Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation

Abstract

Obesity is a major risk factor for cardiovascular disease, stroke and type 2 diabetes (T2D). One risk factor that couples the adipose tissue accumulation characteristic of obesity to increased T2D risk is abdominal fat accumulation, measured by calculating the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI). Body fat distribution is estimated to have 40-80% heritability, which suggests a strong genetic component. Genetic loci associated with WHRadjBMI identified in genome-wide association studies (GWAS) are predicted to act through adipose tissues, but the molecular mechanisms regulating the accumulation of adipose tissue in various fat depots and their consequences for T2D risk are poorly understood. By integrating multi-omic data with colocalization analysis and Tissue of Action score analysis, we predicted colocalization of 79 genetic loci associated with both T2D adjusted for BMI (T2DadjBMI) and WHRadjBMI. Six of these loci were significantly associated with discordant effects on T2DadjBMI and WHRadjBMI, meaning that the alleles of the lead genetic variants in these loci that were protective for T2D were associated with increased abdominal obesity. Genes in these loci could explain the metabolically healthy obesity and lean insulin resistance (MHO/LIR) phenotype; therefore, we predicted functional genes and tissues of action at the discordant loci, and investigated how expression of these genes was linked to metabolic phenotypes. Through this rigorous consensus analysis, we provide evidence for the hypothesis that the genes encoding Thyroid Adenoma Associated Protein Antisense RNA (THADA-AS), Gypsy Retrotransposon Integrase 1 (GIN1), and Peptidylglycine Alpha-Amidating Monooxygenase (PAM) are involved in molecular mechanisms that uncouple abdominal fat accumulation from risk for T2D.