PMID- 23001569 OWN - NLM STAT- MEDLINE DCOM- 20130515 LR - 20240410 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 22 IP - 1 DP - 2013 Jan 1 TI - Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. PG - 184-201 LID - 10.1093/hmg/dds396 [doi] 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. FAU - Guo, Yiran AU - Guo Y AD - Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104, USA. FAU - Lanktree, Matthew B AU - Lanktree MB FAU - Taylor, Kira C AU - Taylor KC FAU - Hakonarson, Hakon AU - Hakonarson H FAU - Lange, Leslie A AU - Lange LA FAU - Keating, Brendan J AU - Keating BJ CN - IBC 50K SNP array BMI Consortium LA - eng GR - MC_U137686857/MRC_/Medical Research Council/United Kingdom GR - G0100222/MRC_/Medical Research Council/United Kingdom GR - R37 AG011099/AG/NIA NIH HHS/United States GR - P01 HL088117/HL/NHLBI NIH HHS/United States GR - K23 DK097307/DK/NIDDK NIH HHS/United States GR - K24 HL084034/HL/NHLBI NIH HHS/United States GR - R01 HL088577/HL/NHLBI NIH HHS/United States GR - P30 DK017047/DK/NIDDK NIH HHS/United States GR - MR/K013351/1/MRC_/Medical Research Council/United Kingdom GR - RG/07/008/23674/BHF_/British Heart Foundation/United Kingdom GR - G19/35/MRC_/Medical Research Council/United Kingdom GR - G8802774/MRC_/Medical Research Council/United Kingdom GR - MR/K006584/1/MRC_/Medical Research Council/United Kingdom GR - CAPMC/CIHR/Canada GR - R01 AG021917/AG/NIA NIH HHS/United States GR - PG/09/022/26739/BHF_/British Heart Foundation/United Kingdom GR - R01 AG016592/AG/NIA NIH HHS/United States GR - G0902037/MRC_/Medical Research Council/United Kingdom GR - U01 DK057136/DK/NIDDK NIH HHS/United States GR - P30 DK072488/DK/NIDDK NIH HHS/United States GR - G0600705/MRC_/Medical Research Council/United Kingdom GR - 090532/WT_/Wellcome Trust/United Kingdom GR - R01 HL111614/HL/NHLBI NIH HHS/United States GR - G9521010/MRC_/Medical Research Council/United Kingdom GR - P50 HL081011/HL/NHLBI NIH HHS/United States GR - U01 DK057131/DK/NIDDK NIH HHS/United States GR - R01 HL091099/HL/NHLBI NIH HHS/United States GR - K07 CA136969/CA/NCI NIH HHS/United States GR - L30 HL097857/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120921 PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 SB - IM MH - *Body Mass Index MH - Cohort Studies MH - Ethnicity/genetics MH - Humans MH - Polymorphism, Single Nucleotide PMC - PMC3522401 FIR - Guo, Yiran IR - Guo Y FIR - Lanktree, Matthew B IR - Lanktree MB FIR - Taylor, Kira C IR - Taylor KC FIR - Fairfax, Benjamin P IR - Fairfax BP FIR - Elbers, Clara C IR - Elbers CC FIR - Barnard, John IR - Barnard J FIR - Farrall, Martin IR - Farrall M FIR - Padmanabhan, Sandosh IR - Padmanabhan S FIR - Baumert, Jens IR - Baumert J FIR - Castillo, Berta A IR - Castillo BA FIR - Gaunt, Tom R IR - Gaunt TR FIR - Gong, Yan IR - Gong Y FIR - Rajagopalan, Ramakrishnan IR - Rajagopalan R FIR - Romaine, Simon P R IR - Romaine SP FIR - Kumari, Meena IR - Kumari M FIR - Rafelt, Suzanne IR - Rafelt S FIR - Smith, Erin N IR - Smith EN FIR - Li, Yun R IR - Li YR FIR - Sivapalaratnam, Suthesh IR - Sivapalaratnam S FIR - van Iperen, Erik P A IR - van Iperen EP FIR - Speliotes, Elizabeth K IR - Speliotes EK FIR - Toskala, Elina IR - Toskala E FIR - Zhang, Li IR - Zhang L FIR - Ochs-Balcom, Heather M IR - Ochs-Balcom HM FIR - Bhangale, Tushar R IR - Bhangale TR FIR - Chandrupatla, Hareesh R IR - Chandrupatla HR FIR - Drenos, Fotios IR - Drenos F FIR - Gieger, Christian IR - Gieger C FIR - Gupta, Jayanta IR - Gupta J FIR - Johnson, Toby IR - Johnson T FIR - Kleber, Marcus E IR - Kleber ME FIR - Makino, Seiko IR - Makino S FIR - Mangino, Massimo IR - Mangino M FIR - Meng, Yan IR - Meng Y FIR - Nelson, Christopher P IR - Nelson CP FIR - Pankow, James S IR - Pankow JS FIR - Pankratz, Nathan IR - Pankratz N FIR - Price, Tom S IR - Price TS FIR - Shaffer, Jonathan IR - Shaffer J FIR - Shen, Haiqing IR - Shen H FIR - Tischfield, Sam IR - Tischfield S FIR - Tomaszewski, Maciej IR - Tomaszewski M FIR - Atwood, Larry D IR - Atwood LD FIR - Bailey, Kristian M IR - Bailey KM FIR - Balasubramanyam, Ashok IR - Balasubramanyam A FIR - Baldwin, Clinton T IR - Baldwin CT FIR - Basart, Hanneke IR - Basart H FIR - Bauer, Florianne IR - Bauer F FIR - Behr, Elijah R IR - Behr ER FIR - Beitelshees, Amber L IR - Beitelshees AL FIR - Berenson, Gerald S IR - Berenson GS FIR - Beresford, Shirley A A IR - Beresford SA FIR - Bezzina, Connie R IR - Bezzina CR FIR - Bhatt, Deepak L IR - Bhatt DL FIR - Boer, Jolanda M A IR - Boer JM FIR - Braund, Peter S IR - Braund PS FIR - Burke, Gregory L IR - Burke GL FIR - Burkley, Ben IR - Burkley B FIR - Carty, Cara IR - Carty C FIR - Chen, Wei IR - Chen W FIR - Clarke, Robert IR - Clarke R FIR - Cooper-DeHoff, Rhonda M IR - Cooper-DeHoff RM FIR - Curtis, Sean P IR - Curtis SP FIR - de Bakker, Paul I W IR - de Bakker PI FIR - de Jong, Jonas S IR - de Jong JS FIR - Delles, Christian IR - Delles C FIR - Dominiczak, Anna F IR - Dominiczak AF FIR - Duggan, David IR - Duggan D FIR - Feldman, Harold I IR - Feldman HI FIR - Furlong, Clement E IR - Furlong CE FIR - Gorski, Mathias M IR - Gorski MM FIR - Gums, John G IR - Gums JG FIR - Hardwick, Robert IR - Hardwick R FIR - Hastie, Claire IR - Hastie C FIR - Heid, Iris M IR - Heid IM FIR - Huang, Guan-Hua IR - Huang GH FIR - Huggins, Gordon S IR - Huggins GS FIR - Humphries, Steve E IR - Humphries SE FIR - Kirkland, Susan A IR - Kirkland SA FIR - Kivimaki, Mika IR - Kivimaki M FIR - Klein, Ronald IR - Klein R FIR - Klein, Barbara E IR - Klein BE FIR - Knowler, William C IR - Knowler WC FIR - Kottke-Marchant, Kandice IR - Kottke-Marchant K FIR - LaCroix, Andrea Z IR - LaCroix AZ FIR - Langaee, Taimour Y IR - Langaee TY FIR - Li, Mingyao IR - Li M FIR - Lyon, Helen N IR - Lyon HN FIR - Maiwald, Steffi IR - Maiwald S FIR - Marshall, Julieann K IR - Marshall JK FIR - Mehta, Amar IR - Mehta A FIR - Meijs, Matthijs F L IR - Meijs MF FIR - Melander, Olle IR - Melander O FIR - Meyer, Nuala IR - Meyer N FIR - Mitra, Nandita IR - Mitra N FIR - Molony, Cliona M IR - Molony CM FIR - Morrow, David A IR - Morrow DA FIR - Murugesan, Gurunathan IR - Murugesan G FIR - Newhouse, Stephen J IR - Newhouse SJ FIR - Nieto, Javier F IR - Nieto JF FIR - Onland-Moret, N Charlotte IR - Onland-Moret NC FIR - Ouwehand, Willem H IR - Ouwehand WH FIR - Palmen, Jutta IR - Palmen J FIR - Pepine, Carl J IR - Pepine CJ FIR - Ranchalis, Jane IR - Ranchalis J FIR - Rosas, Sylvia E IR - Rosas SE FIR - Rosenthal, Elisabeth A IR - Rosenthal EA FIR - Scharnagl, Hubert IR - Scharnagl H FIR - Schork, Nicholas J IR - Schork NJ FIR - Schreiner, Pamela J IR - Schreiner PJ FIR - Shah, Tina IR - Shah T FIR - Shashaty, Michael IR - Shashaty M FIR - Shimbo, Daichi IR - Shimbo D FIR - Srinivasan, Sathanur R IR - Srinivasan SR FIR - Thomas, Fridtjof IR - Thomas F FIR - Tobin, Martin D IR - Tobin MD FIR - Tsai, Michael Y IR - Tsai MY FIR - Verschuren, W M Monique IR - Verschuren WM FIR - Wagenknecht, Lynne E IR - Wagenknecht LE FIR - Winkelmann, Bernhard R IR - Winkelmann BR FIR - Young, Taylor IR - Young T FIR - Yusuf, Salim IR - Yusuf S FIR - Zafarmand, Mohammad H IR - Zafarmand MH FIR - Zmuda, Joseph M IR - Zmuda JM FIR - Zwinderman, Aeilko H IR - Zwinderman AH FIR - Anand, Sonia S IR - Anand SS FIR - Balmforth, Anthony J IR - Balmforth AJ FIR - Boehm, Bernhard O IR - Boehm BO FIR - Boerwinkle, Eric IR - Boerwinkle E FIR - Burton, Paul R IR - Burton PR FIR - Cappola, Thomas P IR - Cappola TP FIR - Casas, Juan P IR - Casas JP FIR - Caulfield, Mark J IR - Caulfield MJ FIR - Christiani, David C IR - Christiani DC FIR - Christie, Jason IR - Christie J FIR - Cruickshanks, Karen J IR - Cruickshanks KJ FIR - Davey-Smith, George IR - Davey-Smith G FIR - Davidson, Karina W IR - Davidson KW FIR - Day, Ian N IR - Day IN FIR - Doevendans, Pieter A IR - Doevendans PA FIR - Dorn, Gerald W 2nd IR - Dorn GW 2nd FIR - FitzGerald, Garret A IR - FitzGerald GA FIR - Hall, Alistair S IR - Hall AS FIR - Hingorani, Aroon D IR - Hingorani AD FIR - Hirschhorn, Joel N IR - Hirschhorn JN FIR - Hofker, Marten H IR - Hofker MH FIR - Hovingh, Kees G IR - Hovingh KG FIR - Illig, Thomas IR - Illig T FIR - Jamshidi, Yalda IR - Jamshidi Y FIR - Jarvik, Gail P IR - Jarvik GP FIR - Johnson, Julie A IR - Johnson JA FIR - Kanetsky, Peter A IR - Kanetsky PA FIR - Kastelein, John J P IR - Kastelein JJ FIR - Koenig, Wolfgang IR - Koenig W FIR - Lawlor, Debbie A IR - Lawlor DA FIR - Marz, Winfried IR - Marz W FIR - McCaffery, Jeanne IR - McCaffery J FIR - Mega, Jessica L IR - Mega JL FIR - Mitchell, Braxton D IR - Mitchell BD FIR - Murray, Sarah S IR - Murray SS FIR - O'Connell, Jeffery R IR - O'Connell JR FIR - Patel, Sanjay R IR - Patel SR FIR - Peters, Annette IR - Peters A FIR - Pettinger, Mary IR - Pettinger M FIR - Rader, Daniel J IR - Rader DJ FIR - Redline, Susan IR - Redline S FIR - Reilly, Muredach P IR - Reilly MP FIR - Sabatine, Marc S IR - Sabatine MS FIR - Schadt, Eric E IR - Schadt EE FIR - Shuldiner, Alan R IR - Shuldiner AR FIR - Silverstein, Roy L IR - Silverstein RL FIR - Spector, Tim D IR - Spector TD FIR - Taylor, Herman A IR - Taylor HA FIR - Thorand, Barbara IR - Thorand B FIR - Trip, Mieke D IR - Trip MD FIR - Watkins, Hugh IR - Watkins H FIR - Wichmann, H-Erich IR - Wichmann HE FIR - Fox, Caroline S IR - Fox CS FIR - Grant, Struan F A IR - Grant SF FIR - Peter, Inga IR - Peter I FIR - Talmud, Philippa J IR - Talmud PJ FIR - Munroe, Patricia B IR - Munroe PB FIR - Wilson, James G IR - Wilson JG FIR - Knight, Julian C IR - Knight JC FIR - Samani, Nilesh J IR - Samani NJ FIR - Hegele, Robert A IR - Hegele RA FIR - Asselbergs, Folkert W IR - Asselbergs FW FIR - Monda, Keri L IR - Monda KL FIR - van der Schouw, Yvonne T IR - van der Schouw YT FIR - Demerath, Ellen W IR - Demerath EW FIR - Wijmenga, Cisca IR - Wijmenga C FIR - Timpson, Nicholas J IR - Timpson NJ FIR - Reiner, Alex P IR - Reiner AP FIR - North, Kari E IR - North KE FIR - Papanicolaou, George J IR - Papanicolaou GJ FIR - Hakonarson, Hakon IR - Hakonarson H FIR - Lange, Leslie A IR - Lange LA FIR - Keating, Brendan J IR - Keating BJ EDAT- 2012/09/25 06:00 MHDA- 2013/05/17 06:00 PMCR- 2014/01/01 CRDT- 2012/09/25 06:00 PHST- 2012/09/25 06:00 [entrez] PHST- 2012/09/25 06:00 [pubmed] PHST- 2013/05/17 06:00 [medline] PHST- 2014/01/01 00:00 [pmc-release] AID - dds396 [pii] AID - 10.1093/hmg/dds396 [doi] PST - ppublish SO - Hum Mol Genet. 2013 Jan 1;22(1):184-201. doi: 10.1093/hmg/dds396. Epub 2012 Sep 21.