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

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 BarnardBas 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, John Connell, George Davey Smith, Whitehall II Study, WHII 50K Grp, PROCARDIS

    Research output: Contribution to journalArticlepeer-review

    97 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)6-18
    Number of pages13
    JournalAmerican Journal of Human Genetics
    Volume88
    Issue number1
    DOIs
    Publication statusPublished - 7 Jan 2011

    Keywords

    • GENOME-WIDE ASSOCIATION
    • BIOLOGICAL PATHWAYS
    • ADULT HEIGHT
    • LOCI
    • POPULATION
    • INTERLEUKIN-11
    • IDENTIFICATION
    • HERITABILITY
    • TRAITS
    • MICE

    Cite this