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Cross-tissue Mendelian randomization prioritizes RAB27B as a brain-derived candidate protein for postpartum depression.

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Τίτλος: Cross-tissue Mendelian randomization prioritizes RAB27B as a brain-derived candidate protein for postpartum depression.
Συγγραφείς: Huang YJ; Department of Obstetrics and Gynecology, Tongji Hospital Affiliated to Tongji University, Putuo District, Shanghai, China.; Department of Obstetrics and Gynecology, Center for Reproductive Medicine, International School of Medicine, the Fourth Affiliated Hospital of School of Medicine, International Institutes of Medicine, Zhejiang University, Zhejiang, China., Chen KW; Department of Obstetrics and Gynecology, Tongji Hospital Affiliated to Tongji University, Putuo District, Shanghai, China., Xu QH; Department of Neurosurgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China., Li HF; Department of Obstetrics and Gynecology, Tongji Hospital Affiliated to Tongji University, Putuo District, Shanghai, China. huaifangli@126.com., Yang Y; Department of Obstetrics and Gynecology, Tongji Hospital Affiliated to Tongji University, Putuo District, Shanghai, China. yangyshine1983@aliyun.com.
Πηγή: European archives of psychiatry and clinical neuroscience [Eur Arch Psychiatry Clin Neurosci] 2026 Oct; Vol. 276 (7), pp. 3847-3855. Date of Electronic Publication: 2026 Aug 12.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer International Country of Publication: Germany NLM ID: 9103030 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1433-8491 (Electronic) Linking ISSN: 09401334 NLM ISO Abbreviation: Eur Arch Psychiatry Clin Neurosci Subsets: MEDLINE
Imprint Name(s): Original Publication: Berlin ; New York : Springer International, c1990-
Ιατρικοί όροι (MeSH): Depression, Postpartum*/genetics , Depression, Postpartum*/metabolism , Depression, Postpartum*/cerebrospinal fluid , Depression, Postpartum*/blood , rab GTP-Binding Proteins*/genetics , rab GTP-Binding Proteins*/metabolism , Brain*/metabolism , Mendelian Randomization Analysis*, Humans ; Female ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci
Περίληψη: Objective: Postpartum depression (PPD) is one of the most common and debilitating complications of childbirth, yet the candidate proteins linking genetic risk to disease remain poorly defined. Building on recent genome-wide association studies (GWAS), we sought to integrate cross-tissue proteogenomic data to identify candidate proteins for PPD and explore therapeutic opportunities.
Methods: We conducted two-sample Mendelian randomization (MR) using genome-wide significant cis-protein QTLs from brain (n = 608 proteins), cerebrospinal fluid (CSF; n = 214), and plasma (n = 612). PPD summary statistics were obtained from FinnGen R8 (13,657 cases, 236,178 controls) and replicated in an independent GWAS. Phenome-wide association (PheWAS) was used to assess pleiotropy. Potential therapeutic targets were evaluated through DSigDB drug repurposing, molecular docking, and molecular dynamics simulations.
Results: Among all proteins tested, RAB27B was the only brain-derived protein surpassing Bonferroni correction (OR = 1.60; 95% CI: 1.30-1.96; P = 6.6 × 10⁻⁶), whereas no significant proteins were identified in CSF or plasma. This association was replicated in an independent GWAS (OR = 1.27; 95% CI: 1.02-1.58; P = 0.037). PheWAS identified no pleiotropic associations at genome-wide significance. In silico drug repurposing identified pregnenolone as a candidate ligand with computationally predicted stable binding to RAB27B, providing a starting point for future experimental validation.
Conclusion: This study provides the first cross-tissue proteogenomic evidence that RAB27B is a brain-derived, reproducible candidate protein genetically associated with PPD. By extending GWAS signals to functional protein-level mechanisms and therapeutic inference, our findings nominate RAB27B and pregnenolone as promising directions for postpartum psychiatric research.
(© 2026. Springer-Verlag GmbH Germany, part of Springer Nature.)
Competing Interests: Declarations. Conflict of interest: All authors declare no conflicts of interest.
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Contributed Indexing: Keywords: Brain-derived protein; Mendelian randomization; Postpartum depression; Pregnenolone; RAB27B
Substance Nomenclature: EC 3.6.5.2 (rab GTP-Binding Proteins)
Entry Date(s): Date Created: 20260812 Date Completed: 20260910 Latest Revision: 20261008
Update Code: 20261008
DOI: 10.1007/s00406-026-02349-0
PMID: 42584685
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1433-8491
DOI:10.1007/s00406-026-02349-0