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JEM: A joint test to estimate the effect of multiple genetic variants on DNA methylation
Author(s) -
Sarnowski Chloé,
Huan Tianxiao,
Jain Deepti,
Liu Chunyu,
Yao Chen,
Joehanes Roby,
Levy Daniel,
Dupuis Josée
Publication year - 2021
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.22369
Subject(s) - genetics , biology , dna methylation , linkage disequilibrium , genetic association , computational biology , trait , framingham heart study , gene , genotype , computer science , single nucleotide polymorphism , gene expression , medicine , framingham risk score , disease , pathology , programming language
Multiple methods have been proposed to aggregate genetic variants in a gene or a region and jointly test their association with a trait of interest. However, these joint tests do not provide estimates of the individual effect of each variant. Moreover, few methods have evaluated the joint association of multiple variants with DNA methylation. We propose a method based on linear mixed models to estimate the joint and individual effect of multiple genetic variants on DNA methylation leveraging genomic annotations. Our approach is flexible, can incorporate covariates and annotation features, and takes into account relatedness and linkage disequilibrium (LD). Our method had correct Type‐I error and overall high power for different simulated scenarios where we varied the number and specificity of functional annotations, number of causal and total genetic variants, frequency of genetic variants, LD, and genetic variant effect. Our method outperformed the family Sequence Kernel Association Test and had more stable estimations of effects than a classical single‐variant linear mixed‐effect model. Applied genome‐wide to the Framingham Heart Study data, our method identified 921 DNA methylation sites influenced by at least one rare or low‐frequency genetic variant located within 50 kilobases (kb) of the DNA methylation site.