Biology subjects

Relton, C. L.

Publications and source records attributed to Relton, C. L..

17 recordsLinked to original sources

bioRxiv2018

Cleft lip/palate and educational attainment: cause, consequence, or correlation? A Mendelian randomization study

ImportancePrevious studies have found that children born with a non-syndromic form of cleft lip and/or palate have lower-than-average educational attainment. These differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as school absence, social stigmatization and impaired speech and language development), or confounding by the prenatal environment. A clearer understanding of this mechanism will inform development of interventions to improve educational attainment in individuals born with a cleft, which could have wide-ranging knock-on effects on their quality of life.\n\nObjectiveTo assess evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.\n\nDesignUsing summary data from genome-wide association studies (GWAS), we performed Linkage Disequilibrium (LD)-score regression and two-sample Mendelian randomization to evaluate the relationship between genetic liability to nsCL/P (GWAS n=3,987) and educational attainment (GWAS n=766,345), and intelligence (GWAS n=257,828).\n\nResultsThere was little evidence for shared genetic aetiology between nsCL/P and educational attainment (rg -0.03, 95% CI -0.14 to 0.08, P 0.58; {beta}MR 0.002, 95% CI -0.001 to 0.005, P 0.417) or intelligence (rg -0.01, 95% CI -0.12 to 0.10, P 0.85; {beta}MR 0.002, 95% CI -0.010 to 0.014, P 0.669).\n\nConclusions and relevanceCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo children born with a non-syndromic cleft lip with or without palate (nsCL/P) have lower-than average academic achievement because of an underlying genetic predisposition to educational attainment and/or intelligence?\n\nFindingsThere was little evidence for shared common variant genetic correlation between nsCL/P, educational attainment and intelligence.\n\nMeaningCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.

genetics↗

bioRxiv2018

DNA methylation links prenatal smoking exposure to later life health outcomes in offspring.

Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1x10-7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

epidemiology↗

bioRxiv2018

Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease

Integrative approaches which harness large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic processes which may play a role in neurological trait variation.\n\nThis was undertaken by applying Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants responsible for influencing intermediate molecular phenotypes as well as neurological traits. In this analysis we leveraged high dimensional quantitative trait loci data derived from prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for 5 neurological traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimers disease).\n\nThere was evidence of colocalization for 118 associations suggesting that the same underlying genetic variant influenced both nearby gene expression as well as neurological trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such as KLC1 and schizophrenia. We also uncovered evidence implicating novel loci in neurological disease susceptibility, including genes expressed predominantly in brain tissue such as MDGA1, KIRREL3 and SLC12A5.\n\nAn inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritise candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.

genetics↗

bioRxiv2018

Predicting cellular aging following exposure to adversity: Does accumulation, recency, or developmental timing of exposure matter?

Exposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous health problems, including neuropsychiatric disease. In recent years, measures of DNA methylation-based epigenetic age - known as \"epigenetic clocks\" - have been used to estimate accelerated epigenetic aging. Yet, few studies have been conducted in children. Using data from the Avon Longitudinal Study of Parents and Children (n=973), we explored the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7 using the Horvath and Hannum epigenetic clocks. With a Least Angle Regression variable selection procedure, we evaluated the effects of the developmental timing, accumulation, and recency of adversity exposure. We found that exposure to sexual or physical abuse, financial stress, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of the Hannum epigenetic age from the chronological age. Secondary sex-stratified analyses identified particularly strong sensitive period effects, such that by age 7, girls who were exposed to abuse at age 3.5 were biologically older than their unexposed peers by almost 2 months. These effects were undetected in analyses comparing children \"exposed\" versus \"unexposed\" to adversity. Our results suggest that exposure to adversity may alter methylation processes in ways that perturb normal cellular aging and that these effects may be heightened during sensitive periods in development. Research is needed to demonstrate the effect of accelerated epigenetic aging on negative health outcomes following childhood adversity exposure.

genetics↗

bioRxiv2018

Prioritizing putative influential genes in early life cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization

BackgroundThe extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analytical framework that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from genetic variant to complex trait.\n\nMethodsWe undertook a transcriptome-wide association study in a population of young individuals to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Two-sample Mendelian randomization was then applied using large-scale datasets to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently performed Bayesian multiple-trait colocalization to further interrogate findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility.\n\nResultsEight genetic loci were associated with changes in gene expression and early life measures of cardiovascular function. Our Mendelian randomization analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol respectively were particularly insightful. Multiple trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also play a role in cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses were able to uncover evidence of tissue-specificity, most prominantly between SORT1 expression in liver tissue and cholesterol levels.\n\nConclusionsDisease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. Our analytical framework should prove valuable in elucidating mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell typse will further improve our capability to understand and prevent disease.

genetics↗

bioRxiv2018

Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study

BackgroundExposure to \"early life\" adversity is known to predict DNA methylation (DNAm) patterns that may be related to prolonged psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.\n\nMethodsUsing a two-stage structured life course modeling approach (SLCMA), we tested the hypothesis that there are sensitive periods when adversity induced greater DNAm changes. We tested this hypothesis in relation to two alternative explanations: an accumulation hypothesis, in which the effect of adversity on DNAm increases with the number of occasions exposed, regardless of timing, and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomics Studies (ARIES), a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC; n=670-776).\n\nResultsAfter covariate adjustment and multiple testing correction, we identified 40 CpG sites that were differentially methylated at age 7 following exposure to adversity. Most loci (n=32) were predicted by the timing of adversity, namely exposures during infancy. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard EWAS of lifetime exposure (vs. no exposure) failed to detect these associations.\n\nConclusionsThe developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Infancy appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed vs. unexposed to \"early life\" adversity may dilute observed effects.

genetics↗

bioRxiv2018

DNA methylation mediates genetic liability to non-syndromic cleft lip/palate

BackgroundNon-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.\n\nMethodsUsing 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.\n\nResultsThere 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.\n\nConclusionsGenetic variation may increase liability to nsCL/P by influencing DNA methylation and gene expression at VAX1, LOC146880 and NTN1.

genetics↗

bioRxiv2017

Causal inference in cancer epidemiology: what is the role of Mendelian randomization?

Observational epidemiological studies are prone to confounding, measurement error, and reverse causation, undermining their ability to generate reliable causal estimates of the effect of risk factors to inform cancer prevention and treatment strategies. Mendelian randomization (MR) is an analytical approach that uses genetic variants to proxy potentially modifiable exposures (e.g. environmental factors, biological traits, and druggable pathways) to permit robust causal inference of the effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within population health research in cardio-metabolic disease, but also holds much promise for identifying possible interventions (e.g., dietary, behavioural, or pharmacological) for cancer prevention and treatment. However, some methodological and conceptual challenges in the implementation of MR are particularly pertinent when applying this method to cancer aetiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies.\n\nIn this review, we provide an overview of the key principles and assumptions of MR focusing on applications of this method to the study of cancer aetiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared to conventional epidemiological studies. Lastly, limitations of MR and recent methodological developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer.

epidemiology↗

bioRxiv2017

Circulating selenium and prostate cancer risk: a Mendelian randomization analysis

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 g/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic risk score comprising eleven single-nucleotide polymorphisms robustly (P<5x10-8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72,729 men in the PRACTICAL Consortium (44,825 cases, 27,904 controls), 114 g/L higher genetically-elevated circulating selenium was not associated with prostate cancer (OR: 1.01; 95% CI: 0.89-1.13). Concordant with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR: 1.21; 95% CI: 0.98-1.49) and type 2 diabetes (OR: 1.18; 95% CI: 0.97-1.43; in a type 2 diabetes GWAS meta-analysis with up to 49,266 cases, 249,906 controls). Mendelian randomization mirrored the outcome of selenium supplementation in SELECT and may offer an approach for the prioritization of interventions for follow-up in large-scale randomized controlled trials.

epidemiology↗

bioRxiv2017

Systematic Mendelian randomization framework elucidates hundreds of genetic loci which may influence disease through changes in DNA methylation levels

We have undertaken an extensive Mendelian randomization (MR) study using methylation quantitative trait loci (mQTL) as genetic instruments to assess the potential causal relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we observed 1,191 effects across 62 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-mQTL) and complex trait variation (P<1.39x10-08). Joint likelihood mapping provided evidence that the causal mQTL for 364 of these effects across 58 traits was also likely the causal variant for trait variation. These effects showed a high rate of replication in the UK Biobank dataset for 14 selected traits, as 121 of the attempted 129 effects replicated. Integrating expression quantitative trait loci (eQTL) data suggested that genetic variants responsible for 319 of the 364 mQTL effects also influence gene expression, which indicates a coordinated system of effects that are consistent with causality. CpG sites were enriched for histone mark peaks in tissue types relevant to their associated trait and implicated genes were enriched across relevant biological pathways. Though we are unable to distinguish mediation from horizontal pleiotropy in these analyses, our findings should prove valuable in identifying candidate loci for further evaluation and help develop mechanistic insight into the aetiology of complex disease.

genetics↗

bioRxiv2017

Imprinted loci may be more widespread in humans than previously appreciated and enable limited assignment of parental allelic transmissions in unrelated individuals

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin dependent gene expression. So far, the precise number of imprinted genes in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at 3 time points (birth, childhood and adolescence) and GWAS data in 740 Mother-Child duos from the Avon Longitudinal Study of Parents and Children (ALSPAC) to systematically identify imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 35 novel and 50 known imprinted regions (10-10< P <10-300). Among the novel loci, we observed signals near genes implicated in cardiovascular disease (PCSK9), and Alzheimers disease (CR1), amongst others. Most of the significant regions exhibited imprinting patterns consistent with uniparental expression, with the exception of twelve loci (including the IGF2, IGF1R, and IGF2R genes), where we observed a bipolar-dominance pattern. POEs were remarkably consistent across time points and were so strong at some loci that methylation levels enabled good discrimination of parental transmissions at these and surrounding genomic regions. The implication is that parental allelic transmissions could be modelled at many imprinted (and linked) loci and hence POEs detected in GWAS of unrelated individuals given a combination of genetic and methylation data. Our results indicate that modelling POEs on DNA methylation is effective to identify loci that may be affected by imprinting.

genomics↗

bioRxiv2017

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.\n\nUsing 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.\n\nWe 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] change 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.\n\nThe 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.

epidemiology↗

bioRxiv2017

Causal epigenome-wide association study identifies CpG sites that influence cardiovascular disease risk

The extent to which genetic influences on complex traits and disease are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits.\n\nWe identified 10 genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits (P < 3.83x10-08). Bivariate fine mapping suggested that the individual variants responsible for the observed effects on cardiovascular traits at the ABO, ADCY3, ADIPOQ, APOA1 and IL6R loci were likely mediated through changes in DNA methylation. Causal effect estimates on cardiovascular traits ranged between 0.109-0.992 per standard deviation change in DNA methylation and were replicated using results from large-scale consortia.\n\nFunctional informatics suggests that the causal variants and CpG sites identified in this study were enriched for histone mark peaks in adipose tissue and gene promoter regions. Integrating our results with expression quantitative trait loci data we provide evidence that variation at these regulatory regions is likely to also influence gene expression at these loci.

epidemiology↗

bioRxiv2017

Meffil: efficient normalisation and analysis of very large DNA methylation samples

AbstractO_ST_ABSBackgroundC_ST_ABSTechnological advances in high throughput DNA methylation microarrays have allowed dramatic growth of a new branch of epigenetic epidemiology. DNA methylation datasets are growing ever larger in terms of the number of samples profiled, the extent of genome coverage, and the number of studies being meta-analysed. Novel computational solutions are required to efficiently handle these data.\n\nMethodsWe have developed meffil, an R package designed to quality control, normalize and perform epigenome-wide association studies (EWAS) efficiently on large samples of Illumina Infinium HumanMethylation450 and MethylationEPIC BeadChip microarrays. We tested meffil by applying it to 6000 450k microarrays generated from blood collected for two different datasets, Accessible Resource for Integrative Epigenomic Studies (ARIES) and The Genetics of Overweight Young Adults (GOYA) study.\n\nResultsA complete reimplementation of functional normalization minimizes computational memory requirements to 5% of that required by other R packages, without increasing running time. Incorporating fixed and random effects alongside functional normalization, and automated estimation of functional normalisation parameters reduces technical variation in DNA methylation levels, thus reducing false positive associations and improving power. We also demonstrate that the ability to normalize datasets distributed across physically different locations without sharing any biologically-based individual-level data may reduce heterogeneity in meta-analyses of epigenome-wide association studies. However, we show that when batch is perfectly confounded with cases and controls functional normalization is unable to prevent spurious associations.\n\nConclusionsmeffil is available online (https://github.com/perishky/meffil/) along with tutorials covering typical use cases.

bioinformatics↗

bioRxiv2017

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. Epigenetic modifications such as DNA methylation could contribute, but data are scarce.\n\nWithin 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.\n\nIn newborns, maternal BMI was associated with modest (<0.2% per BMI unit (1kg/m2), P<1.06*10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. These 86 sites map to several genes reported to be associated with adiposity-related and/or neuropsychiatric traits. At 72/86 sites, the direction of association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites.\n\nIn conclusion, maternal adiposity is associated with modest variations in newborn blood DNA methylation, but the potential biological consequences of these variations are currently unclear.

epidemiology↗

bioRxiv2017

Sex-associated autosomal DNA methylation differences are wide-spread and stablethroughout 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.\n\nSignificance StatementAlthough 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.

epidemiology↗

bioRxiv2017

Distinct Blood DNA Methylation Profiles In Subtypes Of Orofacial Cleft

BackgroundThere 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.\n\nMethodsIn this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles.\n\nIn 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).\n\nResultsWe 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.\n\nConclusionOur 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.

epidemiology↗