title: 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 the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 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 translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (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 SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.
authors.affiliation: Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Lanktree
authors.forename: Kira C
authors.initials: KC
authors.lastname: Taylor
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
mesh_terms: D015992:Body Mass Index; D015331:Cohort Studies; D005006:Ethnicity / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide