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Publication Detail
Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Blokland GAM, Grove J, Chen C-Y, Cotsapas C, Tobet S, Handa R, Schizophrenia Working Group of the Psychiatric Genomics Consortium , St Clair D, Lencz T, Mowry BJ, Periyasamy S, Cairns MJ, Tooney PA, Wu JQ, Kelly B, Kirov G, Sullivan PF, Corvin A, Riley BP, Esko T, Milani L, Jönsson EG, Palotie A, Ehrenreich H, Begemann M, Steixner-Kumar A, Sham PC, Iwata N, Weinberger DR, Gejman PV, Sanders AR, Buxbaum JD, Rujescu D, Giegling I, Konte B, Hartmann AM, Bramon E, Murray RM, Pato MT, Lee J, Melle I, Molden E, Ophoff RA, McQuillin A, Bass NJ, Adolfsson R, Malhotra AK, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium , Martin NG, Fullerton JM, Mitchell PB, Schofield PR, Forstner AJ, Degenhardt F, Schaupp S, Comes AL, Kogevinas M, Guzman-Parra J, Reif A, Streit F, Sirignano L, Cichon S, Grigoroiu-Serbanescu M, Hauser J, Lissowska J, Mayoral F, Müller-Myhsok B, Świątkowska B, Schulze TG, Nöthen MM, Rietschel M, Kelsoe J, Leboyer M, Jamain S, Etain B, Bellivier F, Vincent JB, Alda M, O'Donovan C, Cervantes P, Biernacka JM, Frye M, McElroy SL, Scott LJ, Stahl EA, Landén M, Hamshere ML, Smeland OB, Djurovic S, Vaaler AE, Andreassen OA, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium , Baune BT, Air T, Preisig M, Uher R, Levinson DF, Weissman MM, Potash JB, Shi J, Knowles JA, Perlis RH, Lucae S, Boomsma DI, Penninx BWJH, Hottenga J-J, de Geus EJC, Willemsen G, Milaneschi Y, Tiemeier H, Grabe HJ, Teumer A, Van der Auwera S, Völker U, Hamilton SP, Magnusson PKE, Viktorin A, Mehta D, Mullins N, Adams MJ, Breen G, McIntosh AM, Lewis CM, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium , iPSYCH , Hougaard DM, Nordentoft M, Mors O, Mortensen PB, Werge T, Als TD, Børglum AD, Petryshen TL, Smoller JW, Goldstein JM
  • Publication date:
    01/01/2022
  • Journal:
    Biological Psychiatry
  • Status:
    Published
  • Country:
    United States
  • PII:
    S0006-3223(21)01139-2
  • Language:
    eng
  • Keywords:
    Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences
Abstract
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: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S 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 G×S 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 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.
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Mental Health Neuroscience
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Mental Health Neuroscience
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Division of Psychiatry
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Mental Health Neuroscience
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