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Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals.
Monday,2013-01-14 16:58 America/Los_Angeles — poolea2
| Title | Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. |
| Publication Type | Journal Article |
| Year of Publication | 2013 |
| Authors | Guo, Y, Lanktree, MB, Taylor, KC, Hakonarson, H, Lange, LA, Keating, BJ |
| Corporate/Institutional Authors | IBC 50K SNP array BMI Consortium, |
| Journal | Hum Mol Genet |
| Volume | 22 |
| Issue | 1 |
| Pagination | 184-201 |
| Date Published | 2013 Jan 01 |
| ISSN | 1460-2083 |
| Keywords | Body Mass Index, Cohort Studies, Ethnic Groups, Humans, Polymorphism, Single Nucleotide |
| Abstract | <p>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.</p> |
| DOI | 10.1093/hmg/dds396 |
| Alternate Journal | Hum. Mol. Genet. |
| PubMed ID | 23001569 |
| PubMed Central ID | PMC3522401 |
| Grant List | G9521010 / / Medical Research Council / United Kingdom PG/09/022/26739 / / British Heart Foundation / United Kingdom G0600705 / / Medical Research Council / United Kingdom G19/35 / / Medical Research Council / United Kingdom G0100222 / / Medical Research Council / United Kingdom R37 AG011099 / AG / NIA NIH HHS / United States R01 AG021917 / AG / NIA NIH HHS / United States G8802774 / / Medical Research Council / United Kingdom G0902037 / / Medical Research Council / United Kingdom HHSN268200960009C) / / PHS HHS / United States R01 AG016592 / AG / NIA NIH HHS / United States MC_U137686857 / / Medical Research Council / United Kingdom U01 DK057136 / DK / NIDDK NIH HHS / United States P01 HL088117 / HL / NHLBI NIH HHS / United States K23 DK097307 / DK / NIDDK NIH HHS / United States / / Canadian Institutes of Health Research / Canada P30 DK072488 / DK / NIDDK NIH HHS / United States K24 HL084034 / HL / NHLBI NIH HHS / United States 090532 / / Wellcome Trust / United Kingdom R01 HL111614 / HL / NHLBI NIH HHS / United States P50 HL081011 / HL / NHLBI NIH HHS / United States U01 DK057131 / DK / NIDDK NIH HHS / United States R01 HL091099 / HL / NHLBI NIH HHS / United States R01 HL088577 / HL / NHLBI NIH HHS / United States MR/K006584/1 / / Medical Research Council / United Kingdom K07 CA136969 / CA / NCI NIH HHS / United States L30 HL097857 / HL / NHLBI NIH HHS / United States P30 DK017047 / DK / NIDDK NIH HHS / United States RG/07/008/23674 / / British Heart Foundation / United Kingdom RG/10/12/28456 / / British Heart Foundation / United Kingdom |