Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders
Authors: Blokland Gabriëlla A. M. , Grove Jakob , Chen Chia-Yen , Cotsapas Chris , Tobet Stuart , Handa Robert ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, 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. ,   Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, 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 , Świątkowska 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. ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 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. ,   Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium,   The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), 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. 
Published: August 2020

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 encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating 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) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene locus (rs11665282;p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509;p=1.1×10−7) in a locus containingIDO2, 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.