Bayesian reassessment of the epigenetic architecture of complex traits

Trejo Banos, Daniel; McCartney, Daniel L.; Patxot, Marion; Anchieri, Lucas; Battram, Thomas; Christiansen, Colette; Costeira, Ricardo; Walker, Rosie M.; Morris, Stewart W.; Campbell, Archie; Zhang, Qian; Porteous, David J.; McRae, Allan F.; Wray, Naomi R.; Visscher, Peter M.; Haley, Chris S.; Evans, Kathryn L.; Deary, Ian J.; McIntosh, Andrew M.; Hemani, Gibran; Bell, Jordana T.; Marioni, Riccardo E. and Robinson, Matthew R. (2020). Bayesian reassessment of the epigenetic architecture of complex traits. Nature Communications, 11(1)



Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% CI 71.70–79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3–51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed >1.5 times larger associations with >95% posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.

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