BACKGROUND Sex differences in the incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across these disorders suggest possible shared sex-dependent genetic risk. METHODS We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction analysis of risk for these disorders, using data from 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTS Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 gene (rs117780815; p =3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes important for neuronal excitability. Three additional loci showed evidence ( p <1×10−6) for cross-disorder GxS interaction (rs7302529, p =1.6×10−7; rs73033497, p =8.8×10−7; rs7914279, p =6.4×10−7) with various potential functions. Gene-based analyses identified GxS interaction across disorders ( p =8.97×10−7) with transcriptional inhibitor SLTM . Most significant in SCZ was a locus in the MOCOS gene (rs11665282; p =1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the SCZ PGC dataset detected a noteworthy interaction (rs13265509; p =1.1×10−7) in a locus containing IDO2 , a kynurenine pathway enzyme with an immunoregulatory function previously implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD ( p FDR<0.05). CONCLUSIONS In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sexdependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels. ### Competing Interest Statement All authors declare that they have no conflicts of interest. JG is on the scientific advisory board for and has equity in Cala Health; and TLP is an employee of Concert Pharmaceuticals. However, these affiliations are unrelated to this study. JWS is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe.

Download data

• Downloaded 501 times
• Download rankings, all-time:
  • Site-wide: 36,086 out of 100,819
  • In genetics: 2,086 out of 5,019
• Year to date:
  • Site-wide: 7,346 out of 100,819
• Since beginning of last month:
  • Site-wide: 2,368 out of 100,819

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide