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Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants
Open accessAbstract
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.
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“analyses of the distribution of risk allele frequencies across 8 traits argues that if anything minor allele frequencies are skewed to be greater than 0.2, providing strong empirical evidence that rare alleles are not alone responsible53.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [53]
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“No-one doubts that some fraction of the total risk for any complex disease is due to rare alleles, but these studies argue that it is not the majority.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [53]
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“In several instances where SNP-wise GWAS has uncovered few loci, this approach has provided clear evidence for polygenic risk, but it must be recognized that the high variance in estimation of effects results in noisy scores that, although highly significant in the replication sample, only capture over an order of magnitude less of the variance and are far from predictive.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [53]
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Metadata
- Authors
- Park, J.-H., Gail, M. H., Weinberg, C. R., Carroll, R. J., Chung, C. C., Wang, Z., Chanock, S. J., Fraumeni, J. F., & Chatterjee, N.
- Affiliations
- National Institutes of Health (US)
- Texas A&M University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-10-14
- Volume
- 108
- Issue
- 44
- Pages
- 18026-18031
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3207674
- OpenAlex
- W2074498980
- Cited by
- 280
- References
- 31
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 21 · 2023: 23 · 2022: 16 · 2021: 26 · 2020: 21 · 2019: 22 · 2018: 22 · 2017: 24 · 2016: 13 · 2015: 17 · 2014: 19 · 2013: 22 · 2012: 9
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OakTrust (Texas A&M University Libraries) (submittedVersion)
- UTS ePRESS (University of Technology Sydney) (submittedVersion)
- Funders
- National Institutes of Health (5r37ca057030-23)
- National Cancer Institute ((R37-CA057030), U01CA057030, R27-CA057030, R01CA057030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- allele frequency distribution, effect size distribution, genetic risk variants, single nucleotide polymorphisms, statistical power, minor allele frequency, regression effect, type 1 diabetes, type 2 diabetes, human height, cancer susceptibility, heritability, complex traits, population genetics, natural selection
- MeSH terms
- Calibration, Gene Frequency, Humans, Genetic Variation, Polymorphism, Single Nucleotide
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