Caroline Relton

BackgroundChildhood adversity is a potent determinant of mental health, especially when exposure occurs during sensitive periods. Importantly, recent studies suggest DNA methylation (DNAm) may capture these time-dependent effects of adversity. Here, we present results from the first meta-analysis of time-varying exposures to childhood adversity and DNAm.MethodsUsing data from seven population-based studies (n= 2,347-3,279), we examined five types of childhood adversity and epigenome-wide DNAm measured from blood or saliva between ages 7-17. We used the Structured Life Course Modeling Approach (SLCMA) to investigate the time-varying relationship between each adversity and DNAm profiles. The SLCMA allowed us to simultaneously test six different life course models: 1-4) exposure during one of four sensitive periods (ages 0-1, 2-3, 4-5, or 6-7); 5) accumulation of risk (total exposures …

PurposeTo investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.MethodsOur study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome.ResultsDuring a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence …

High body mass index (BMI) is a causal risk factor for endometrial cancer but the molecular mechanisms underlying this association remain elusive. Here we sought to characterize the tumor genomic landscape of endometrial cancers that have developed on a germline genetic background of predisposition to elevated BMI. We built a polygenic score (PGS) for adult BMI in women using effect size estimates and allele information on 242 independent (r2<0.05) variants associated with BMI at genome-wide significance (P<5x10-9) in 379,501 women of European ancestry. We performed sample and germline (blood) genotype quality control and imputation into the 1000 Genomes reference panel on data from 354 endometrial cancer cases of genetically inferred European ancestry from The Cancer Genome Atlas (TCGA). We assigned each woman in this TCGA cohort her genetically predicted life-course BMI based …

Background Hypotheses about what phenotypes to include in causal analyses (that in turn can have clinical and policy implications) can be guided by hypothesis-free approaches, leveraging the epigenome for example. Materials & methods Minimally adjusted epigenome-wide association studies (EWAS) using ALSPAC data were performed for example conditions, dysmenorrhea and heavy menstrual bleeding (HMB). Differentially methylated CpGs were searched in the EWAS Catalog and associated traits identified. Traits were compared between those with and without the example conditions in ALSPAC. Results Seven CpG sites were associated with dysmenorrhea and two with HMB. Smoking and adverse childhood experience score were associated with both conditions in the hypothesis-testing phase. Conclusion Hypothesis-generating EWAS can help identify associations for future analyses.

High body mass index (BMI) is a causal risk factor for endometrial cancer but the tumor molecular mechanisms affected by adiposity and their therapeutic relevance remain poorly understood. Here we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic exposure to elevated BMI. We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted life-course BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to …

Objective.To determine if accelerated epigenetic aging is associated with exposures to diverse measures of racialized, economic, and environmental injustice measured at different levels and time periods.Design.Cross-sectional My Body My Story Study (MBMS; US, 2008–2010) and Exam 5 Multi-Ethnic Atherosclerosis Study (MESA; US, 2010–2012). MBMS DNA extraction: 2021; linkage of structural measures to MBMS and MESA: 2022.Setting:MBMS recruited a random sample of US-born Black non-Hispanic (BNH) and white non-Hispanic (WNH) participants from 4 community health centers in Boston, MA. The MESA Exam 5 epigenetic component included 975 randomly selected US-born BNH, WNH, and Hispanic participants from four field sites: Baltimore, MD; Forsyth County, NC; New York City, NY; St. Paul, MN.Participants:US-born persons (MBMS: 224 BNH, 69 WNH; MESA: 229 BNH, 555 WNH, 191 …

Background: Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk. Methods: A nationwide nested case-control study was conducted using data from the Cancer Registry of Norway, the National Registry and the Norwegian Prescription Database in 2004–15. Ten controls were randomly selected for each melanoma case, matched on sex and birth year. The study included 12 048 cases and 117 895 controls. We estimated rate ratios (RRs) with 95% confidence intervals (CIs). All analyses were adjusted for ambient ultraviolet radiation (UVR). We additionally performed active comparator analyses, and sensitivity analyses by only including new users, distinguishing between exclusive and mixed users, allowing for different latency periods, and subgroup analyses by melanoma subtype and clinical stage.Results: Compared with non-use, we observed a slightly increased melanoma risk in users of diuretics (RR 1.08, CI 1.01–1.15), calcium-channel blockers (RR 1.10, CI 1.04–1.18) and drugs affecting the renin-angiotensin system (RR 1.10, CI 1.04–1.16), but not for beta blockers (RR 0.97, CI 0.92–1.03). We found no heterogeneity of associations by

Integrating findings from genome-wide association studies with molecular datasets can help develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention-deficit hyperactivity disorder, Alzheimer’s disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10−6), with multiple trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified the evidence of enrichment, which may reflect …

Childhood adversity is a potent but preventable risk factor for many physical and mental illnesses (1–3). Although the mechanisms underlying these associations remain unknown, DNA methylation (DNAm) and other epigenetic modifications have emerged as potential pathways for the biological embedding of early-life environments (4). In a recent publication (5), we showed that 7 types of childhood adversity had time-dependent effects on DNAm at age 7 years. Data came from the Avon Longitudinal Study of Parents and Children (ALSPAC) and were analyzed using the structured life course modeling approach (SLCMA)(6, 7). We identified potential sensitive periods, largely occurring in the first 3 years of life, when childhood adversity exposure appeared to have greater effects on DNAm (5). Since the publication of this research, several improvements were made to increase the accuracy and robustness of the …

BackgroundChildhood adversity is a potent determinant of health across development. Altered DNA methylation (DNAm) signatures have been identified in children exposed to adversity and may be more common among children exposed during sensitive periods in development. However, it remains unclear if adversity has persistent epigenetic associations across childhood and adolescence. We examined the relationship between time-varying adversity and genome-wide DNAm, measured three times from birth to adolescence using prospective data from the Avon Longitudinal Study of Parents and Children.MethodsWe investigated the relationship between the timing of exposure to seven adversity types (measured 5-8 times between ages 0-11) and blood DNAm at age 15 using a structured life course modeling approach. We also assessed the persistence of adversity-DNAm associations we previously …

BackgroundChildhood adversity is a potent determinant of mental health across development. Recent evidence suggests these stressful events may be particularly detrimental during sensitive periods, or high-risk stages in the lifespan when life experiences can induce more potent and long-term impacts. Although the mechanisms underlying these effects remain unclear, DNA methylation (DNAm) may capture some time-dependent effects of early life adversity. However, most studies have only investigated the effects of time-varying adversity in a single cohort, limiting their statistical power and generalizability across socio-demographic contexts. Here, we present results from the first meta-analysis of time-varying exposures to childhood adversity and DNAm.MethodsWe pooled data from up to seven population-based studies (n=2,347-3,279) with repeated measures of childhood adversity and epigenome-wide …

Background: Obesity is recognised as one of the leading public health threats globally. Over the last few years, Visceral Adiposity Index (VAI), and Body Adiposity Index (BAI), derived from anthropometric measures, and biochemical parameters, have gained importance as a measure of obesity. However, unlike other common indices like body mass index, and waist circumference, the genetic underpinning of VAI, and BAI has not been well examined.Methods: 2265 sib-pairs from Indian Migration Study were used for estimating the VAI, and BAI and for examining the association of genetic variants from the Cardio-Metabochip array with them. Mixed linear regression models were run, and all inferences were drawn based on the within-sib component of the Fulker’s association models. Gene-environment/lifestyle interaction analyses were also undertaken.Findings: The average age of the participants was 40.80 years rs6659428 at LOC400796| SEC16B (ꞵ=-0.26, SE= 0.05, p-value< 0.001), and rs7611535 at DRD3| LOC645180 (ꞵ= 0.18, SE= 0.04, p-value< 0.001) were associated with VAI at suggestive significance value of< 8.21× 10-6. For BAI, rs73300702 at JAZF1-AS1 (ꞵ= 0.27, SE= 0.06), was the top hit at p-value< 8.21× 10-6. rs6659428 showed marginal effect modification with location (ꞵ= 0.26, SE= 0.13, p-value= 0.047), and rs73300702 with physical activity (ꞵ=-0.29, SE= 0.14, p-value= 0.034).Interpretation: We report three novel loci associated with VAI, and BAI in Indians. More studies of the kind are needed for identifying loci of relevance to VAI, and BAI, and related functional studies for understanding the biological mechanisms to …

Epigenetic clocks are increasingly being used as a tool to assess the impact of a wide variety of phenotypes and exposures on healthy ageing, with a recent focus on social determinants of health. However, little attention has been paid to the sociodemographic characteristics of participants on whom these clocks have been based. Participant characteristics are important because sociodemographic and socioeconomic factors are known to be associated with both DNA methylation variation and healthy ageing. It is also well known that machine learning algorithms have the potential to exacerbate health inequities through the use of unrepresentative samples – prediction models may underperform in social groups that were poorly represented in the training data used to construct the model. To address this gap in the literature, we conducted a review of the sociodemographic characteristics of the participants …

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 …

BackgroundChildhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study.MethodsWe first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort …

BackgroundThe causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.MethodsUsing a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures.FindingsGenetically elevated PUFA desaturase activity …

Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of …

Objective:Our study tests the hypothesis that DNAm is a mechanism by which racial discrimination, economic adversity, and air pollution become biologically embodied.Design:A series of cross-sectional EWAS, conducted in My Body My Story (MBMS, biological specimens collected 2008–2010, DNAm assayed in 2021); and the Multi Ethnic Study of Atherosclerosis (MESA; biological specimens collected 2010–2012, DNAm assayed in 2012–2013); using new georeferenced social exposure data for both studies (generated in 2022).Setting:MBMS was recruited from four community health centers in Boston; MESA was recruited from four field sites in: Baltimore, MD; Forsyth County, NC; New York City, NY; and St. Paul, MN.Participants:Two population-based samples of US-born Black non-Hispanic (Black NH), white non-Hispanic (white NH), and Hispanic individuals (MBMS; n= 224 Black NH and 69 white NH) and …

Background Epigenetic alterations may provide valuable insights into gene–environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn’s disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD …

BackgroundPinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk.ResultsWe report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2358 blood samples from three UK cohorts. Methylation levels at 34.2% of CpGs are affected by SNPs, and 98% of effects are cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both SNPs and CpGs with meQTLs are overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identify 1520 co-localisations across 1325 unique CpGs and 34 phenotypes …