Shared genetic architecture between premenstrual disorder symptoms and major psychiatric disorders suggests a role for calcium signaling

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Abstract
Background: Major psychiatric disorders (MPDs) and premenstrual disorders (PMDs) are often comorbid, with indications of shared genetic architecture. However, the specific genetic variants underlying this comorbidity remain elusive. The aim of this study was to identify genomic loci shared between MPDs and PMDs, and to assess the functional characteristics of genes mapped to these loci. Methods: We used genome-wide association data for symptoms of PMDs (S-PMD, n = 67 068) from the Norwegian Mother, Father and Child Cohort Study (MoBa), and for MPDs (schizophrenia, n = 130 644; bipolar disorder, n = 827 335; major depression, n = 1 918 432) from the Psychiatric Genomic Consortium. Shared genetic loci were identified with the conjunctional false discovery rate (conjFDR). Genes mapped to the identified loci were included in functional and pharmacological gene-set enrichment analyses (GSEAs). Results: We identified 20 loci shared between S-PMD and the MPDs, including 19 novel loci for S-PMD (conjFDR<0.05). GSEA revealed genes involved in calcium signaling and neuronal projection pathways. The drug enrichment analysis identified 36 drugs, including riluzole and mianserin, significantly associated with the identified molecular pathways. Conclusions: We identified 20 genetic loci shared between the S-PMD and MPDs, implicating calcium transmission in the pathogenesis of PMDs. Together with the drug enrichment results, this provides a biological basis for repurposing existing drugs in the treatment of PMD.
Funding Information
  • Norges Forskningsråd (324252)
  • National Institutes of Health (U24DA041123 and U24DA055330)
  • HORIZON EUROPE European Innovation Council (847776 CoMorMent and 964874 RealMent)
  • Norges Forskningsråd (296030)
  • HORIZON EUROPE European Innovation Council (964874)
  • Norges Forskningsråd (334920)
  • National Institutes of Health (5R01MH124839-02 (PGC4))
  • Norges Forskningsråd (223273, 248778)
  • Helse Sør-Øst RHF (2022-087)
  • HORIZON EUROPE European Innovation Council (847776, CoMorMent and 964874, RealMent)

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