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

By Gabriëlla AM 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 J Cairns, Paul A Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F Sullivan, Aiden Corvin, Brien P Riley, Tonu 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 Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M Hartmann, Elvira Bramon, Robin M Murray, Michele Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A Ophoff, Andrew McQuillin, Nicholas Bass, Rolf Adolfsson, Anil K. Malhotra, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Nicholas G Martin, Janice M. Fullerton, Philip Mitchell, Peter Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, Jose Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Twarowska-Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Mueller-Myhsok, Beata Świątkowska, Thomas G Schulze, Markus M Nothen, Marcella Rietschel, John R. Kelsoe, Marion Leboyer, Stephane JAMAIN, Bruno ETAIN, Frank BELLIVIER, John B Vincent, Martin Alda, Claire O'Donovan, Pablo Cervantes, Joanna M Biernacka, Mark A. Frye, Susan L McElroy, Laura J Scott, Eli A Stahl, Mikael Landen, Marian L Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E Vaaler, Ole Rasmus 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 WJH Penninx, Jouke Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Lorenza Dall'Aglio, Hans-Jorgen Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P Hamilton, Patrik Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J Adams, Gerome Breen, Andrew McIntosh, Cathryn 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 Bo Mortensen, Thomas Werge, Thomas D. Als, Anders 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 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 (GxS) interaction of risk for these disorders, using 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 (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<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 sex-dependent 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.

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