This project actually started as one trying to understand the impact of sex-stratification on expression outlier discovery. We saw a small change (0.1-0.2% genes changed outlier status), but one that indicated a reduction in false outliers.
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We then wanted to understand the functional impact of rare variants, both with and without sex-stratification. In males, but not females, we found that rare variants had a stronger functional impact when on the X-chromosome as compared to the autosomes.
We (Taibo Li) then trained a Bayesian model to predict variants with different functional effects by sex. We identified 753 variants with a predicted sex bias across 464 genes.
Sex differences are often overstated, so I want to be clear. Males and females are more similar than they are different. We identified just 0.04% of total rare variants to have a difference by sex.
We show these sex-biased variants are enriched for being in pharmacogenes with adverse-drug reactions, including those with known sex-biased adverse drug reactions. To my knowledge no study had previously looked at pharmacogenetic implications of sex-biased rare variants.
Many thanks to my second author Taibo Li, who was wonderful to work with and even helped finish this project even after returning to the MD side of his MD-PhD. I am also grateful for the mentorship of @sbmontgom.bsky.social throughout this project.
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