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. Romaine; Meena 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

doi:10.1093/hmg/dds396

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

Institute of Statistics

Research output: Contribution to journal › Article › peer-review

72 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 language	English
Pages (from-to)	184-201
Number of pages	18
Journal	Human Molecular Genetics
Volume	22
Issue number	1
DOIs	https://doi.org/10.1093/hmg/dds396
State	Published - 1 Jan 2013

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10.1093/hmg/dds396

Cite this

Guo, Y., Lanktree, M. B., Taylor, K. C., Hakonarson, H., Lange, L. A., Keating, B. J., Guo, Y., Lanktree, M. B., Taylor, K. C., Fairfax, B. P., Elbers, C. C., Barnard, J., Farrall, M., Padmanabhan, S., Baumert, J., Castillo, B. A., Gaunt, T. R., Gong, Y., Rajagopalan, R., ... Keating, B. J. (2013). Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. Human Molecular Genetics, 22(1), 184-201. https://doi.org/10.1093/hmg/dds396

@article{2592d9c7b1094cafbb165fa8a06aa131,

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

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.",

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

year = "2013",

month = jan,

day = "1",

doi = "10.1093/hmg/dds396",

language = "English",

volume = "22",

pages = "184--201",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "1",

}

Guo, Y, Lanktree, MB, Taylor, KC, Hakonarson, H, Lange, LA, Keating, BJ, 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, SPR, Kumari, M, Rafelt, S, Smith, EN, Li, YR, Sivapalaratnam, S, van Iperen, EPA, 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, SAA, Bezzina, CR, Bhatt, DL, Boer, JMA, Braund, PS, Burke, GL, Burkley, B, Carty, C, Chen, W, Clarke, R, Cooper-DeHoff, RM, Curtis, SP, de Bakker, PIW, de Jong, JS, Delles, C, Dominiczak, AF, Duggan, D, Feldman, HI, Furlong, CE, Gorski, MM, Gums, JG, Hardwick, R, Hastie, C, Heid, IM, Huang, G-H, Huggins, GS, Humphries, SE, Kirkland, SA, Kivimaki, M, Klein, R, Klein, BE, Knowler, WC, Kandice Kottke-Marchant, K-M, LaCroix, AZ, Langaee, TY, Li, M, Lyon, HN, Maiwald, S, Marshall, JK, Mehta, A, Meijs, MFL, 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, Monique 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, FitzGerald, GA, Hall, AS, Hingorani, AD, Hirschhorn, JN, Hofker, MH, Hovingh, KG, Illig, T, Jamshidi, Y, Jarvik, GP, Johnson, JA, Kanetsky, PA, John JP Kastelein, JPK, 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, SFA, 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 2013, 'Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals', Human Molecular Genetics, vol. 22, no. 1, pp. 184-201. https://doi.org/10.1093/hmg/dds396

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 - Guo, Yiran

AU - Lanktree, Matthew B.

AU - Taylor, Kira C.

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 - Shen, Haiqing

AU - Tischfield, Sam

AU - Tomaszewski, Maciej

AU - Atwood, Larry D.

AU - Bailey, Kristian M.

AU - Balasubramanyam, Ashok

AU - Baldwin, Clinton T.

AU - Basart, Hanneke

AU - Bauer, Florianne

AU - Behr, Elijah R.

AU - Beitelshees, Amber L.

AU - Berenson, Gerald S.

AU - Beresford, Shirley A.A.

AU - Bezzina, Connie R.

AU - Bhatt, Deepak L.

AU - Boer, Jolanda M.A.

AU - Braund, Peter S.

AU - Burke, Gregory L.

AU - Burkley, Ben

AU - Carty, Cara

AU - Chen, Wei

AU - Clarke, Robert

AU - Cooper-DeHoff, Rhonda M.

AU - Curtis, Sean P.

AU - de Bakker, Paul I.W.

AU - de Jong, Jonas S.

AU - Delles, Christian

AU - Dominiczak, Anna F.

AU - Duggan, David

AU - Feldman, Harold I.

AU - Furlong, Clement E.

AU - Gorski, Mathias M.

AU - Gums, John G.

AU - Hardwick, Robert

AU - Hastie, Claire

AU - Heid, Iris M.

AU - Huang, Guan-Hua

AU - Huggins, Gordon S.

AU - Humphries, Steve E.

AU - Kirkland, Susan A.

AU - Kivimaki, Mika

AU - Klein, Ronald

AU - Klein, Barbara E.

AU - Knowler, William C.

AU - Kandice Kottke-Marchant, Kottke-Marchant

AU - LaCroix, Andrea Z.

AU - Langaee, Taimour Y.

AU - Li, Mingyao

AU - Lyon, Helen N.

AU - Maiwald, Steffi

AU - Marshall, Julieann K.

AU - Mehta, Amar

AU - Meijs, Matthijs F.L.

AU - Melander, Olle

AU - Meyer, Nuala

AU - Mitra, Nandita

AU - Molony, Cliona M.

AU - Morrow, David A.

AU - Murugesan, Gurunathan

AU - Newhouse, Stephen J.

AU - Nieto, Javier F.

AU - Onland-Moret, N. Charlotte

AU - Ouwehand, Willem H.

AU - Palmen, Jutta

AU - Pepine, Carl J.

AU - Ranchalis, Jane

AU - Rosas, Sylvia E.

AU - Rosenthal, Elisabeth A.

AU - Scharnagl, Hubert

AU - Schork, Nicholas J.

AU - Schreiner, Pamela J.

AU - Shah, Tina

AU - Shashaty, Michael

AU - Shimbo, Daichi

AU - Srinivasan, Sathanur R.

AU - Thomas, Fridtjof

AU - Tobin, Martin D.

AU - Tsai, Michael Y.

AU - Monique Verschuren, W. M.

AU - Wagenknecht, Lynne E.

AU - Winkelmann, Bernhard R.

AU - Young, Taylor

AU - Yusuf, Salim

AU - Zafarmand, Mohammad H.

AU - Zmuda, Joseph M.

AU - Zwinderman, Aeilko H.

AU - Anand, Sonia S.

AU - Balmforth, Anthony J.

AU - Boehm, Bernhard O.

AU - Boerwinkle, Eric

AU - Burton, Paul R.

AU - Cappola, Thomas P.

AU - Casas, Juan P.

AU - Caulfield, Mark J.

AU - Christiani, David C.

AU - Christie, Jason

AU - Cruickshanks, Karen J.

AU - Davey-Smith, George

AU - Davidson, Karina W.

AU - Day, Ian N.

AU - Doevendans, Pieter A.

AU - Dorn, Gerald W.

AU - FitzGerald, Garret A.

AU - Hall, Alistair S.

AU - Hingorani, Aroon D.

AU - Hirschhorn, Joel N.

AU - Hofker, Marten H.

AU - Hovingh, Kees G.

AU - Illig, Thomas

AU - Jamshidi, Yalda

AU - Jarvik, Gail P.

AU - Johnson, Julie A.

AU - Kanetsky, Peter A.

AU - John JP Kastelein, JP Kastelein

AU - Koenig, Wolfgang

AU - Lawlor, Debbie A.

AU - März, Winfried

AU - McCaffery, Jeanne

AU - Mega, Jessica L.

AU - Mitchell, Braxton D.

AU - Murray, Sarah S.

AU - O'Connell, Jeffery R.

AU - Patel, Sanjay R.

AU - Peters, Annette

AU - Pettinger, Mary

AU - Rader, Daniel J.

AU - Redline, Susan

AU - Reilly, Muredach P.

AU - Sabatine, Marc S.

AU - Schadt, Eric E.

AU - Shuldiner, Alan R.

AU - Silverstein, Roy L.

AU - Spector, Tim D.

AU - Taylor, Herman A.

AU - Thorand, Barbara

AU - Trip, Mieke D.

AU - Watkins, Hugh

AU - Wichmann, H. Erich

AU - Fox, Caroline S.

AU - Grant, Struan F.A.

AU - Peter, Inga

AU - Talmud, Philippa J.

AU - Munroe, Patricia B.

AU - Wilson, James G.

AU - Knight, Julian C.

AU - Samani, Nilesh J.

AU - Hegele, Robert A.

AU - Asselbergs, Folkert W.

AU - Monda, Keri L.

AU - van der Schouw, Yvonne T.

AU - Demerath, Ellen W.

AU - Wijmenga, Cisca

AU - Timpson, Nicholas J.

AU - Reiner, Alex P.

AU - North, Kari E.

AU - Papanicolaou, George J.

AU - Hakonarson, Hakon

AU - Lange, Leslie A.

AU - Keating, Brendan J.

PY - 2013/1/1

Y1 - 2013/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84871223778&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds396

DO - 10.1093/hmg/dds396

M3 - Article

C2 - 23001569

AN - SCOPUS:84871223778

SN - 0964-6906

VL - 22

SP - 184

EP - 201

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 1

ER -

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

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