Institute for Human Genetics Seminar Series
Host: Jeff Spence, PhD
Speaker: Hakhamanesh Mostafavi, PhD
Title/Position: Assistant Professor
Affiliation: Center for Human Genetics and Genomics, Department of Population Health, NYU Grossman School of Medicine
Website: https://www.mostafavilab.org/
Talk Title: Revisiting gene-sex interaction patterns in complex traits
Date: March 30, 2026
Time: 10:00am-11:00am PT
Location: UCSF Rock Hall, Room RH-102 (in-person attendance strongly encouraged)
Abstract:
Most complex traits differ between men and women, yet how these differences interact with genetic effects remains unclear. Many traits show genetic correlations below one (e.g., SHBG, waist-to-hip ratio), suggesting differences in genetic effects between sexes, but the underlying loci are largely unknown.
Here, we systematically analyze gene-by-sex interactions across quantitative traits in UK Biobank. Consistent with earlier work, we observe pervasive interactions following an amplification pattern, where genetic effects change proportionally between sexes. These patterns are sensitive to phenotype scale, as recently suggested, though this sensitivity varies by trait and is not trivially removed by standard transformations (e.g., log or IRNT). Similar patterns are observed for other environmental factors.
We remain agnostic about whether amplification is biological or a statistical artifact. Nevertheless, we argue that it obscures the loci driving imperfect genetic correlation between sexes, a point largely overlooked in studies of interaction. Under this model, standard interaction tests or sex-stratified GWAS largely rediscover main effects as interactions. Instead, we propose identifying biologically informative loci as outliers from the genome-wide correlation pattern, rather than deviations from equality between sexes. We illustrate this framework using traits including SHBG, LDL, and urate.
Overall, this work refines the interpretation of gene-by-sex effects and suggests a more general framework for studying genetic interactions in complex traits.
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