A Novel Statistical Method for Unmasking Sex-Specific Genomics Signatures in Complex Traits

Genotype–phenotype association studies have advanced our understanding of complex traits but often overlook sex-specific genetic signals. The growing awareness of sex-specific influences on human traits and diseases necessitates tailored statistical methodologies to dissect these genetic intricacies. Rare genetic variants play a significant role in disease development, often exhibiting stronger per-allele effects than common variants. In sex-dimorphic analysis, traits are viewed as having two sex-specific subsets rather than being uniformly defined. Existing methods for gene-based analysis of rare variants across multiple traits can identify shared genetic signals but cannot reveal the specific subsets from which significant signals originate. This means that when a significant signal is detected, it remains unclear whether it arises from the male samples, female samples, or both. To address this limitation, we propose SubsetRV, a new methodology capable of identifying genes associated with specific traits or diseases in males, females, or both. SubsetRV can also be applied to broader applications in multiple traits analysis. Simulation studies have demonstrated SubsetRV's reliability, and real data analysis on bipolar disorder and schizophrenia has revealed potential sex-specific genetic signals. SubsetRV offers a valuable tool for identifying sex-specific genetic candidates, aiding in understanding disease mechanisms. An R package for SubsetRV is available on GitHub. It can be accessed directly through this link: https://github.com/Mansouri-S/SubsetRV.