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. 2025 Apr 17;229(4):iyae210.
doi: 10.1093/genetics/iyae210.

Characterizing selection on complex traits through conditional frequency spectra

Roshni A Patel  1   2 , Clemens L Weiß  3 , Huisheng Zhu  4 , Hakhamanesh Mostafavi  5   6 , Yuval B Simons  7 , Jeffrey P Spence  1 , Jonathan K Pritchard  1   4
Affiliations

Characterizing selection on complex traits through conditional frequency spectra

Roshni A Patel et al. Genetics. .

Abstract

Natural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of its frequency and effect size - but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. Recognizing the biases inherent to GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insights into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.

Keywords: GWAS; allele frequency spectra; complex traits; polygenic scores; selection.

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Conflict of interest statement

Conflicts of interest: The author(s) declare no conflicts of interest.

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References

    1. International IBD Genetics Consortium (IIBDGC), Agliardi C, Alfredsson L, Alizadeh M, Anderson C, Andrews R, Søndergaard HB, Baker A, Band G, Baranzini SE. 2013. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 45:1353–1360. doi:10.1038/ng.2770. - DOI - PMC - PubMed
    1. Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, Weeks EM, Wang M, Hindy G, Zhou W, et al. . 2022. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 54:1803–1815. doi:10.1038/s41588-022-01233-6. - DOI - PMC - PubMed
    1. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, Clark AG, Donnelly P, Eichler EE, et al. . 2015. A global reference for human genetic variation. Nature. 526:68–74. doi:10.1038/nature15393. - DOI - PMC - PubMed
    1. Baharian S, Gravel S. 2018. On the decidability of population size histories from finite allele frequency spectra. Theor Popul Biol. 120:42–51. doi:10.1016/j.tpb.2017.12.008. - DOI - PubMed
    1. Baumdicker F, Bisschop G, Goldstein D, Gower G, Ragsdale AP, Tsambos G, Zhu S, Eldon B, Ellerman EC, Galloway JG, et al. . 2022. Efficient ancestry and mutation simulation with msprime 1.0. Genetics. 220:iyab229. doi:10.1093/genetics/iyab229. - DOI - PMC - PubMed

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