251. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height
- Author
-
Wolfgang Koenig, Patricia B. Munroe, Yvonne T. van der Schouw, Cecilia E. Kim, Yiran Guo, Thomas S. Price, Danish Saleheen, Philippa J. Talmud, Daniel J. Rader, David A. Morrow, Robert A. Hegele, Frank D. Mentch, Jessica L. Mega, Qing Li, Gerald S. Berenson, Andrea Z. LaCroix, Nicholas J. Timpson, Thomas P. Cappola, Paul N. Lanken, Anthonius de Boer, Denis C. Shields, Gary Swergold, Kristian M. Bailey, Martin Farrall, Bernhard O. Boehm, Abiodun Onipinla, Toby Johnson, Sonia S. Anand, Mieke D. Trip, Bonnie Ky, Clara C. Elbers, Eric J. Topol, Dave Nondahl, Nancy K. Sweitzer, Gerald W. Dorn, Edward C. Frackelton, Muhammed Murtaza, Nathan Pankratz, Marc S. Sabatine, Mac Iej Tomaszweski, Nicholas J. Schork, Garret A. FitzGerald, John F. Peden, Hareesh R. Chandrupatla, Simon P. R. Romaine, Martin D. Tobin, Clement E. Furlong, Sam Tischfield, John Barnard, Sandosh Padmanabhan, Jeffrey R. O'Connell, Brendan J. Keating, Kelly A. Thomas, Mary E. Putt, Pamela J. Schreiner, James C. Engert, Erin N. Smith, Debbie A Lawlor, Alistair S. Hall, Sean P. Curtis, Guan-Hua Huang, Santiago Rodriguez, Barbara Thorand, Peter S. Braund, Cisca Wijmenga, Sathanur R. Srinivasan, Aroon D. Hingorani, Marten H. Hofker, Guillaume Lettre, Jolanda M. A. Boer, Alan R. Shuldiner, Jason D. Christie, Dongling Zheng, N. Charlotte Onland-Moret, Maximilian T. Lobmeyer, Philip Howard, Ronald Klein, Hakon Hakonarson, Eric Boerwinkle, Juan P. Casas, Haitao Zhang, Bas J M Peters, James C. Fang, Anuj Goel, Matthew B. Lanktree, N. Klopp, Stephen Newhouse, Elijah R. Behr, Alexandre Montpetit, Braxton D. Mitchell, Chris Wallace, Winfried März, Cara L. Carty, Suthesh Sivapalaratnam, Anders Hamsten, George Davey Smith, Erik P A Van Iperen, Leslie A. Lange, M. Hadi Zafarmand, Wei Chen, Ramakrishnan Rajagopalan, Muredach P. Reilly, Christian Delles, Gail P. Jarvik, W. M. Monique Verschuren, Robert Clarke, Mika Kivimäki, Barry D. Fuchs, Paul I.W. de Bakker, Peter S. Sever, Roy L. Silverstein, Li Zhang, Mark J. Caulfield, Joseph M. Zmuda, Ian N. M. Day, Eric E. Schadt, Anna F. Dominiczak, Radwan Safa, Claire E. Hastie, Kai Wang, Sanjey R. Patel, Halit Ongen, Struan F.A. Grant, W. Craig Johnson, Morris Brown, Folkert W. Asselbergs, Caroline S. Fox, Bernhard R. Winkelmann, John Danesh, Karen J. Cruickshanks, Amar J. Mehta, Patrick M. A. Sleiman, Larry D. Atwood, Jutta Palmen, Haiqing Shen, Joseph T. Glessner, Mingyao Li, Kari E. North, James S. Pankow, Tom R. Gaunt, Sonia Shah, Yan Gong, Barbara E.K. Klein, F. George Otieno, Anke-Hilse Maitland-van der Zee, Christian Gieger, Florianne Bauer, Julie A. Johnson, Quince Gibson, Nuala J. Meyer, Fotios Drenos, Jonathan P. Bradfield, George J. Papanicolaou, Alice Stanton, Yun Li, Olle Melander, Yalda Jamshidi, David Duggan, Jens Baumert, Thomas Illig, Paul Burton, Christopher P. Nelson, Keri L. Monda, Nicole Soranzo, Cliona M. Maloney, Vanessa Marshall, Steve E. Humphries, Diederik E. Grobbee, Karen Nakayama, Gurunathan Murugesan, Charles Kooperberg, David C. Christiani, Suzanne Rafelt, Douglas B. Sawyer, John M. C. Connell, Anthony J. Balmforth, Sarah S. Murray, Deepak L. Bhatt, Kira C. Taylor, Kandice Kottke-Marchant, Christine Suver, Mark Lathrop, Pieter A. Doevendans, Joel N. Hirschhorn, Nilesh J. Samani, Tushar Bhangale, Olaf H. Klungel, Chrysoula Dalgeorgou, Marcus E. Kleber, Susan Redline, Swneke D. Bailey, Alexander P. Reiner, Claire L. Simpson, Other departments, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Pulmonology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
- Subjects
Male ,LOCI ,Genome-wide association study ,Cardiovascular System ,0302 clinical medicine ,Gene Frequency ,Genetics(clinical) ,POPULATION ,Genetics (clinical) ,ADULT HEIGHT ,Genetics ,0303 health sciences ,education.field_of_study ,HERITABILITY ,Hispanic or Latino ,Interleukin-11 ,030220 oncology & carcinogenesis ,Meta-analysis ,BIOLOGICAL PATHWAYS ,Allelic heterogeneity ,Female ,Erratum ,TRAITS ,Adult ,Population ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,White People ,Article ,03 medical and health sciences ,Genetic Heterogeneity ,Asian People ,Humans ,Smad3 Protein ,GENOME-WIDE ASSOCIATION ,education ,Allele frequency ,030304 developmental biology ,Genetic association ,IDENTIFICATION ,Human genetics ,Body Height ,Minor allele frequency ,Black or African American ,MICE ,Evolutionary biology ,Genetic Loci ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10-6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10-8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10-11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait. © 2011 The American Society of Human Genetics.