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

Yiran Guo, Matthew B. Lanktree, Kira C. Taylor, Hakon Hakonarson, Leslie A. Lange, Brendan J. Keating, Yiran Guo, Matthew B. Lanktree, Kira C. Taylor, Benjamin P. Fairfax, Clara C. Elbers, John Barnard, Martin Farrall, Sandosh Padmanabhan, Jens Baumert, Berta A. Castillo, Tom R. Gaunt, Yan Gong, Ramakrishnan Rajagopalan, Simon P.R. RomaineMeena Kumari, Suzanne Rafelt, Erin N. Smith, Yun R. Li, Suthesh Sivapalaratnam, Erik P.A. van Iperen, Elizabeth K. Speliotes, Elina Toskala, Li Zhang, Heather M. Ochs-Balcom, Tushar R. Bhangale, Hareesh R. Chandrupatla, Fotios Drenos, Christian Gieger, Jayanta Gupta, Toby Johnson, Marcus E. Kleber, Seiko Makino, Massimo Mangino, Yan Meng, Christopher P. Nelson, James S. Pankow, Nathan Pankratz, Tom S. Price, Jonathan Shaffer, Haiqing Shen, Sam Tischfield, Maciej Tomaszewski, Larry D. Atwood, Kristian M. Bailey, Ashok Balasubramanyam, Clinton T. Baldwin, Hanneke Basart, Florianne Bauer, Elijah R. Behr, Amber L. Beitelshees, Gerald S. Berenson, Shirley A.A. Beresford, Connie R. Bezzina, Deepak L. Bhatt, Jolanda M.A. Boer, Peter S. Braund, Gregory L. Burke, Ben Burkley, Cara Carty, Wei Chen, Robert Clarke, Rhonda M. Cooper-DeHoff, Sean P. Curtis, Paul I.W. de Bakker, Jonas S. de Jong, Christian Delles, Anna F. Dominiczak, David Duggan, Harold I. Feldman, Clement E. Furlong, Mathias M. Gorski, John G. Gums, Robert Hardwick, Claire Hastie, Iris M. Heid, Guan-Hua Huang, Gordon S. Huggins, Steve E. Humphries, Susan A. Kirkland, Mika Kivimaki, Ronald Klein, Barbara E. Klein, William C. Knowler, Kottke-Marchant Kandice Kottke-Marchant, Andrea Z. LaCroix, Taimour Y. Langaee, Mingyao Li, Helen N. Lyon, Steffi Maiwald, Julieann K. Marshall, Amar Mehta, Matthijs F.L. Meijs, Olle Melander, Nuala Meyer, Nandita Mitra, Cliona M. Molony, David A. Morrow, Gurunathan Murugesan, Stephen J. Newhouse, Javier F. Nieto, N. Charlotte Onland-Moret, Willem H. Ouwehand, Jutta Palmen, Carl J. Pepine, Jane Ranchalis, Sylvia E. Rosas, Elisabeth A. Rosenthal, Hubert Scharnagl, Nicholas J. Schork, Pamela J. Schreiner, Tina Shah, Michael Shashaty, Daichi Shimbo, Sathanur R. Srinivasan, Fridtjof Thomas, Martin D. Tobin, Michael Y. Tsai, W. M. Monique Verschuren, Lynne E. Wagenknecht, Bernhard R. Winkelmann, Taylor Young, Salim Yusuf, Mohammad H. Zafarmand, Joseph M. Zmuda, Aeilko H. Zwinderman, Sonia S. Anand, Anthony J. Balmforth, Bernhard O. Boehm, Eric Boerwinkle, Paul R. Burton, Thomas P. Cappola, Juan P. Casas, Mark J. Caulfield, David C. Christiani, Jason Christie, Karen J. Cruickshanks, George Davey-Smith, Karina W. Davidson, Ian N. Day, Pieter A. Doevendans, Gerald W. Dorn, Garret A. FitzGerald, Alistair S. Hall, Aroon D. Hingorani, Joel N. Hirschhorn, Marten H. Hofker, Kees G. Hovingh, Thomas Illig, Yalda Jamshidi, Gail P. Jarvik, Julie A. Johnson, Peter A. Kanetsky, JP Kastelein John JP Kastelein, Wolfgang Koenig, Debbie A. Lawlor, Winfried März, Jeanne McCaffery, Jessica L. Mega, Braxton D. Mitchell, Sarah S. Murray, Jeffery R. O'Connell, Sanjay R. Patel, Annette Peters, Mary Pettinger, Daniel J. Rader, Susan Redline, Muredach P. Reilly, Marc S. Sabatine, Eric E. Schadt, Alan R. Shuldiner, Roy L. Silverstein, Tim D. Spector, Herman A. Taylor, Barbara Thorand, Mieke D. Trip, Hugh Watkins, H. Erich Wichmann, Caroline S. Fox, Struan F.A. Grant, Inga Peter, Philippa J. Talmud, Patricia B. Munroe, James G. Wilson, Julian C. Knight, Nilesh J. Samani, Robert A. Hegele, Folkert W. Asselbergs, Keri L. Monda, Yvonne T. van der Schouw, Ellen W. Demerath, Cisca Wijmenga, Nicholas J. Timpson, Alex P. Reiner, Kari E. North, George J. Papanicolaou, Hakon Hakonarson, Leslie A. Lange, Brendan J. Keating

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58 Scopus citations

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.

Original languageEnglish
Article numberdds396
Pages (from-to)184-201
Number of pages18
JournalHuman Molecular Genetics
Volume22
Issue number1
DOIs
StatePublished - 1 Jan 2013

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