| Title: | Sex differences in polygenic risk for sex-biased brain disorders: Associations with diagnostic status and brain age gap |
| Journal: | Translational Psychiatry |
| Published: | 25 Aug 2026 |
| DOI: | https://doi.org/10.1038/s41398-026-04220-1 |
| URL: | http://dx.doi.org/10.1038/s41398-026-04220-1 |
Publication 20907
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Abstract
Biological sex influences the prevalence and progression of several brain disorders, yet it remains unclear whether genetic risk interacts with sex in relation to case-control status or brain health. Using data from up to 220 836 females and 187 651 males in the UK Biobank (aged 39-81), we assessed how sex and polygenic risk scores (PRSs) for major depressive disorder (PRSMDD), Alzheimer's disease (PRSAD), schizophrenia (PRSSCZ), and Parkinson's disease (PRSPD) relate to case-control status and MRI-derived brain age gap (BAG) as a proxy of brain health. We tested for sex differences in PRSs and performed regression analyses examining associations between sex, PRSs, and both outcomes. We then compared models with sex-pooled or sex-specific PRSs to explore whether sex-specific PRSs improve predictive accuracy. PRSSCZ was higher in females, while no other PRSs differed by sex. A significant PRSAD-by-sex interaction revealed weaker associations with AD case-control status in males than females. Sex-pooled models outperformed sex-specific models for case-control status, apart from PRSAD, where the female-only PRSAD model outperformed the sex-pooled model. No sex-by-PRS interactions were significantly associated with BAG. However, male sex, higher PRSMDD, higher PRSAD, and lower PRSPD were associated with higher BAG, indicative of an older brain age. BAG model performance did not differ between sex-pooled and sex-specific PRS models. In summary, while sex-specific PRSs currently offer limited value over sex-pooled scores, the superior performance of the female-specific PRSAD model suggests that the value of sex-specific PRSs will likely grow with increased statistical power. Link to preregistration and preprint: https://osf.io/a8pt2/.</p>
12 Authors
- Arielle Crestol
- Dennis van der Meer
- Nadine Parker
- Ann-Marie G. de Lange
- Espen Hagen
- Hannah Oppenheimer
- Stener Nerland
- Édith Breton
- Christian K. Tamnes
- Ole A. Andreassen
- Ingrid Agartz
- Claudia Barth
1 Application
| Application ID | Title |
|---|---|
| 27412 | Boosting the power of GWAS using novel statistical tools |
Enabling scientific discoveries that improve human health