Abstract
Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.
Highlights
Genetic factors contribute to the risk of complex metabolic diseases such as obesity and type 2 diabetes
Out of the significant cis-methylation quantitative trait locus (mQTL), we found 62 single nucleotide polymorphism (SNP) associated with body mass index (BMI), 185 with waist-hip ratio (WHR), 77 with fasting glucose, 62 with fasting insulin, 91 with homeostasis model of beta-cell function (HOMA-B), 49 with homeostasis model insulin resistance (HOMA-IR), 146 with hemoglobin A1c (HbA1c), 85 with total cholesterol, 84 with triglycerides, 197 with high-density lipoprotein (HDL), 67 with low density lipoprotein (LDL) in both our study cohort and consortia data with the same direction of allele effects and with P 0.05 (S8 Table)
These data demonstrate how genetic variants may mediate their effects on metabolic traits via altered DNA methylation in human adipose tissue
Summary
Genetic factors contribute to the risk of complex metabolic diseases such as obesity and type 2 diabetes. Recent studies showed that common genetic variation regulates DNA methylation levels, so called methylation quantitative trait loci (mQTLs) [16,17,18,19,20] Most of these studies have been limited to analyses of ~0.1% of human CpG sites in promoter regions [17,18,19] or restricted to SNPs located within 100 kb from analyzed CpG sites [16]. It remains to be tested if genetic and epigenetic variation interacts throughout the genome in human adipose tissue and subsequently affect gene expression and metabolic traits such as BMI, lipid levels and hemoglobin A1c (HbA1c) in the studied individuals
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