Biology subjects

Richardson, T. G.

Publications and source records attributed to Richardson, T. G..

9 recordsLinked to original sources

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

Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers of autoimmune and atopic disease

Immune mediated diseases (IMDs) arise from a lack of immune tolerance, causing chronic inflammation. Despite their growing prevalence, targeted therapies to treat IMDs are lacking. Cytokines and their receptors, which mediate inflammation, have been associated with IMD susceptibility. However, the complex signalling networks and multiple cell-types required to orchestrate inflammatory responses have made it difficult to pinpoint specific cytokines and immune cell-types which drive IMDs.\n\nIn this study, we developed an analytical framework which integrates Mendelian randomisation (MR) and multiple-trait colocalization (moloc) analyses to determine putative cell-specific drivers of IMDs. We used MR to determine the likelihood of causal associations between the levels of 10 circulating cytokines/cytokine receptors and 9 IMDs within human populations of European descent. Conservative (single SNP) and liberal (multiple SNP) MR analysis supported a causal role for IL-18 in inflammatory bowel disease (P = 1.17 x 10-4) and eczema/dermatitis (P = 2.81 x 10-3), as well as roles for IL-2r and IL-6R in several IMDs.\n\nWhere associations between cytokines/cytokine receptors and IMDs were discovered using MR, we undertook moloc analyses. This was to assess the likelihood that cytokine/cytokine receptor protein quantitative trait loci (pQTL) and IMD-associated loci share a causal genetic variant along with expression QTL (eQTL) using data from 3 immune cell-types: monocytes, neutrophils and T cells. We found a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis, amongst evidence supporting several other cell-specific inflammatory drivers of IMDs. Our study helps to elucidate causal pathways for the pathogeneses of IMDs which, together with other studies, highlights possible therapeutic targets for their treatment.

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

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↗

bioRxiv2018

Identification of loci where DNA methylation potentially mediate genetic risk of type 1 diabetes

The risk of Type 1 Diabetes (T1D) comprises both genetic and environmental components. We investigated whether genetic susceptibility to T1D could be mediated by changes in DNA methylation, an epigenetic mechanism that potentially plays a role in autoimmune diabetes. Using data from a non-diabetic population comprising blood samples taken at birth (n=844), childhood (n=911) and adolescence (n=907), we evaluated the associations between 65 top GWAS single nucleotide polymorphisms (SNPs) and genome-wide DNA methylation levels. We identified 159 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis), and 7 distal SNP-CpG associations (trans) at birth, childhood, and adolescence. There was also a systematic enrichment for methylation related SNPs to be associated with T1D across the genome, after controlling for genomic characteristics of the SNPs, implying that methylation could either be on the causal pathway to T1D or a non-causal biomarker. Combining the principles of Mendelian Randomization and genetic colocalization analysis, we provided evidence that at 5 loci, ITGB3BP, AFF3, PTPN2, CTSH and CTLA4, DNA methylation is potentially on the causal pathway to T1D.

genomics↗

bioRxiv2017

Conditioning on a collider may induce spurious associations: Do the results of Gale et al. (2017) support a protective effect of neuroticism in population sub-groups?

Introduction Introduction Methods Results Discussion References Gale and colleagues (Gale et al., 2017) examined the association between neuroticism and mortality in a large sample (N > 300,000) drawn from the UK Biobank study (Sudlow et al., 2015). They observed that neuroticism was associated with an increase in all-cause mortality, but that following adjustment for self-rated health neuroticism was associated with a reduction in all-cause mortality. Further analyses stratified on self-rated health suggested that higher neuroticism was associated with reduced mortality only among those with fair or poor self-rated health. The authors conclude that neuroticism may have protective effects among certain sub-groups, and finding that generated substantial interest (TIME, 2017).\n\nThe availability ...

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

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↗