TY - JOUR
T1 - Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals
AU - Guo, Yiran
AU - Lanktree, Matthew B.
AU - Taylor, Kira C.
AU - Hakonarson, Hakon
AU - Lange, Leslie A.
AU - Keating, Brendan J.
AU - AUTHOR GROUP
AU - Fairfax, Benjamin P.
AU - Elbers, Clara C.
AU - Barnard, John
AU - Farrall, Martin
AU - Padmanabhan, Sandosh
AU - Baumert, Jens
AU - Castillo, Berta A.
AU - Gaunt, Tom R.
AU - Gong, Yan
AU - Rajagopalan, Ramakrishnan
AU - Romaine, Simon P. R.
AU - Kumari, Meena
AU - Rafelt, Suzanne
AU - Smith, Erin N.
AU - Li, Yun R.
AU - Sivapalaratnam, Suthesh
AU - van Iperen, Erik P. A.
AU - Speliotes, Elizabeth K.
AU - Toskala, Elina
AU - Zhang, Li
AU - Ochs-Balcom, Heather M.
AU - Bhangale, Tushar R.
AU - Chandrupatla, Hareesh R.
AU - Drenos, Fotios
AU - Gieger, Christian
AU - Gupta, Jayanta
AU - Johnson, Toby
AU - Kleber, Marcus E.
AU - Makino, Seiko
AU - Mangino, Massimo
AU - Meng, Yan
AU - Nelson, Christopher P.
AU - Pankow, James S.
AU - Pankratz, Nathan
AU - Price, Tom S.
AU - Shaffer, Jonathan
AU - Bezzina, Connie R.
AU - Chen, Wei
AU - de Jong, Jonas S.
AU - Zafarmand, Mohammad H.
AU - Zwinderman, Aeilko H.
AU - Hovingh, Kees G.
AU - Kastelein, John J. P.
AU - Trip, Mieke D.
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - https://doi.org/10.1093/hmg/dds396
DO - https://doi.org/10.1093/hmg/dds396
M3 - Article
C2 - 23001569
SN - 0964-6906
VL - 22
SP - 184
EP - 201
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 1
ER -