in the relationship between in utero and post-natal environmental exposures and risk of childhood acute lymphoblastic leukaemia
The aetiology of childhood acute lymphoblastic leukaemia (ALL) is unclear. Genetic abnormalities have been identified in a number of ALL cases, although these alone are not sufficient for leukaemic transformation. Various in utero and post-natal environmental exposures have been suggested to alter risk of childhood ALL. DNA methylation patterns can be influenced by environmental exposures, and are reported to be altered in ALL, suggesting a potential mediating mechanism between environment and ALL disease risk. To investigate this, we used a ‘meet in the middle’ approach, investigating the overlap between exposure-associated and disease-associated methylation change. Genome-wide DNA methylation changes in response to possible ALL-risk exposures (i.e. breast feeding, infection history, day care attendance, maternal smoking, alcohol, caffeine, folic acid, iron and radiation exposure) were investigated in a sub-population of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort using an epigenome-wide association study (EWAS) approach (n = 861–927), and compared to a list of ALL disease-associated methylation changes compiled from published data. Hypergeometric probability tests suggested that the number of directionally concordant gene methylation changes observed in ALL disease and in response to the following exposures; maternal radiation exposure (p = 0.001), alcohol intake (p = 0.006); sugary caffeinated drink intake during pregnancy (p = 0.045); and infant day care attendance (p = 0.003), were not due to chance. Data presented suggests that DNA methylation may be one mediating mechanism in the multiple hit pathway needed for ALL disease manifestation.
Abstract.
Kazmi N, Sharp GC, Reese SE, Vehmeijer FO, Lahti J, Page CM, Zhang W, Rifas-Shiman SL, Rezwan FI, Simpkin AJ, et al (2019). Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns: Findings from the Pregnancy and Childhood Epigenetics Consortium.
Hypertension,
74(2), 375-383.
Abstract:
Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns: Findings from the Pregnancy and Childhood Epigenetics Consortium
Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.
Abstract.
Martin CL, Jima D, Sharp GC, McCullough LE, Park SS, Gowdy KM, Skaar D, Cowley M, Maguire RL, Fuemmeler B, et al (2019). Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study.
Epigenetics,
14(4), 325-340.
Abstract:
Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study
Pre-pregnancy obesity is an established risk factor for adverse sex-specific cardiometabolic health in offspring. Epigenetic alterations, such as in DNA methylation (DNAm), are a hypothesized link; however, sex-specific epigenomic targets remain unclear. Leveraging data from the Newborn Epigenetics Study (NEST) cohort, linear regression models were used to identify CpG sites in cord blood leukocytes associated with pre-pregnancy obesity in 187 mother-female and 173 mother-male offsprings. DNAm in cord blood was measured using the Illumina HumanMethylation450k BeadChip. Replication analysis was conducted among the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Associations between pre-pregnancy obesity-associated CpG sites and offspring BMI z-score (BMIz) and blood pressure (BP) percentiles at 4–5-years of age were also examined. Maternal pre-pregnacy obesity was associated with 876 CpGs in female and 293 CpGs in male offspring (false discovery rate
Abstract.
Küpers LK, Monnereau C, Sharp GC, Yousefi P, Salas LA, Ghantous A, Page CM, Reese SE, Wilcox AJ, Czamara D, et al (2019). Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.
Nature Communications,
10(1).
Abstract:
Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy and Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (P Bonferroni < 1.06 x 10 −7 ). In additional analyses in 7,278 participants,
Abstract.
den Dekker HT, Burrows K, Felix JF, Salas LA, Nedeljkovic I, Yao J, Rifas-Shiman SL, Ruiz-Arenas C, Amin N, Bustamante M, et al (2019). Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course.
European Respiratory Journal,
53(4).
Abstract:
Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course
Rationale: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. Methods: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7–13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. Results: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. Interpretation: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.
Abstract.
Xiong Z, Dankova G, Howe LJ, Lee MK, Hysi PG, de Jong MA, Zhu G, Adhikari K, Li D, Li Y, et al (2019). Novel genetic loci affecting facial shape variation in humans.
Sharp GC, Lawlor DA (2019). Paternal impact on the life course development of obesity and type 2 diabetes in the offspring.
Diabetologia,
62(10), 1802-1810.
Abstract:
Paternal impact on the life course development of obesity and type 2 diabetes in the offspring
The aetiologies of obesity and type 2 diabetes are incredibly complex, but the potential role of paternal influences remains relatively understudied. A better understanding of paternal influences on offspring risk of obesity and type 2 diabetes could have profound implications for public health, clinical practice and society. In this review, we outline potential biological and social mechanisms through which fathers might exert an impact on the health of their offspring. We also present a systematically compiled overview of the current evidence linking paternal factors to offspring development of obesity and type 2 diabetes throughout the life course. Although evidence is accumulating to support paternal associations with offspring outcomes, more high-quality research is needed to overcome specific methodological challenges and provide stronger causal evidence.
Abstract.
Howe LJ, Sharp GC, Hemani G, Zuccolo L, Richmond S, Lewis SJ (2019). Prenatal alcohol exposure and facial morphology in a UK cohort.
Drug and Alcohol Dependence,
197, 42-47.
Abstract:
Prenatal alcohol exposure and facial morphology in a UK cohort
Background: High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including fetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterized. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects. Methods: in the Avon Longitudinal Study of Parents and Children, we tested for an association between maternal alcohol consumption and six FAS-related facial phenotypes in their offspring, using both self-report questionnaires and the maternal genotype at rs1229984 in ADH1B as measures of maternal alcohol consumption. Results: in both self-reported alcohol consumption (N = 4233) and rs1229984 genotype (N = 3139) analyses, we found no strong statistical evidence for an association between maternal alcohol consumption and facial phenotypes tested. The directions of effect estimates were compatible with the known effects of heavy alcohol exposure, but confidence intervals were largely centered around zero. Conclusions: There is no strong evidence, in a sample representative of the general population, for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.
Abstract.
Sharp GC, Schellhas L, Richardson SS, Lawlor DA (2019). Time to cut the cord: Recognizing and addressing the imbalance of DOHaD research towards the study of maternal pregnancy exposures. Journal of Developmental Origins of Health and Disease, 10(5), 509-512.
2018
Ambatipudi S, Sharp GC, Clarke SLN, Plant D, Tobias JH, Evans DM, Barton A, Relton CL (2018). Assessing the role of DNA methylation-derived neutrophil-to-lymphocyte ratio in rheumatoid arthritis.
Journal of Immunology Research,
2018Abstract:
Assessing the role of DNA methylation-derived neutrophil-to-lymphocyte ratio in rheumatoid arthritis
Rheumatoid arthritis (RA) is a disease of chronic systemic inflammation (SI). In the present study, we used four datasets to explore whether methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) might be a marker of SI in new onset, untreated, and treated prevalent RA cases and/or a marker of treatment response to the tumour necrosis factor inhibitor (TNFi) etanercept. mdNLR was associated with increased odds of being a new onset RA case (OR = 2.32, 95% CI = 1.95–2.80, P < 2 × 10−16) and performed better in distinguishing new onset RA cases from controls compared to covariates: age, gender, and smoking status. In untreated preclinical RA cases and controls, mdNLR at baseline was associated with diagnosis of RA in later life after adjusting for batch (OR = 4.30, 95% CI = 1.52–21.71, P = 0 029) although no association was observed before batch correction. When prevalent RA cases were treated, there was no association with mdNLR in samples before and after batch correction (OR = 0.34, 95% CI = 0.05–1.82, P = 0 23), and mdNLR was not associated with treatment response to etanercept (OR = 1.10, 95% CI = 0.75–1.68, P = 0 64). Our results indicate that SI measured by DNA methylation data is indicative of the recent onset of RA. Although preclinical RA was associated with mdNLR, there was no difference in the mean mdNLR between preclinical RA cases and controls. mdNLR was not associated with RA case status if treatment for RA has commenced, and it is not associated with treatment response. In the future, mdNLR estimates may be used as a valuable research tool to reliably estimate SI in the absence of freshly collected blood samples.
Abstract.
Arathimos R, Sharp GC, Granell R, Tilling K, Relton CL (2018). Associations of sex hormone-binding globulin and testosterone with genome-wide DNA methylation 06 Biological Sciences 0604 Genetics.
BMC Genetics,
19(1).
Abstract:
Associations of sex hormone-binding globulin and testosterone with genome-wide DNA methylation 06 Biological Sciences 0604 Genetics
Background: Levels of sex hormone-binding globulin (SHBG) and the androgen testosterone have been associated with risk of diseases throughout the lifecourse. Although both SHBG and testosterone have been shown to be highly heritable, only a fraction of that heritability has been explained by genetic studies. Epigenetic modifications such as DNA methylation may explain some of the missing heritability and could potentially inform biological knowledge of endocrine disease mechanisms involved in development of later life disease. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored cross-sectional associations of SHBG, total testosterone and bioavailable testosterone in childhood (males only) and adolescence (both males and females) with genome-wide DNA methylation. We also report associations of a SHBG polymorphism (rs12150660) with DNA methylation, which leads to differential levels of SHBG in carriers, as a genetic proxy of circulating SHBG levels. Results: We identified several novel sites and genomic regions where levels of SHBG, total testosterone, and bioavailable testosterone were associated with DNA methylation, including one region associated with total testosterone in males (annotated to the KLHL31 gene) in both childhood and adolescence and a second region associated with bioavailable testosterone (annotated to the CMYA5 gene) at both time-points. We also identified one region where both SHBG and bioavailable testosterone in males in childhood (annotated to the ZNF718 gene) was associated with DNA methylation. Conclusion: Our findings have important implications in the understanding of the biological processes of SHBG and testosterone, with the potential for future work to determine the molecular mechanisms that could underpin these associations.
Abstract.
Dardani C, Howe LJ, Stergiakouli E, Wren Y, Humphries K, Davies A, Ho K, Mangold E, Ludwig KU, Relton CL, et al (2018). Cleft lip/palate and educational attainment: cause, consequence, or correlation? a Mendelian randomization study.
Felix JF, Joubert BR, Baccarelli AA, Sharp GC, Almqvist C, Annesi-Maesano I, Arshad H, Baiz N, Bakermans-Kranenburg MJ, Bakulski KM, et al (2018). Cohort profile: Pregnancy and childhood epigenetics (PACE) consortium. International Journal of Epidemiology, 47(1), 22-23u.
Howe L, Richardson T, Arathimos R, Alvizi L, Passos-Bueno M-R, Stanier P, Nohr E, Ludwig K, Mangold E, Knapp M, et al (2018). DNA methylation mediates genetic liability to non-syndromic cleft lip/palate.
Abstract:
DNA methylation mediates genetic liability to non-syndromic cleft lip/palate
Background Non-syndromic cleft lip/palate (nsCL/P) is a complex trait with genetic and environmental risk factors. Around 40 distinct genetic risk loci have been identified for nsCL/P, but many reside in non-protein-coding regions with an unclear function. We hypothesised that one possibility is that the genetic risk variants influence susceptibility to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Methods Using nsCL/P Genome-wide association study summary data and methylation data from four studies, we used Mendelian randomization and joint likelihood mapping to identify putative loci where genetic liability to nsCL/P may be mediated by variation in DNA methylation in blood. Results There was evidence at three independent loci, VAX1 ( 10q25.3 ), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant. Follow up analyses using DNA methylation data, derived from lip and palate tissue, and gene expression catalogues provided further insight into possible biological mechanisms. Conclusions Genetic variation may increase liability to nsCL/P by influencing DNA methylation and gene expression at VAX1, LOC146880 and NTN1.
Abstract.
Sharp GC, Stergiakouli E, Sandy J, Relton C (2018). Epigenetics and Orofacial Clefts: a Brief Introduction. Cleft Palate-Craniofacial Journal, 55(6), 795-797.
Howe LJ, Lee MK, Sharp GC, Davey Smith G, St Pourcain B, Shaffer JR, Ludwig KU, Mangold E, Marazita ML, Feingold E, et al (2018). Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.
PLoS Genetics,
14(8).
Abstract:
Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology
There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.
Abstract.
Howe L, Lee MK, Sharp G, Smith GD, Pourcain BS, Shaffer J, Marazita M, Feingold E, Zhurov A, Stergiakouli E, et al (2018). Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.
Abstract:
Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology
There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 0.00002). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.
Abstract.
Sharp GC, Lawlor DA, Richardson SS (2018). It's the mother!: How assumptions about the causal primacy of maternal effects influence research on the developmental origins of health and disease.
Social Science and Medicine,
213, 20-27.
Abstract:
It's the mother!: How assumptions about the causal primacy of maternal effects influence research on the developmental origins of health and disease
Research on the developmental origins of health and disease (DOHaD) has traditionally focused on how maternal exposures around the time of pregnancy might influence offspring health and risk of disease. We acknowledge that for some exposures this is likely to be correct, but argue that the focus on maternal pregnancy effects also reflects implicit and deeply-held assumptions that 1) causal early life exposures are primarily transmitted via maternal traits or exposures, 2) maternal exposures around the time of pregnancy and early infancy are particularly important, and 3) other factors, such as paternal factors and postnatal exposures in later life, have relatively little impact in comparison. These implicit assumptions about the “causal primacy” of maternal pregnancy effects set the agenda for DOHaD research and, through a looping effect, are reinforced rather than tested. We propose practical strategies to redress this imbalance through maintaining a critical perspective about these assumptions.
Abstract.
Sharp GC, Arathimos R, Reese SE, Page CM, Felix J, Küpers LK, Rifas-Shiman SL, Liu C, Burrows K, Zhao S, et al (2018). Maternal alcohol consumption and offspring DNA methylation: Findings from six general population-based birth cohorts.
Epigenomics,
10(1), 27-42.
Abstract:
Maternal alcohol consumption and offspring DNA methylation: Findings from six general population-based birth cohorts
Aim: Alcohol consumption during pregnancy is sometimes associated with adverse outcomes in offspring, potentially mediated by epigenetic modifications. We aimed to investigate genome-wide DNA methylation in cord blood of newborns exposed to alcohol in utero. Materials & methods: We meta-analyzed information from six population-based birth cohorts within the Pregnancy and Childhood Epigenetics consortium. Results: We found no strong evidence of association at either individual CpGs or across larger regions of the genome. Conclusion: Our findings suggest no association between maternal alcohol consumption and offspring cord blood DNA methylation. This is in stark contrast to the multiple strong associations previous studies have found for maternal smoking, which is similarly socially patterned. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure, exploration of a different tissue and a more global assessment of genomic DNA methylation might show evidence of association.
Abstract.
Viuff AC, Sharp GC, Rai D, Henriksen TB, Pedersen LH, Kyng KJ, Staunstrup NH, Cortes A, Neumann A, Felix JF, et al (2018). Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children.
Translational Psychiatry,
8(1).
Abstract:
Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children
Up to 13% of women may experience symptoms of depression during pregnancy or in the postpartum period. Depression during pregnancy has been associated with an increased risk of adverse neurodevelopmental outcomes in the child and epigenetic mechanisms could be one of the biological pathways to explain this association. In 844 mother–child pairs from the Avon Longitudinal Study of Parents and Children, we carried out an epigenome-wide association study (EWAS) to investigate associations between prospectively collected data on maternal depression ascertained by the Edinburgh Postnatal Depression Scale in pregnancy and DNA methylation in the cord blood of newborn offspring. In individual site analysis, we identified two CpG sites associated with maternal depression in the middle part of pregnancy. In our regional analysis, we identified 39 differentially methylated regions (DMRs). Seven DMRs were associated with depression at any time point during pregnancy, 7 associated with depression in mid-pregnancy, 23 were associated with depression in late pregnancy, and 2 DMRs were associated with depression throughout pregnancy. Several of these map to genes associated with psychiatric disease and brain development. We attempted replication in the Generation R Study and could not replicate our results. Although our findings in ALSPAC suggest that maternal depression could be associated with cord blood DNA methylation the results should be viewed as preliminary and hypothesis generating until further replicated in a larger sample.
Abstract.
Xiong Z, Zhou H, Dankova G, Howe LJ, Lee MK, Hysi PG, de Jong MA, Zhu G, Adhikari K, Li D, et al (2018). Novel Genetic Loci Affecting Facial Shape Variation in Humans.
Howe L, Sharp G, Hemani G, Zuccolo L, Richmond S, Lewis S (2018). Prenatal alcohol exposure and facial morphology in a UK cohort.
Abstract:
Prenatal alcohol exposure and facial morphology in a UK cohort
High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including foetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterised. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects. Therefore, in the Avon Longitudinal Study of Parents and Children, we tested for an association between maternal alcohol consumption and six FAS-related facial phenotypes in their offspring, using both self-report questionnaires and the maternal genotype at rs1229984 in ADH1B as measures of maternal alcohol consumption. In both self-reported alcohol consumption (N=4,233) and rs1229984 genotype (N=3,139) analyses, we found no strong statistical evidence for an association between maternal alcohol consumption and facial phenotypes tested. The directions of effect estimates were compatible with the known effects of heavy alcohol exposure, but confidence intervals were largely centred around zero. We conclude that, in a sample representative of the general population, there is no strong evidence for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.
Abstract.
Beckmeyer-Borowko A, Imboden M, Rezwan FI, Wielscher M, Amaral AFS, Jeong A, Schaffner E, Auvinen J, Sebert S, Karhunen V, et al (2018). SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts.
Respiratory Research,
19(1).
Abstract:
SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts
Background: the pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. A family based study of predominantly smoking adults found methylation at two Cytosine-phosphate-Guanine sites (CpGs) in SERPINA1 gene to be associated with chronic obstructive pulmonary disease risk. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort. Methods: DNA methylation using Illumina Infinium Human Methylation 450k and EPIC beadchips and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. Associations of methylation at 119 CpG sites in the SERPINA gene cluster (PP4R4-SERPINA13P) with lung functions and circulating alpha-1-antitripsin (AAT) were assessed using multivariable cross-sectional and longitudinal regression models. Results: Methylation at cg08257009 in the SERPINA gene cluster, located 32kb downstream of SERPINA1, not annotated to a gene, was associated with FEV1/FVC at the Bonferroni corrected level in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing. Conclusions: the results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed.
Abstract.
Richmond RC, Sharp GC, Herbert G, Atkinson C, Taylor C, Bhattacharya S, Campbell D, Hall M, Kazmi N, Gaunt T, et al (2018). The long-term impact of folic acid in pregnancy on offspring DNA methylation: Follow-up of the Aberdeen folic acid supplementation trial (AFAST).
International Journal of Epidemiology,
47(3), 928-937.
Abstract:
The long-term impact of folic acid in pregnancy on offspring DNA methylation: Follow-up of the Aberdeen folic acid supplementation trial (AFAST)
Background: it has been proposed that maternal folic-acid supplement use may alter the DNA-methylation patterns of the offspring during the in-utero period, which could influence development and later-life health outcomes. Evidence from human studies suggests a role for prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood. Methods: to better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen Folic Acid Supplementation Trial (AFAST—a trial of two different doses: 0.2 and 5 mg, folic acid vs placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single-site and differentially methylated region analyses were performed. Results: We found an association at cg09112514 (p ¼ 4.0310 –9 ), a CpG located in the 5’ untranslated region of PDGFRA, in the main analysis comparing the intervention arms [low- (0.2 mg) and high-dose (5 mg) folic acid combined (N ¼ 43)] vs placebo (N ¼ 43). Furthermore, a dose–response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome that were differentially methylated in response to the intervention (Sidak p-value
Abstract.
2017
Sharp GC, Ho K, Davies A, Stergiakouli E, Humphries K, McArdle W, Sandy J, Davey Smith G, Lewis SJ, Relton CL, et al (2017). Distinct DNA methylation profiles in subtypes of orofacial cleft.
Clinical Epigenetics,
9(1).
Abstract:
Distinct DNA methylation profiles in subtypes of orofacial cleft
Background: Epigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors. Given the evidence that different subtypes of orofacial cleft have distinct aetiologies, we explored whether children with different cleft subtypes showed distinct epigenetic profiles. Methods: in whole-blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only (CLO) n = 50; cleft palate only (CPO) n = 50; cleft lip and palate (CLP) n = 50). We also compared methylation in the blood to methylation in the lip or palate tissue using genome-wide data from the same 150 children and conducted an EWAS of CLO compared to CLP in lip tissue. Results: We found four genomic regions in blood differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. Several regions mapped to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA), and over 250 associations were novel. Methylation in blood correlated with that in lip/palate at some regions. There were 14 regions differentially methylated in the lip tissue from children with CLO and CLP, with one region (near KIAA0415) showing up in both the blood and lip EWAS. Conclusions: Our finding of distinct methylation profiles in different orofacial cleft (OFC) subtypes represents a promising first step in exploring the potential role of epigenetic modifications in the aetiology of OFCs and/or as clinically useful biomarkers of OFC subtypes.
Abstract.
Sharp G, Ho K, Davies A, Stergiakouli E, Humphries K, McArdie W, Sandy J, Davey Smith G, Lewis S, Relton C, et al (2017). Distinct blood DNA methylation profiles in subtypes of orofacial cleft.
Abstract:
Distinct blood DNA methylation profiles in subtypes of orofacial cleft
Background There is evidence that different subtypes of orofacial cleft have distinct aetiologies, although the precise molecular mechanisms underlying these are unknown. Given the key role of epigenetic processes such as DNA methylation in embryonic development, it is likely that aberrant DNA methylation may also play a part in the development of orofacial clefts. Methods in this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles. In whole blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only CLO n=50; cleft palate only CPO n=50; cleft lip and palate CLP n=50). Results We found four genomic regions differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. These regions included several mapping to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA ) and over 250 novel associations. Conclusion Our finding of distinct methylation profiles in different cleft subtypes might reflect differences in their aetiologies, with DNA methylation either playing a causal role in development of OFC subtypes or reflecting causal genetic or environmental factors.
Abstract.
Sharp GC, Relton CL (2017). Epigenetics and noncommunicable diseases. Epigenomics, 9(6), 789-791.
Arathimos R, Suderman M, Sharp G, Burrows K, Granell R, Tilling K, Gaunt T, Henderson J, Ring S, Richmond R, et al (2017). Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
Abstract:
Epigenome-wide association study of asthma and wheeze in childhood and adolescence
Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis. Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 years and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma. We identified 302 CpGs associated with current asthma status (FDR-adjusted P-value
Abstract.
Arathimos R, Suderman M, Sharp G, Burrows K, Granell R, Tilling K, Richmond R, Haycock P, Relton C (2017). Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
Author URL.
Arathimos R, Suderman M, Sharp GC, Burrows K, Granell R, Tilling K, Gaunt TR, Henderson J, Ring S, Richmond RC, et al (2017). Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
Clinical Epigenetics,
9(1).
Abstract:
Epigenome-wide association study of asthma and wheeze in childhood and adolescence
Background: Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis. Methods: Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma. Results: We identified 302 CpGs associated with current asthma status (FDR-adjusted P value < 0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a - 2.32 [95% CI - 1.47, - 3.18] and - 2.49 [95% CI - 1.56, - 3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years. Conclusion: the majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.
Abstract.
Caramaschi D, Sharp GC, Nohr EA, Berryman K, Lewis SJ, Smith GD, Relton CL (2017). Exploring a causal role of DNA methylation in the relationship between maternal vitamin B-12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment: a two-step Mendelian randomization study.
HUMAN MOLECULAR GENETICS,
26(15), 3001-3013.
Author URL.
Sharp G, Salas L, Monnereau C, Allard C, Yousefi P, Everson T, Bohlin J, Xu Z, Huang R-C, Reese S, et al (2017). Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the Pregnancy and Childhood Epigenetics (PACE) consortium.
Abstract:
Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the Pregnancy and Childhood Epigenetics (PACE) consortium
Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (
Abstract.
Sharp GC, Salas LA, Monnereau C, Allard C, Yousefi P, Everson TM, Bohlin J, Xu Z, Huang RC, Reese SE, et al (2017). Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the pregnancy and childhood epigenetics (PACE) consortium.
Human Molecular Genetics,
26(20), 4067-4085.
Abstract:
Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the pregnancy and childhood epigenetics (PACE) consortium
Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (
Abstract.
Sharp G, Arathimos R, Reese S, Page C, Felix J, Küpers L, Rifas-Shiman S, Liu C, Burrows K, Zhao S, et al (2017). Maternal alcohol consumption during pregnancy and offspring epigenome-wide DNA methylation: findings from six general population-based birth cohorts.
Abstract:
Maternal alcohol consumption during pregnancy and offspring epigenome-wide DNA methylation: findings from six general population-based birth cohorts
Some evidence suggests that light-to-moderate alcohol consumption during pregnancy is associated with adverse outcomes in the offspring, but the precise biological mechanisms underlying such associations are currently unknown. Epigenetic modifications have been suggested as one potential explanation. Within the Pregnancy and Childhood Epigenetics (PACE) consortium, we performed meta-analysis to combine information from six population-based birth cohort studies to investigate DNA methylation at over 450,000 sites in the cord blood of newborns differentially exposed to alcohol in utero. We were primarily interested in the effects of sustained consumption throughout pregnancy (data available for five cohorts, 3,075 mother-child pairs), which represents a prolonged prenatal exposure to alcohol, but we also explored binge-drinking and timing-specific exposures. In addition to looking for differential methylation at individual CpG sites, we also used two different methods, Comb-P and DMRcate, to identify differentially methylated regions (DMRs). We found no strong evidence of association between any of our alcohol exposure measures and DNA methylation at any individual CpG site. Using Comb-P, we identified 19 DMRs in the offspring of mothers who drank throughout pregnancy compared to the offspring of mothers who gave up drinking at the start of pregnancy, but these were not validated using DMRcate. In this multi-cohort study of the general population we found no evidence that maternal alcohol consumption during pregnancy is associated with offspring cord blood DNA methylation, which is in stark contrast to the multiple, strong associations that previous studies have found for maternal smoking. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure and a more global assessment of genomic DNA methylation might show evidence of association.
Abstract.
Suderman M, Simpkin A, Sharp G, Gaunt T, Lyttleton O, McArdle W, Ring S, Davey Smith G, Relton C (2017). Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood.
Abstract:
Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood
Almost all species show sexual discordance in many traits and diseases. DNA methylation is known to contribute to these differences through well-established mechanisms including X-inactivation in females, imprinting and parent-of-origin effects. Here we investigate sex discordance in DNA methylation throughout childhood in a sample of 700 individuals from the Avon Longitudinal Study of Parents and Children. We show that autosomal sex-discordant methylation is widespread, affecting approximately 12,000 CpG sites at any given age, and stable; at least 8,500 sites are consistently different across all time points and a large proportion discordant in both the fetal and adult brain cortices. Just over 1,000 methylation differences change from birth to late adolescence, 90% of these between birth and around age seven. Sexually discordant CpG sites are enriched in genomic loci containing androgen but not estrogen targets and in genes involved in tissue development but not housekeeping functions. A methylation-derived sex score capturing the variance was calculated at each time point and found to be highly correlated between time points. This score is nominally associated with sex hormone levels in childhood as well as some phenotypes previously linked to sex hormone levels. These findings suggest that sex-discordant autosomal DNA methylation is widespread throughout the genome, likely due to the first androgen exposures in utero. It is then stably maintained from birth to late adolescence. Methylation variation at sex-discordant sites within the sexes, as summarized by the methylation sex score, likely reflects in utero androgen exposure which is relevant to human health. Significance Statement Although we know that sex hormones are critical for establishing sexual discordance, less is known about how this discordance is achieved and maintained. Here we present evidence for widespread differences in DNA methylation between male and female children. We show that most of these differences are established prenatally, likely due to the first androgen exposures in utero, and then stably maintained throughout childhood, despite extreme fluctuations in the levels of these very same hormones. Our results support a role for DNA methylation as a means for recording and maintaining the effects of exposure to sex hormones and thus to better understand sexual variation and how it is driven by the prenatal environment.
Abstract.
2016
Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, Reese SE, Markunas CA, Richmond RC, Xu CJ, et al (2016). DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.
American Journal of Human Genetics,
98(4), 680-696.
Abstract:
DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis
Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy and Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g. orofacial clefts and asthma) or adult smoking (e.g. certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10-16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Abstract.
Richmond RC, Sharp GC, Ward ME, Fraser A, Lyttleton O, McArdle WL, Ring SM, Gaunt TR, Lawlor DA, Smith GD, et al (2016). DNA methylation and BMI: Investigating identified methylation sites at HIF3A in a causal framework.
Diabetes,
65(5), 1231-1244.
Abstract:
DNA methylation and BMI: Investigating identified methylation sites at HIF3A in a causal framework
Multiple differentially methylated sites and regions associated with adiposity have now been identified in largescale cross-sectional studies. We tested for replication of associations between previously identified CpG sites at HIF3A and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality. Overall, our results were discordant with those expected if HIF3A methylation has a causal effect on BMI and provided more evidence for causality in the reverse direction (i.e. an effect of BMI on HIF3A methylation). These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation. Our results also highlight an apparent long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity and HIF3A methylation. Further work is required to replicate and uncover the mechanisms underlying the direct and intergenerational effect of adiposity on DNA methylation.
Abstract.
Simpkin AJ, Hemani G, Suderman M, Gaunt TR, Lyttleton O, Mcardle WL, Ring SM, Sharp GC, Tilling K, Horvath S, et al (2016). Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies.
Human Molecular Genetics,
25(1), 191-201.
Abstract:
Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies
DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.
Abstract.
Sharp GC, Hutchinson JL, Hibbert N, Freeman TC, Saunders PTK, Norman JE (2016). Transcription analysis of the myometrium of labouring and non-labouring women.
PLoS ONE,
11(5).
Abstract:
Transcription analysis of the myometrium of labouring and non-labouring women
An incomplete understanding of the molecular mechanisms that initiate normal human labour at term seriously hampers the development of effective ways to predict, prevent and treat disorders such as preterm labour. Appropriate analysis of large microarray experiments that compare gene expression in non-labouring and labouring gestational tissues is necessary to help bridge these gaps in our knowledge. In this work, gene expression in 48 (22 labouring, 26 non-labouring) lower-segment myometrial samples collected at Caesarean section were analysed using Illumina HT-12 v4.0 BeadChips. Normalised data were compared between labouring and non-labouring groups using traditional statistical methods and a novel network graph approach. We sought technical validation with quantitative realtime PCR, and biological replication through inverse variance-weighted meta-analysis with published microarray data. We have extended the list of genes suggested to be associated with labour: Compared to non-labouring samples, labouring samples showed apparent higher expression at 960 probes (949 genes) and apparent lower expression at 801 probes (789 genes) (absolute fold change ≥1.2, rank product percentage of false positive value (RP-PFP)
Abstract.
2015
Sharp GC, Lawlor DA, Richmond RC, Fraser A, Simpkin A, Suderman M, Shihab HA, Lyttleton O, McArdle W, Ring SM, et al (2015). Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: Findings from the Avon Longitudinal Study of Parents and Children.
International Journal of Epidemiology,
44(4), 1288-1304.
Abstract:
Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: Findings from the Avon Longitudinal Study of Parents and Children
Background: Evidence suggests that in utero exposure to undernutrition and overnutrition might affect adiposity in later life. Epigenetic modification is suggested as a plausible mediating mechanism. Methods: We used multivariable linear regression and a negative control design to examine offspring epigenome-wide DNA methylation in relation to maternal and offspring adiposity in 1018 participants. Results: Compared with neonatal offspring of normal weight mothers, 28 and 1621 CpG sites were differentially methylated in offspring of obese and underweight mothers, respectively [false discovert rate (FDR)-corrected P-value
Abstract.
2014
Sharp GC, Stock SJ, Norman JE (2014). Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes.
Cochrane Database of Systematic Reviews,
2014(10).
Abstract:
Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes
Background: Fetal assessment following preterm prelabour rupture of membranes (PPROM) may result in earlier delivery due to earlier detection of fetal compromise. However, early delivery may not always be in the fetal or maternal interest, and the effectiveness of different fetal assessment methods in improving neonatal and maternal outcomes is uncertain. Objectives: to study the effectiveness of fetal assessment methods for improving neonatal and maternal outcomes in PPROM. Examples of fetal assessment methods that would be eligible for inclusion in this review include fetal cardiotocography, fetal movement counting and Doppler ultrasound. Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2014) and reference lists of retrieved studies. Selection criteria: Randomised controlled trials comparing any fetal assessment methods, or comparing one fetal assessment method to no assessment. Data collection and analysis: Two review authors independently assessed trials for inclusion into the review. The same two review authors independently assessed trial quality and independently extracted data. Data were checked for accuracy. Main results: We included three studies involving 275 women (data reported for 271) with PPROM at up to 34 weeks' gestation. All three studies were conducted in the United States. Each study investigated different methods of fetal assessment. One study compared weekly endovaginal ultrasound scans with no assessment (n = 93), one compared amniocentesis with no assessment (n = 47), and one compared daily nonstress testing with daily modified biophysical profiling (n = 135). We were unable to perform a meta-analysis, but were able to report data from individual studies. There was no convincing evidence of increased risk of neonatal death in the group receiving endovaginal ultrasound scans compared with the group receiving no assessment (risk ratio (RR) 7.30, 95% confidence interval (CI) 0.39 to 137.54; one study, 92 women), or in the group receiving amniocentesis compared with the group receiving no amniocentesis (RR 1.00, 95% CI 0.07 to 15.00; one study, 44 women). For both these interventions, we inferred that there were no fetal deaths in the intervention or control groups. The study comparing daily nonstress testing with daily modified biophysical profiling did not report fetal or neonatal death. Primary outcomes of maternal death and serious maternal morbidity were not reported in any study. Overall, there were few statistically significant differences in outcomes between the comparisons. The overall quality of evidence is poor, because participant blinding was not possible for any study. Authors' conclusions: There is insufficient evidence on the benefits and harms of fetal assessment methods for improving neonatal and maternal outcomes in women with PPROM to draw firm conclusions. The overall quality of evidence that does exist is poor. Further high-quality randomised controlled trials are required to guide clinical practice.
Abstract.
Sharp GC, Saunders PTK, Greene SA, Morris AD, Norman JE (2014). Intergenerational transmission of postpartum hemorrhage risk: Analysis of 2 Scottish birth cohorts.
American Journal of Obstetrics and Gynecology,
211(1), 51.e1-51.e7.
Abstract:
Intergenerational transmission of postpartum hemorrhage risk: Analysis of 2 Scottish birth cohorts
Objective the purpose of this study was to determine risk factors for postpartum hemorrhage (PPH) that includes intergenerational transmission of risk of postpartum hemorrhage. Study Design We linked birth records of women and their daughters and granddaughters in 2 Scottish birth cohorts: the Walker cohort (collected from 1952-1966) and the Scottish Morbidity Records cohort (collected from 1975-present). We determined clinical risk factors for PPH. We then quantified the risk of PPH in women whose mothers/grandmothers had postpartum hemorrhage before and after adjustment for these risk factors. Results the risk of PPH in women whose mothers/grandmothers had PPH was no greater than in those whose mothers/grandmothers did not have PPH. Our study had sufficient power (80%) to detect an odds ratio of 1.3, should such an increase in odds that is associated with familial history exist. In contrast, the adjusted odds ratios that were conferred by nulliparity, having a large baby, cesarean delivery, and genital tract trauma were 1.47, 1.84, 8.20, and 9.61, respectively. Conclusion Women whose mothers/grandmothers had PPH do not appear to be at increased risk themselves. We confirmed an increased risk of PPH that was associated with nulliparity, delivering a large baby, cesarean delivery, and genital tract trauma. We were unable to demonstrate an effect of intergenerational transmission of PPH, although our study was underpowered to detect an odds ratio
Abstract.
2013
Sharp GC, Ma H, Saunders PTK, Norman JE (2013). A Computational Model of Lipopolysaccharide-Induced Nuclear Factor Kappa B Activation: a Key Signalling Pathway in Infection-Induced Preterm Labour.
PLoS ONE,
8(7).
Abstract:
A Computational Model of Lipopolysaccharide-Induced Nuclear Factor Kappa B Activation: a Key Signalling Pathway in Infection-Induced Preterm Labour
Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be "tested". Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field. © 2013 Sharp et al.
Abstract.
Sharp G, Freeman T, Saunders P, Norman J (2013). A NOVEL NETWORK GRAPH APPROACH FOR THE ANALYSIS AND VISUALISATION OF EPIDEMIOLOGICAL DATA.
Author URL.
Sharp GC, Saunders PTK, Norman JE (2013). Computer models to study uterine activation at labour.
Molecular Human Reproduction,
19(11), 711-717.
Abstract:
Computer models to study uterine activation at labour
Improving our understanding of the initiation of labour is a major aim of modern obstetric research, in order to better diagnose and treat pregnantwomenin which the process occurs abnormally. In particular, increased knowledge will help us identify the mechanisms responsible for pretermlabour, the single biggest cause of neonatal morbidity and mortality. Attempts to improve our understanding of the initiation of labour have been restricted by the inaccessibility of gestational tissues to study during pregnancy and at labour, and by the lack of fully informative animal models. However, computer modelling provides an exciting new approach to overcome these restrictions and offers new insights into uterine activation during term and preterm labour. Such models could be used to test hypotheses about drugs to treat or prevent pretermlabour.With further development, an effective computer model could be used by healthcare practitioners to develop personalized medicine for patients on a pregnancy-by-pregnancy basis. Very promising work is already underway to build computer models of the physiology of uterine activation and contraction. These models aim to predict changes and patterns in uterine electrical excitation during term labour. There have been far fewer attempts to build computer models of the molecular pathways driving uterine activation and there is certainly scope for further work in this area. The integration of computer models of the physiological and molecular mechanisms that initiate labour will be particularly useful. © the Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
Abstract.
2012
Sharp GC, Stock SJ, Norman JE (2012). Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes. In (Ed) Cochrane Database of Systematic Reviews.
