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Amplification is the primary mode of gene-by-sex interaction in complex human traits

2023/04/06 by Carrie Zhu, Matthew J. Ming, Jared M. Cole +3 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Psychology · #Evolutionary Psychology and Human Behavior #Genetic Associations and Epidemiology #Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

paper · doi:10.1016/j.xgen.2023.100297

openalex publication_date 2023/04/06 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

Sex differences in complex traits are suspected to be in part due to widespread gene-by-sex interactions (GxSex), but empirical evidence has been elusive. Here, we infer the mixture of ways in which polygenic effects on physiological traits covary between males and females. We find that GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects ("amplification") rather than in the identity of causal variants. Amplification patterns account for sex differences in trait variance. In some cases, testosterone may mediate amplification. Finally, we develop a population-genetic test linking GxSex to contemporary natural selection and find evidence of sexually antagonistic selection on variants affecting testosterone levels. Our results suggest that amplification of polygenic effects is a common mode of GxSex that may contribute to sex differences and fuel their evolution.

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