Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants

Ju Hyun Park, Mitchell H. Gail, Clarice R. Weinberg, Raymond J. Carroll, Charles C. Chung, Zhaoming Wang, Stephen J. Chanock, Joseph F. Fraumeni, Nilanjan Chatterjee

Research output: Contribution to journalArticlepeer-review


Recent discoveries of hundreds of common susceptibility SNPs from genome-wide association studies provide a unique opportunity to examine population genetic models for complex traits. In this report, we investigate distributions of various population genetic parameters and their interrelationships using estimates of allele frequencies and effect-size parameters for about 400 susceptibility SNPs across a spectrum of qualitative and quantitative traits. We calibrate our analysis by statistical power for detection of SNPs to account for overrepresentation of variants with larger effect sizes in currently known SNPs that are expected due to statistical power for discovery. Across all qualitative disease traits, minor alleles conferred "risk" more often than "protection."Across all traits, an inverse relationship existed between "regression effects" and allele frequencies. Both of these trends were remarkably strong for type I diabetes, a trait that is most likely to be influenced by selection, but were modest for other traits such as human height or late-onset diseases such as type II diabetes and cancers. Across all traits, the estimated effect-size distribution suggested the existence of increasingly large numbers of susceptibility SNPs with decreasingly small effects. For most traits, the set of SNPs with intermediate minor allele frequencies (5-20%) contained an unusually small number of susceptibility loci and explained a relatively small fraction of heritability compared with what would be expected from the distribution of SNPs in the general population. These trends could have several implications for future studies of common and uncommon variants.

Original languageEnglish (US)
Pages (from-to)18026-18031
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 1 2011
Externally publishedYes


  • Genetic prediction
  • Missing heritability
  • Population genetics

ASJC Scopus subject areas

  • General


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