Better together against genetic heterogeneity: A sex-combined joint main and interaction analysis of 290 quantitative traits in the UK Biobank

Genetic effects can be sex-specific, particularly for traits such as testosterone, a sex hormone. While sex-stratified analysis provides easily interpretable sex-specific effect size estimates, the presence of sex-differences in SNP effect implies a SNP×sex interaction. This suggests the usage of the often overlooked joint test, testing for an SNP’s main and SNP×sex interaction effects simultaneously. Notably, even without individual-level data, the joint test statistic can be derived from sex-stratified summary statistics through an omnibus meta-analysis. Utilizing the available sex-stratified summary statistics of the UK Biobank, we performed such omnibus meta-analyses for 290 quantitative traits. Results revealed that this approach is robust to genetic effect heterogeneity and can outperform the traditional sex-stratified or sex-combined main effect-only tests. Therefore, we advocate using the omnibus meta-analysis that captures both the main and interaction effects. Subsequent sex-stratified analysis should be conducted for sex-specific effect size estimation and interpretation.