️Episode 218: SIM1 and the multi-ancestry genomics of erectile dysfunction

In this episode of PaperCast Base by Base, we explore A large multi-ancestry GWAS meta-analysis identifies a dominant SIM1-linked locus and multiple genetic connections between electronic health record-defined erectile dysfunction and cardiometabolic, psychiatric, and substance-use traits

Study Highlights: Meta-analysis of 913,194 European and 125,315 African ancestry individuals (136,867 and 51,599 cases respectively) identified 40 independent variants in Europeans, two in Africans, and 51 lead SNPs in cross-ancestry analyses.

The strongest associations mapped to a non-coding region regulating SIM1, led by rs78677597 in Europeans and rs17185536 in Africans and in the cross-ancestry meta-analysis. Genetic correlations and local analyses linked EHR-defined ED with psychiatric disorders, cardiometabolic traits, and substance use traits, and Mendelian randomization inferred bidirectional and directional causal relationships involving obesity, type 2 diabetes, cannabis use disorder and opioid use disorder.

Polygenic risk scores explained up to 9.2% of variance but showed limited predictive power (AUC = 0.52), while gene-based and TWAS analyses highlighted ESR1, CTNNB1 and SLC39A8 and drug-repurposing nominated ER-α antagonists and sulindac as candidates. Conclusion: The study confirms a dominant SIM1-associated genetic signal for erectile dysfunction and reveals a complex, multi-factorial genetic architecture linking ED to cardiometabolic, psychiatric, and substance-use biology

Music: Enjoy the music based on this article at the end of the episode.

Reference: Bright U, Chen Y, Deak JD, Zhou H, Levey DF, Gelernter J. Multi-ancestry investigation of the genomics of erectile dysfunction. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66723-7

License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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