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https://hdl.handle.net/2440/119436
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Type: | Journal article |
Title: | Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals |
Author: | Guo, Y. Lanktree, M. Taylor, K. Hakonarson, H. Lange, L. Keating, B. Guo, Y. Taylor, K. Fairfax, B. Elbers, C. Barnard, J. Farrall, M. Padmanabhan, S. Baumert, J. Castillo, B. Gaunt, T. Gong, Y. Rajagopalan, R. Romaine, S. Kumari, M. et al. |
Citation: | Human Molecular Genetics, 2013; 22(1):184-201 |
Publisher: | Oxford University Press |
Issue Date: | 2013 |
ISSN: | 0964-6906 1460-2083 |
Statement of Responsibility: | Yiran Guo, Matthew B. Lanktree, Kira C. Taylor, Hakon Hakonarson, Leslie A. Lange ... Deborah Lawlor ... et al. (The IBC 50K SNP array BMI Consortium) |
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. |
Keywords: | IBC 50K SNP array BMI Consortium Humans Body Mass Index Cohort Studies Polymorphism, Single Nucleotide Ethnic Groups |
Rights: | © The Author 2012. Published by Oxford University Press. All rights reserved. |
DOI: | 10.1093/hmg/dds396 |
Published version: | http://dx.doi.org/10.1093/hmg/dds396 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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