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Hum Mol Genet. 2013 Jan 1;22(1):184-201. doi: 10.1093/hmg/dds396. Epub 2012 Sep 21.

Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals.

Collaborators (198)

Guo Y, Lanktree MB, Taylor KC, Fairfax BP, Elbers CC, Barnard J, Farrall M, Padmanabhan S, Baumert J, Castillo BA, Gaunt TR, Gong Y, Rajagopalan R, Romaine SP, Kumari M, Rafelt S, Smith EN, Li YR, Sivapalaratnam S, van Iperen EP, Speliotes EK, Toskala E, Zhang L, Ochs-Balcom HM, Bhangale TR, Chandrupatla HR, Drenos F, Gieger C, Gupta J, Johnson T, Kleber ME, Makino S, Mangino M, Meng Y, Nelson CP, Pankow JS, Pankratz N, Price TS, Shaffer J, Shen H, Tischfield S, Tomaszewski M, Atwood LD, Bailey KM, Balasubramanyam A, Baldwin CT, Basart H, Bauer F, Behr ER, Beitelshees AL, Berenson GS, Beresford SA, Bezzina CR, Bhatt DL, Boer JM, Braund PS, Burke GL, Burkley B, Carty C, Chen W, Clarke R, Cooper-DeHoff RM, Curtis SP, de Bakker PI, de Jong JS, Delles C, Dominiczak AF, Duggan D, Feldman HI, Furlong CE, Gorski MM, Gums JG, Hardwick R, Hastie C, Heid IM, Huang GH, Huggins GS, Humphries SE, Kirkland SA, Kivimaki M, Klein R, Klein BE, Knowler WC, Kottke-Marchant K, LaCroix AZ, Langaee TY, Li M, Lyon HN, Maiwald S, Marshall JK, Mehta A, Meijs MF, Melander O, Meyer N, Mitra N, Molony CM, Morrow DA, Murugesan G, Newhouse SJ, Nieto JF, Onland-Moret NC, Ouwehand WH, Palmen J, Pepine CJ, Ranchalis J, Rosas SE, Rosenthal EA, Scharnagl H, Schork NJ, Schreiner PJ, Shah T, Shashaty M, Shimbo D, Srinivasan SR, Thomas F, Tobin MD, Tsai MY, Verschuren WM, Wagenknecht LE, Winkelmann BR, Young T, Yusuf S, Zafarmand MH, Zmuda JM, Zwinderman AH, Anand SS, Balmforth AJ, Boehm BO, Boerwinkle E, Burton PR, Cappola TP, Casas JP, Caulfield MJ, Christiani DC, Christie J, Cruickshanks KJ, Davey-Smith G, Davidson KW, Day IN, Doevendans PA, Dorn GW 2nd, FitzGerald GA, Hall AS, Hingorani AD, Hirschhorn JN, Hofker MH, Hovingh KG, Illig T, Jamshidi Y, Jarvik GP, Johnson JA, Kanetsky PA, Kastelein JJ, Koenig W, Lawlor DA, März W, McCaffery J, Mega JL, Mitchell BD, Murray SS, O'Connell JR, Patel SR, Peters A, Pettinger M, Rader DJ, Redline S, Reilly MP, Sabatine MS, Schadt EE, Shuldiner AR, Silverstein RL, Spector TD, Taylor HA, Thorand B, Trip MD, Watkins H, Wichmann HE, Fox CS, Grant SF, Peter I, Talmud PJ, Munroe PB, Wilson JG, Knight JC, Samani NJ, Hegele RA, Asselbergs FW, Monda KL, van der Schouw YT, Demerath EW, Wijmenga C, Timpson NJ, Reiner AP, North KE, Papanicolaou GJ, Hakonarson H, Lange LA, Keating BJ.

Author information

1
Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104, USA.

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.

PMID:
23001569
PMCID:
PMC3522401
DOI:
10.1093/hmg/dds396
[Indexed for MEDLINE]
Free PMC Article

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