BACKGROUND: Sex differences in 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 disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: ) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
| Authors | Blokland, Gabriëlla A M; Grove, Jakob; Chen, Chia-Yen; Cotsapas, Chris; Tobet, Stuart; Handa, Robert; , ; St Clair, David; Lencz, Todd; Mowry, Bryan J; Periyasamy, Sathish; Cairns, Murray J; Tooney, Paul A; Wu, Jing Qin; Kelly, Brian; Kirov, George; Sullivan, Patrick F; Corvin, Aiden; Riley, Brien P; Esko, Tõnu; Milani, Lili; Jönsson, Erik G; Palotie, Aarno; Ehrenreich, Hannelore; Begemann, Martin; Steixner-Kumar, Agnes; Sham, Pak C; Iwata, Nakao; Weinberger, Daniel R; Gejman, Pablo V; Sanders, Alan R; Buxbaum, Joseph D; Rujescu, Dan; Giegling, Ina; Konte, Bettina; Hartmann, Annette M; Bramon, Elvira; Murray, Robin M; Pato, Michele T; Lee, Jimmy; Melle, Ingrid; Molden, Espen; Ophoff, Roel A; McQuillin, Andrew; Bass, Nicholas J; Adolfsson, Rolf; Malhotra, Anil K; , ; Martin, Nicholas G; Fullerton, Janice M; Mitchell, Philip B; Schofield, Peter R; Forstner, Andreas J; Degenhardt, Franziska; Schaupp, Sabrina; Comes, Ashley L; Kogevinas, Manolis; Guzman-Parra, José; Reif, Andreas; Streit, Fabian; Sirignano, Lea; Cichon, Sven; Grigoroiu-Serbanescu, Maria; Hauser, Joanna; Lissowska, Jolanta; Mayoral, Fermin; Müller-Myhsok, Bertram; Swiatkowska, Beata; Schulze, Thomas G; Nöthen, Markus M; Rietschel, Marcella; Kelsoe, John; Leboyer, Marion; Jamain, Stéphane; Etain, Bruno; Bellivier, Frank; Vincent, John B; Alda, Martin; O'Donovan, Claire; Cervantes, Pablo; Biernacka, Joanna M; Frye, Mark; McElroy, Susan L; Scott, Laura J; Stahl, Eli A; Landén, Mikael; Hamshere, Marian L; Smeland, Olav B; Djurovic, Srdjan; Vaaler, Arne E; Andreassen, Ole A; , ; Baune, Bernhard T; Air, Tracy; Preisig, Martin; Uher, Rudolf; Levinson, Douglas F; Weissman, Myrna M; Potash, James B; Shi, Jianxin; Knowles, James A; Perlis, Roy H; Lucae, Susanne; Boomsma, Dorret I; Penninx, Brenda W J H; Hottenga, Jouke-Jan; de Geus, Eco J C; Willemsen, Gonneke; Milaneschi, Yuri; Tiemeier, Henning; Grabe, Hans J; Teumer, Alexander; Van der Auwera, Sandra; Völker, Uwe; Hamilton, Steven P; Magnusson, Patrik K E; Viktorin, Alexander; Mehta, Divya; Mullins, Niamh; Adams, Mark J; Breen, Gerome; McIntosh, Andrew M; Lewis, Cathryn M; , ; , ; Hougaard, David M; Nordentoft, Merete; Mors, Ole; Mortensen, Preben B; Werge, Thomas; Als, Thomas D; Børglum, Anders D; Petryshen, Tracey L; Smoller, Jordan W; Goldstein, Jill M |
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| Journal | BIOLOGICAL PSYCHIATRY |
| Pages | 102-117 |
| Volume | 91 |
| Date | 1/01/2021 |
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| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/j.biopsych.2021.02.972 |