Extreme Polygenicity of Complex Traits Is Explained by Negative Selection
Open accessAbstract
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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Genic and LoF intolerant regions are strongly under negative selection.
“Genic and LoF intolerant regions are strongly under negative selection [46].”
From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [46]
In “GWAS Signals of Biologically Important Genes Are Constrained by Negative Selection” (page unavailable), the paper describes loss-of-function-intolerant genes as strongly constrained and links gene-level constraint to negative selection. It finds these genes more strongly constrained than genic SNPs overall, so it does not establish that genic regions generally are strongly under negative selection. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe lack of enrichment of Neandertal associations with psychiatric and neurological diagnostic categories by the present study and McArthur et al. is consistent with previous studies that have shown that many complex traits, and in particular diseases, are targets of purifying selection.
“In general, the lack of an enrichment of Neandertal associations with psychiatric and neurological diagnostic categories by our study and McArthur et al. is consistent with previous studies that have shown that many complex traits, and in particular diseases, are targets of purifying selection [45, 46].”
From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [46]
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A phenome-wide scan reveals convergence of common and rare variant associations
Zhou, D., Zhou, Y., Xu, Y., Meng, R., & Gamazon, E. R. (2023) · Genome Medicine · doi:10.1186/s13073-023-01253-9 · Cited by 15 · see citing works
Maintenance of Complex Trait Variation: Classic Theory and Modern Data
Koch, E. M., & Sunyaev, S. R. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.763363 · Cited by 18 · see citing works
- 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.
- 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)
- 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
- 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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