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Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

By Gabriëlla A. M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, Schizophrenia Working Group of the Psychiatric Genomics Consortium, David St Clair, Todd Lencz, Bryan J Mowry, Sathish Periyasamy, Murray Cairns, Paul A Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C Sham, Nakao Iwata, Daniel R Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M Murray, Michele T Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J Bass, Rolf Adolfsson, Anil K. Malhotra, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Nicholas G Martin, Janice M. Fullerton, Philip B Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L McElroy, Laura J Scott, Eli A Stahl, Mikael Landén, Marian L. Hamshere, Olav B Smeland, Srdjan Djurovic, Arne E Vaaler, Ole A Andreassen, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W. J. H. Penninx, Jouke-Jan Hottenga, Eco J. C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K. E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), David M Hougaard, Merete Nordentoft, Ole Mors, Preben B Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M Goldstein

Posted 17 Aug 2020
bioRxiv DOI: 10.1101/2020.08.13.249813

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.

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