![]() ![]() SNP selection included the use of resequencing data from the SeattleSNPs and National Institute of Environmental Health Sciences (NIEHS) SNP consortia, as well as the International HapMap Consortium, to ensure deeper capture of variation within genes of interest. Ten of the 32 GWAS-identified BMI loci reported to date are included on the IBC array however, many genes with plausible roles in metabolism and in the etiology of obesity, but which have not previously been implicated, are specifically tagged on the array. ![]() Robust associations have been shown on the IBC array for a range of phenotypes including coronary artery disease ( 20, 21), heart failure ( 22, 23), lipids ( 24), height ( 25) and T2D ( 26). Content was selected for the IBC array using data from first waves of CVD-related GWAS results, additional high-priority candidate genes of interest and analysis of cardiovascular, inflammatory and metabolic pathways. We used the ITMAT-Broad-CARe (IBC) array ( 19), also referred to as the CardioChip or the human CVD BeadChip (Illumina, San Diego, CA, USA), which comprises up to 49 320 single nucleotide polymorphisms (SNPs) selected across ∼2100 metabolic and cardiovascular-related loci with variation in most targeted genes captured at a density greater or equal to the standard genome-wide genotyping arrays. In this study we aimed to identify BMI-associated variants that may have been missed by previous studies and sought to confirm previously reported associations. Variants that are rare in individuals of EA but may be more common in other ancestries, or those loci that require environmental exposures that differ by the population subgroup, exist and require approaches beyond standard GWAS in only European-based samples to be identified ( 17, 18). These studies have specifically searched for and identified common genetic variants that associate with BMI in individuals of EA and follow an additive genetic model. As of March 2012, common genetic variants in 32 human loci from genome-wide association studies (GWAS) have been reported to be associated with the body mass index (BMI) in individuals of European ancestry (EA) ( 12– 16). Although sedentary behaviors and poor nutrition certainly contribute to the pathogenesis of obesity, genetic variation also plays a role, with estimated heritability ranging from 40% to as high as 90% ( 9– 11). Obesity increases the risk of metabolic conditions such as cardiovascular diseases (CVDs) ( 4, 5), type 2 diabetes (T2D) ( 6), hyperlipidemia ( 7) as well as certain cancers ( 8). Obesity is a complex disorder affecting more than one-third of the US adult population ( 1, 2) and approximately half a billion people worldwide ( 3). These multi-ethnic meta-analyses expand our knowledge of BMI genetics. 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. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor ( MC4R) regions. ![]() Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. 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 in the Phase IV meta-analysis. 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. 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. Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). ![]()
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