Genomic relationship between polyendocrine metabolic ovarian syndrome and bipolar disorder
Women with bipolar disorder (BIP) have a higher risk of developing polyendocrine metabolic ovarian syndrome (PMOS). Shared genetic architecture may underlie this comorbidity. Valproate, a mood-stabilizer commonly used to treat BIP, increases the risk of PMOS. Still, the mechanism underlying PMOS in BIP remains unknown. Here, we aimed to identify genetic variants shared between BIP and PMOS, as well as their interaction with valproate. We used the results of large-scale genome-wide association studies of BIP (41,510 cases and 354,340 controls), and PMOS (3609 cases and 229,788 controls). Using conditional false discovery rate, we discovered genetic variants jointly associated with BIP and PMOS. Gene mapping of identified variants was performed using the Open Targets platforms. We analyzed the tissue-specific expression, interaction with valproate, and involvement in biological pathways of the mapped genes. We identified two loci shared between BIP and PMOS. Among the 10 genes mapped to the locus on chromosome 8:11,444,837-11,463,015, GATA4, NEIL2, and FDFT1 showed expression profiles suggesting their role in the observed comorbidity. Mapped to the locus on chromosome 12:2499,849-2514,270, CACNA1C, FKBP4, DCP1B, and ITFG2 are expressed in both the ovaries and the brain. Valproate interacts with CACNA1C, and CACNA1C is part of biological pathways that also include other genes interacting with valproate. We identified shared genetic underpinnings of BIP and PMOS and highlighted genes that may potentially contribute to the biological mechanisms underlying their comorbidity and to a hypothesized role of valproate in these mechanisms.
Authors
- Markos Tesfaye (ORCID: https://orcid.org/0000-0002-3351-701X)
- Piotr Jahołkowski (ORCID: https://orcid.org/0000-0001-9408-3107)
- Pravesh Parekh (ORCID: https://orcid.org/0000-0002-1930-1167)
- Ole A. Andreassen (ORCID: https://orcid.org/0000-0002-4461-3568)
- Shahram Bahrami (ORCID: https://orcid.org/0000-0002-8179-2788)
- Erik D Wiström (ORCID: https://orcid.org/0009-0000-4498-9795)
- Vera Fominykh (ORCID: https://orcid.org/0000-0001-5490-2390)
- Alexey A. Shadrin (ORCID: https://orcid.org/0000-0002-7467-250X)
- Srdjan Djurovic (ORCID: https://orcid.org/0000-0002-8140-8061)
- Anna E. Bauer (ORCID: https://orcid.org/0000-0002-7771-930X)
- Jaroslav Rokicki (ORCID: https://orcid.org/0000-0003-3258-1674)
- Elise Koch (ORCID: https://orcid.org/0000-0003-3727-4470)
- Paweł Trzaskoma (ORCID: https://orcid.org/0000-0002-5823-6572)
- Oleksandr Frei (ORCID: https://orcid.org/0000-0002-6427-2625)
- Zillur Rahman (ORCID: https://orcid.org/0000-0003-2785-0200)
- Anders M. Dale (ORCID: https://orcid.org/0000-0002-6126-2966)
- Kevin S. O’Connell
- Nadine Parker
Institutions
- University of North Carolina at Chapel Hill (US)
- Oslo University Hospital (NO)
- National Institutes of Health (US)
- J. Craig Venter Institute (US)
- Vilnius Gediminas Technical University (LT)
- Duke University (US)
- SUNY Downstate Health Sciences University (US)
- University of Oslo (NO)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
Publication Details
- Journal
- European Neuropsychopharmacology
- Published
- 2026-06-25
- DOI
- https://doi.org/10.1016/j.euroneuro.2026.112903
- Primary Topic
- Ovarian function and disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Norges Forskningsråd
- Helsedirektoratet
- National Institutes of Health
- Helse Sør-Øst RHF
- EEA Grants
- National Institute of Mental Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- HORIZON EUROPE Marie Sklodowska-Curie Actions
- HORIZON EUROPE European Innovation Council