Gene-centric meta-analyses of 108,912 individuals confirm known body mass index loci and reveal three novel signals

Abstract

Recent genetic association studies have made progress in uncovering components of the genetic architecture of body mass index (BMI). We used the ITMAT-Broad-CARe (IBC) array comprising up to 49,320 single nucleotide polymorphisms (SNPs) across ~2,100 metabolic and cardiovascular-related loci to genotype up to 108,912 individuals of European ancestry (EA), African Americans, Hispanics, and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P<2.40E-06), we identify novel BMI associations in loci TOMM40-APOE-APOC1 (rs2075650, P=2.95E-10), SREBF2 (a sterol regulatory element binding transcription factor gene, rs5996074, P=9.43E-07) and NTRK2 (a BDNF receptor, rs1211166, P=1.04E-06) in the Phase IV meta-analysis. Of ten loci with previous evidence for BMI association represented on IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI associated signals in BDNF and MC4R regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B1 notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics