Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height


Lanktree, MB; Guo, YR; Murtaza, M; Glessner, JT; Bailey, SD; Onland-Moret, NC; Lettre, G; Ongen, H; Rajagopalan, R; Johnson, T; Shen, HQ; Nelson, CP; Klopp, N; Baumert, J; Padmanabhan, S; Pankratz, N; Pankow, JS; Shah, S; Taylor, K; Barnard, J; Peters, BJ; Maloney, CM; Lobmeyer, MT; Stanton, A; Zafarmand, MH; Romaine, SPR; Mehta, A; van Iperen, EPA; Gong, Y; Price, TS; Smith, EN; Kim, CE; LI, YR; Asselbergs, FW; Atwood, LD; Bailey, KM; Bhatt, D; Bauer, F; Behr, ER; Bhangale, T; Boer, JMA; Boehm, BO; Bradfield, JP; Brown, M; Braund, PS; Burton, PR; Carty, C; Chandrupatla, HR; Chen, W; Connell, J; Dalgeorgou, C; de Boer, A; Drenos, F; Elbers, CC; Fang, JC; Fox, CS; Frackelton, EC; Fuchs, B; Furlong, CE; Gibson, Q; Gieger, C; Goe, A; Grobbee, DE; Hastie, C; Howard, PJ; Huang, GH; Johnson, WC; LI, Q; Kleber, ME; Klein, BEK; Klein, R; Kooperberg, C; Ky, B; Lacroix, A; Lanken, P; Lathrop, M; LI, MY; Marshal, V; Melander, O; Mentch, FD; Meyer, NJ; Monda, KL; Montpetit, A; Murugesan, G; Nakayama, K; Nondah, D; Onipinla, A; Rafelt, S; Newhouse, SJ; Otieno, FG; Patel, SR; Putt, ME; Rodriguez, S; Safa, RN; Sawyer, DB; Schreiner, PJ; Simpson, C; Sivapalaratnam, S; Srinivasan, SR; Suver, C; Swergold, G; Sweitzer, NK; Thomas, KA; Thorand, B; Timpson, NJ; Tischfield, S; Tobin, M; Tomaszweski, M; Verschuren, WMM; Wallace, C; Winkelmann, B; Zhang, HT; Zheng, DL; Zhang, L; Zmuda, JM; Clarke, R; Balmforth, AJ; Danesh, J; Day, IN; Schork, NJ; de Bakker, PIW; Delles, C; Duggan, D; Hingorani, AD; Hirschhorn, JN; Hofker, MH; Humphries, SE; Kivimaki, M; Lawlor, DA; Kottke-Marchant, K; Mega, JL; Mitchell, BD; Morrow, DA; Palmen, J; Redline, S; Shields, DC; Shuldiner, AR; Sleiman, PM; Smith, GD; Farrall, M; Jamshidi, Y; Christiani, DC; Casas, JP; Hall, AS; Doevendans, PA; Christie, JD; Berenson, GS; Murray, SS; Illig, T; Dorn, GW; Cappola, TP; Boerwinkle, E; Sever, P; Rader, DJ; Reilly, MP; Caulfield, M; Talmud, PJ; Topol, E; Engert, JC; Wang, K; Dominiczak, A; Hamsten, A; Curtis, SP; Silverstein, RL; Lange, LA; Sabatine, MS; Trip, M; Saleheen, D; Peden, JF; Cruickshanks, KJ; Marz, W; O'Connell, JR; Klungel, OH; Wijmenga, C; Maitland-van der Zee, AH; Schadt, EE; Johnson, JA; Jarvik, GP; Papanicolaou, GJ; Watkins, H; Grant, SFA; Munroe, PB; North, KE; Samani, NJ; Koenig, W; Gaunt, TR; Anand, SS; van der Schouw, YT; Kumari, M; Soranzo, N; Fitzgerald, GA; Reiner, A; Hegele, RA; Hakonarson, H; Keating, BJ; (2011) Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. American journal of human genetics, 88 (1). pp. 6-18. ISSN 0002-9297 DOI: https://doi.org/10.1016/j.ajhg.2010.11.007

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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 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 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 x 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.

Item Type: Article
Keywords: GENOME-WIDE ASSOCIATION, BIOLOGICAL PATHWAYS, ADULT HEIGHT, LOCI, POPULATION, INTERLEUKIN-11, IDENTIFICATION, HERITABILITY, TRAITS, MICE, Adult, African Americans, genetics, Asian Continental Ancestry Group, genetics, Body Height, genetics, Cardiovascular System, European Continental Ancestry Group, genetics, Female, Gene Frequency, Genetic Heterogeneity, Genetic Loci, Genome-Wide Association Study, Hispanic Americans, genetics, Humans, Interleukin-11, genetics, Male, Polymorphism, Single Nucleotide, Smad3 Protein, genetics
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Research Centre: Centre for Global Non-Communicable Diseases (NCDs)
PubMed ID: 21194676
Web of Science ID: 286501500001
URI: http://researchonline.lshtm.ac.uk/id/eprint/1111

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