Biology subjects

Battram, T.

Publications and source records attributed to Battram, T..

5 recordsLinked to original sources

bioRxiv2022

Evaluating the potential benefits and pitfalls of combining protein and expression quantitative trait loci in evidencing drug targets

Molecular quantitative trait loci (molQTL), which can provide functional evidence on the mechanisms underlying phenotype-genotype associations, are increasingly used in drug target validation and safety assessment. In particular, protein abundance QTLs (pQTLs) and gene expression QTLs (eQTLs) are the most commonly used for this purpose. However, questions remain on how to best consolidate results from pQTLs and eQTLs for target validation. In this study, we combined blood cell-derived eQTLs and plasma-derived pQTLs to form QTL pairs representing each gene and its product. We performed a series of enrichment analyses to identify features of QTL pairs that provide consistent evidence for drug targets based on the concordance of the direction of effect of the pQTL and eQTL. We repeated these analyses using eQTLs derived in 49 tissues. We found that 25-30% of blood-cell derived QTL pairs have discordant effects. The difference in tissues of origin for molecular markers contributes to, but is not likely a major source of, this observed discordance. Finally, druggable genes were as likely to have discordant QTL pairs as concordant. Our analyses suggest combining and consolidating evidence from pQTLs and eQTLs for drug target validation is crucial and should be done whenever possible, as many potential drug targets show discordance between the two molecular phenotypes that could be misleading if only one is considered. We also encourage investigating QTL tissue-specificity in target validation applications to help identify reasons for discordance and emphasise that concordance and discordance of QTL pairs across tissues are both informative in target validation.

genetics↗

bioRxiv2020

Exploring the variance in complex traits captured by DNA methylation assays

Following years of epigenome-wide association studies (EWAS), traits analysed to date tend to yield few associations. Reinforcing this observation, we conducted EWAS on 400 traits and 16 yielded at least one association at the conventional significance threshold (P<1x10-7). To investigate why EWAS yield is low, we formally estimated the proportion of phenotypic variation captured by 421,693 blood derived DNA methylation markers (h2EWAS) across all 400 traits. The mean h2EWAS was zero, with evidence for regular cigarette smoking exhibiting the largest association with all markers (h2EWAS=0.42) and the only one surpassing a false discovery rate < 0.1. Though underpowered to determine the h2EWAS value for any one trait, h2EWAS was predictive of the number of EWAS hits across the traits analysed (AUC=0.7). Modelling the contributions of the methylome on a per-site versus a per-region basis gave varied h2EWAS estimates (r=0.47) but neither approach obtained substantially higher model fits across all traits. Our analysis indicates that most complex traits do not heavily associate with markers commonly measured in EWAS within blood. However, it is likely DNA methylation does capture variation in some traits and h2EWAS may be a reasonable way to prioritise traits that are likely to yield associations.

genetics↗

bioRxiv2020

Assortative mating and within-spouse pair comparisons

Comparisons between cohabitating spouses have been proposed as an aetiological design method to reduce confounding and evaluate effects of the shared adulthood environment. However, assortative mating, a phenomenon where individuals select phenotypically similar mates, could distort associations. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological epidemiological research. Using directed acyclic graphs and simulations, we demonstrated that the WSP model can reduce confounding if spouses are correlated for an unmeasured confounder, but that WSP comparisons are susceptible to collider bias induced by assortative mating. Empirical analyses using spouse pairs in UK Biobank found evidence that genetic association estimates from the WSP model are attenuated compared to random pairs for single nucleotide polymorphisms (SNPs) associated with height (shrinkage: 23%; 95% CI 20%, 25%), educational attainment (74%; 95% CI 66%, 81%) and body mass index (23%; 95% CI 14%, 32%) as well as for an alcohol consumption SNP (29%, 95% CI 5%, 46%). Some of these attenuations are likely to reflect effects of assortative mating because height and educational attainment are unlikely to be strongly influenced by the adulthood environment. In contrast, effect estimates of increasing age on coronary artery disease and systolic blood pressure were found to be concordant between random and spouse pairs. Assortative mating is likely to induce phenotypic and genetic structure between an individual and their spouse which complicates the interpretation of spousal comparisons in an aetiological context. A further consideration is that the joint participation of non-independent spouses in cohort studies could induce selection bias.

genetics↗

bioRxiv2018

Bayesian reassessment of the epigenetic architecture of complex traits

1Epigenetic DNA modification is partly under genetic control, and occurs in response to a wide range of environmental exposures. Linking epigenetic marks to clinical outcomes may provide greater insight into underlying molecular processes of disease, assist in the identification of therapeutic targets, and improve risk prediction. Here, we present a statistical approach, based on Bayesian inference, that estimates associations between disease risk and all measured epigenetic probes jointly, automatically controlling for both data structure (including cell-count effects, relatedness, and experimental batch effects) and correlations among probes. We benchmark our approach in simulation study, finding improved estimation of probe associations across a wide range of scenarios over existing approaches. Our method estimates the total proportion of disease risk captured by epigenetic probe variation, and when we applied it to measures of body mass index (BMI) and cigarette consumption behaviour in 5,101 individuals, we find that 66.7% (95% CI 60.0-72.8) of the variation in BMI and 67.7% (95% CI 58.4-76.9) of the variation in cigarette consumption can be captured by methylation array data from whole blood, independent of the variation explained by single nucleotide polymorphism markers. We find novel associations, with smoking behaviour associated with a methylation probe at the MNDA gene with >95% posterior inclusion probability, which is a myeloid cell nuclear differentiation antigen gene previously implicated as a biomarker for inflammation and non-Hodgkin lymphoma risk. We conduct unique genome-wide enrichment analyses, identifying blood cholesterol, lipid transport and sterol metabolism pathways for BMI, and response to xenobiotic stimulus and negative regulation of RNA polymerase II promoter transcription for smoking, all with >95% posterior inclusion probability of having methylation probes with associations >1.5 times larger than the average. Finally, we improve phenotypic prediction in two independent cohorts by 28.7% and 10.2% for BMI and smoking respectively over a LASSO model. These results imply that probe measures may capture large amounts of variance because they are likely a consequence of the phenotype rather than a cause. As a result, 'omics' data may enable accurate characterization of disease progression and identification of individuals who are on a path to disease. Our approach facilitates better understanding of the underlying epigenetic architecture of complex common disease and is applicable to any kind of genomics data.

genomics↗

bioRxiv2018

Appraising the causal relevance of DNA methylation for risk of lung cancer

DNA methylation changes in peripheral blood have been identified in relation to lung cancer risk. However, the causal nature of these associations remains to be fully elucidated. Meta-analysis of four epigenome-wide association studies (918 cases, 918 controls) revealed differential methylation at 16 CpG sites (FDR < 0.05) in relation to lung cancer risk. A two-sample Mendelian randomization analysis, using genetic instruments for methylation at 14 of the 16 CpG sites, and 29,863 cases and 55,586 controls from the TRICL-ILCCO lung cancer consortium, was performed to appraise the causal role of methylation at these sites on lung cancer. This approach provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites play a causal role in lung cancer development, including for cg05575921 AHRR, where methylation is strongly associated with lung cancer risk. Further studies are needed to investigate the causal role played by DNA methylation in lung tissue.

epidemiology↗