PT  - JOURNAL ARTICLE
AU  - Gabriëlla A. M. Blokland
AU  - Jakob Grove
AU  - Chia-Yen Chen
AU  - Chris Cotsapas
AU  - Stuart Tobet
AU  - Robert Handa
AU  - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU  - David St Clair
AU  - Todd Lencz
AU  - Bryan J. Mowry
AU  - Sathish Periyasamy
AU  - Murray J. Cairns
AU  - Paul A. Tooney
AU  - Jing Qin Wu
AU  - Brian Kelly
AU  - George Kirov
AU  - Patrick F. Sullivan
AU  - Aiden Corvin
AU  - Brien P. Riley
AU  - Tõnu Esko
AU  - Lili Milani
AU  - Erik G. Jönsson
AU  - Aarno Palotie
AU  - Hannelore Ehrenreich
AU  - Martin Begemann
AU  - Agnes Steixner-Kumar
AU  - Pak C. Sham
AU  - Nakao Iwata
AU  - Daniel R. Weinberger
AU  - Pablo V. Gejman
AU  - Alan R. Sanders
AU  - Joseph D. Buxbaum
AU  - Dan Rujescu
AU  - Ina Giegling
AU  - Bettina Konte
AU  - Annette M. Hartmann
AU  - Elvira Bramon
AU  - Robin M. Murray
AU  - Michele T. Pato
AU  - Jimmy Lee
AU  - Ingrid Melle
AU  - Espen Molden
AU  - Roel A. Ophoff
AU  - Andrew McQuillin
AU  - Nicholas J. Bass
AU  - Rolf Adolfsson
AU  - Anil K. Malhotra
AU  - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
AU  - Nicholas G. Martin
AU  - Janice M. Fullerton
AU  - Philip B. Mitchell
AU  - Peter R. Schofield
AU  - Andreas J. Forstner
AU  - Franziska Degenhardt
AU  - Sabrina Schaupp
AU  - Ashley L. Comes
AU  - Manolis Kogevinas
AU  - José Guzman-Parra
AU  - Andreas Reif
AU  - Fabian Streit
AU  - Lea Sirignano
AU  - Sven Cichon
AU  - Maria Grigoroiu-Serbanescu
AU  - Joanna Hauser
AU  - Jolanta Lissowska
AU  - Fermin Mayoral
AU  - Bertram Müller-Myhsok
AU  - Beata Świątkowska
AU  - Thomas G. Schulze
AU  - Markus M. Nöthen
AU  - Marcella Rietschel
AU  - John Kelsoe
AU  - Marion Leboyer
AU  - Stéphane Jamain
AU  - Bruno Etain
AU  - Frank Bellivier
AU  - John B. Vincent
AU  - Martin Alda
AU  - Claire O’Donovan
AU  - Pablo Cervantes
AU  - Joanna M. Biernacka
AU  - Mark Frye
AU  - Susan L. McElroy
AU  - Laura J. Scott
AU  - Eli A. Stahl
AU  - Mikael Landén
AU  - Marian L. Hamshere
AU  - Olav B. Smeland
AU  - Srdjan Djurovic
AU  - Arne E. Vaaler
AU  - Ole A. Andreassen
AU  - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU  - Bernhard T. Baune
AU  - Tracy Air
AU  - Martin Preisig
AU  - Rudolf Uher
AU  - Douglas F. Levinson
AU  - Myrna M. Weissman
AU  - James B. Potash
AU  - Jianxin Shi
AU  - James A. Knowles
AU  - Roy H. Perlis
AU  - Susanne Lucae
AU  - Dorret I. Boomsma
AU  - Brenda W. J. H. Penninx
AU  - Jouke-Jan Hottenga
AU  - Eco J. C. de Geus
AU  - Gonneke Willemsen
AU  - Yuri Milaneschi
AU  - Henning Tiemeier
AU  - Hans J. Grabe
AU  - Alexander Teumer
AU  - Sandra Van der Auwera
AU  - Uwe Völker
AU  - Steven P. Hamilton
AU  - Patrik K. E. Magnusson
AU  - Alexander Viktorin
AU  - Divya Mehta
AU  - Niamh Mullins
AU  - Mark J. Adams
AU  - Gerome Breen
AU  - Andrew M. McIntosh
AU  - Cathryn M. Lewis
AU  - Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium
AU  - The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)
AU  - David M. Hougaard
AU  - Merete Nordentoft
AU  - Ole Mors
AU  - Preben B. Mortensen
AU  - Thomas Werge
AU  - Thomas D. Als
AU  - Anders D. Børglum
AU  - Tracey L. Petryshen
AU  - Jordan W. Smoller
AU  - Jill M. Goldstein
TI  - Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders
AID  - 10.1101/2020.08.13.249813
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.08.13.249813
4099  - http://biorxiv.org/content/early/2021/01/30/2020.08.13.249813.short
4100  - http://biorxiv.org/content/early/2021/01/30/2020.08.13.249813.full
AB  - 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=3.2×10−8), 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 inhibitor SLTM. Most significant in SCZ was a MOCOS gene 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 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.Competing Interest StatementAll 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.