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Presence of multiple independent effects in risk loci of common complex human diseases.

Abstract

Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases.

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    • Authors

    Ke X

    Institution

    Medical Research Council Centre of Epidemiology for Child Health, Institute of Child Health, University College London, UK. x.ke@ucl.ac.uk

    Source

    American journal of human genetics 91:1 2012 Jul 13 pg 185-92

    MeSH

    Arthritis, Rheumatoid
    Case-Control Studies
    Crohn Disease
    Diabetes Mellitus, Type 1
    Diabetes Mellitus, Type 2
    Gene Frequency
    Genetic Loci
    Genetic Predisposition to Disease
    HapMap Project
    Humans
    Polymorphism, Single Nucleotide
    Risk

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22770979