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

Authors:
Dr Stephen J Newhouse, BSc, MSc, PhD
Dr Stephen J Newhouse, BSc, MSc, PhD
Clinical Pharmacology and The Genome Centre
Lodnon | United Kingdom
Dr Stephen Newhouse, BSc, MSc, PhD
Dr Stephen Newhouse, BSc, MSc, PhD
Institute of Psychiatry
London | United Kingdom
Matthew B Lanktree Yiran Guo Muhammed Murtaza Joseph T Glessner Swneke D Bailey N Charlotte Onland-Moret Guillaume Lettre Halit Ongen Ramakrishnan Rajagopalan Toby Johnson Haiqing Shen Christopher P Nelson Norman Klopp Jens Baumert Sandosh Padmanabhan Nathan Pankratz James S Pankow Sonia Shah Kira Taylor John Barnard Bas J Peters Cliona M Maloney Maximilian T Lobmeyer Alice Stanton M Hadi Zafarmand Simon P R Romaine Amar Mehta Erik P A van Iperen Yan Gong Tom S Price Erin N Smith Cecilia E Kim Yun R Li Folkert W Asselbergs Larry D Atwood Kristian M Bailey Deepak Bhatt Florianne Bauer Elijah R Behr Tushar Bhangale Jolanda M A Boer Bernhard O Boehm Jonathan P Bradfield Morris Brown Peter S Braund Paul R Burton Cara Carty Hareesh R Chandrupatla Wei Chen John Connell Chrysoula Dalgeorgou Anthonius de Boer Fotios Drenos Clara C Elbers James C Fang Caroline S Fox Edward C Frackelton Barry Fuchs Clement E Furlong Quince Gibson Christian Gieger Anuj Goel Diederik E Grobbee Claire Hastie Philip J Howard Guan-Hua Huang W Craig Johnson Qing Li Marcus E Kleber Barbara E K Klein Ronald Klein Charles Kooperberg Bonnie Ky Andrea Lacroix Paul Lanken Mark Lathrop Mingyao Li Vanessa Marshall Olle Melander Frank D Mentch Nuala J Meyer Keri L Monda Alexandre Montpetit Gurunathan Murugesan Karen Nakayama Dave Nondahl Abiodun Onipinla Suzanne Rafelt F George Otieno Sanjey R Patel Mary E Putt Santiago Rodriguez Radwan N Safa Douglas B Sawyer Pamela J Schreiner Claire Simpson Suthesh Sivapalaratnam Sathanur R Srinivasan Christine Suver Gary Swergold Nancy K Sweitzer Kelly A Thomas Barbara Thorand Nicholas J Timpson Sam Tischfield Martin Tobin Maciej Tomaszewski Maciej Tomaszweski W M Monique Verschuren Chris Wallace Bernhard Winkelmann Haitao Zhang Dongling Zheng Li Zhang Joseph M Zmuda Robert Clarke Anthony J Balmforth John Danesh Ian N Day Nicholas J Schork Paul I W de Bakker Christian Delles David Duggan Aroon D Hingorani Joel N Hirschhorn Marten H Hofker Steve E Humphries Mika Kivimaki Debbie A Lawlor Kandice Kottke-Marchant Jessica L Mega Braxton D Mitchell David A Morrow Jutta Palmen Susan Redline Denis C Shields Alan R Shuldiner Patrick M Sleiman George Davey Smith Martin Farrall Yalda Jamshidi David C Christiani Juan P Casas Alistair S Hall Pieter A Doevendans Jason D Christie Gerald S Berenson Sarah S Murray Thomas Illig Gerald W Dorn Thomas P Cappola Eric Boerwinkle Peter Sever Daniel J Rader Muredach P Reilly Mark Caulfield Philippa J Talmud Eric Topol James C Engert Kai Wang Anna Dominiczak Anders Hamsten Sean P Curtis Roy L Silverstein Leslie A Lange Marc S Sabatine Mieke Trip Danish Saleheen John F Peden Karen J Cruickshanks Winfried März Jeffrey R O'Connell Olaf H Klungel Cisca Wijmenga Anke Hilse Maitland-van der Zee Eric E Schadt Julie A Johnson Gail P Jarvik George J Papanicolaou Struan F A Grant Patricia B Munroe Kari E North Nilesh J Samani Wolfgang Koenig Tom R Gaunt Sonia S Anand Yvonne T van der Schouw Nicole Soranzo Garret A Fitzgerald Alex Reiner Robert A Hegele Hakon Hakonarson Brendan J Keating

Am J Hum Genet 2011 Jan 30;88(1):6-18. Epub 2010 Dec 30.

Department of Medicine and Biochemistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.

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.

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Source
http://dx.doi.org/10.1016/j.ajhg.2010.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014369PMC
January 2011
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