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Extreme Polygenicity of Complex Traits Is Explained by Negative Selection

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O'Connor, Luke J., Schoech, Armin P., Hormozdiari, Farhad, Gazal, Steven, Patterson, Nick, Price, Alkes L.·2019·The American Journal of Human Genetics

DOI 10.1016/j.ajhg.2019.07.003PMC PMC6732528

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Abstract

Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection-purging large-effect mutations in these regions-leaves behind common-variant associations in thousands of less critical regions instead. We refer to this phenomenon as flattening. To quantify its effects, we introduce a mathematical definition of polygenicity, the effective number of independently associated SNPs (M e), which describes how evenly the heritability of a trait is spread across the genome. We developed a method, stratified LD fourth moments regression (S-LD4M), to estimate M e, validating that it produces robust estimates in simulations. Analyzing 33 complex traits (average N = 361k), we determined that heritability is spread ∼4× more evenly among common SNPs than among low-frequency SNPs. This difference, together with evolutionary modeling of new mutations, suggests that complex traits would be orders of magnitude less polygenic if not for the influence of negative selection. We also determined that heritability is spread more evenly within functionally important regions in proportion to their heritability enrichment; functionally important regions do not harbor common SNPs with greatly increased causal effect sizes, due to selective constraint. Our results suggest that for most complex traits, the genes and loci with the most critical biological effects often differ from those with the strongest common-variant associations.

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Authors: O'Connor, L. J., Schoech, A. P., Hormozdiari, F., Gazal, S., Patterson, N., & Price, A. L.
Affiliations: Harvard University (US)
Broad Institute (US)
Corresponding author: Price, Alkes L.
ORCID: Schoech, Armin P.
Hormozdiari, Farhad
Gazal, Steven
Patterson, Nick
Price, Alkes L.
Venue: The American Journal of Human Genetics
Publisher: Elsevier BV
Published: 2019-09
Volume: 105
Issue: 3
Pages: 456-476
ISSN: 0002-9297 (ISSN-L)
DOI: 10.1016/j.ajhg.2019.07.003
PMC: PMC6732528
OpenAlex: W2966010373
Cited by: 268
References: 72
Citations by year: 2026: 43 · 2025: 37 · 2024: 40 · 2023: 47 · 2022: 35 · 2021: 34 · 2020: 24 · 2019: 8
FWCI: 15.22
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 186 d)
Locations: The American Journal of Human Genetics (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (R01 MH101244, R01 MH107649, R01 MH109978, T32 HG002295, U01 HG009088, U01 HG009379)
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 › Evolution and Genetic Dynamics
Keywords: polygenicity, complex traits, negative selection, heritability, common SNPs, novel mutations, evolutionary modeling, heritability enrichment, selective constraint
MeSH terms: Humans, Selection, Genetic, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide

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Extreme Polygenicity of Complex Traits Is Explained by Negative Selection

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