Patel Roshni A, Weiß Clemens L, Zhu Huisheng, Mostafavi Hakhamanesh, Simons Yuval B, Spence Jeffrey P, Pritchard Jonathan K
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
Genetics. 2025 Apr 17;229(4). doi: 10.1093/genetics/iyae210.
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.
对复杂性状的自然选择难以研究，部分原因在于全基因组关联研究（GWAS）中固有的确定过程。在GWAS中检测与性状相关变异的能力是其频率和效应大小的函数——但对于处于选择中的性状，变异的效应大小决定了针对它的选择强度，从而限制了其频率。认识到GWAS确定过程中固有的偏差，我们建议研究各群体中等位基因频率的联合分布，并以GWAS队列中的频率为条件。在考虑这些条件频率谱之前，我们首先描述了选择和非平衡人口统计学对不同时间方向上等位基因频率动态的影响。然后，我们利用这些结果来理解现实人类人口统计学下的条件频率谱。最后，我们研究了与106个复杂性状相关的GWAS变异的经验条件频率谱，发现了稳定选择或纯化选择的有力证据。我们的结果为多基因评分的可移植性以及通过GWAS确定的变异的其他特性提供了见解，突出了条件频率谱的实用性。
