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

Blokland GA, Grove J, Chen CY, Cotsapas C, Tobet S, Handa R, 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, 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, Swiatkowska 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, Baune BT, Air TM, Preisig M, Uher R, Levinson DF, Weissman MM, Potash JB, Shi J, Knowles JA, Perlis RH, Lucae S, Boomsma DI, Penninx BW, Hottenga JJ, de Geus EJ, Willemsen G, Milaneschi Y, Tiemeier H, Grabe HJ, Teumer A, Van der Auwera S, Völker U, Hamilton SP, Magnusson PK, Viktorin A, Mehta D, Mullins N, Adams MJ, Breen G, McIntosh AM, Lewis CM, Hougaard DM, Nordentoft M, Mors O, Mortensen PB, Werge T, Als TD, Børglum AD, Petryshen TL, Smoller JW, Goldstein JM, Ripke S, Neale BM, Walters JT, Farh KH, Holmans PA, Lee PH, Bulik-Sullivan B, Collier DA, Huang H, Pers TH, Agartz I, Agerbo E, Albus M, Alexander M, Amin F, Bacanu SA, Bene J, Bergen SE, Bevilacqua E, Bigdeli TB, Black DW, Bruggeman R, Buccola NG, Buckner RL, Byerley W, Cahn W, Cai G, Campion D, Cantor RM, Carr VJ, Carrera N, Catts SV, Chambert KD, Chan RC, Chen RY, Chen EY, Cheng W, Cheung EF, Chong SA, Cloninger CR, Cohen D, Cohen N, Cormican P, Crowley JJ, Curtis D, Davidson M, Davis KL, Demontis D, Dikeos D, Dinan T, Donohoe G, Drapeau E, Duan J, Dudbridge F, Durmishi N, Eichhammer P, Eriksson J, Escott-Price V, Essioux L, Fanous AH, Farrell MS, Frank J, Franke L, Freedman R, Freimer NB, Friedl M, Friedman JI, Fromer M, Genovese G, Georgieva L, Giusti-Rodríguez P, Godard S, Goldstein JI, Golimbet V, Gopal S, Gratten J, de Haan L, Hammer C, Hansen M, Hansen TF, Haroutunian V, Henskens FA, Herms S, Hirschhorn JN, Hoffmann P, Hofman A, Hollegaard MV, Ikeda M, Joa I, Julià A, Kahn RS, Kalaydjieva L, Karachanak-Yankova S, Karjalainen J, Kavanagh D, Keller MC, Kennedy JL, Khrunin A, Kim Y, Klovins J, Kucinskas V, Kucinskiene ZA, Kuzelova-Ptackova H, Kähler AK, Laurent C, Keong JLC, Lee SH, Legge SE, Lerer B, Li M, Li T, Liang KY, Lieberman J, Limborska S, Loughland CM, Lubinski J, Lönnqvist J, Macek M, Maher BS, Maier W, Mallet J, Marsal S, Mattingsdal M, McCarley RW, McDonald C, Meier S, Meijer CJ, Melegh B, Mesholam-Gately RI, Metspalu A, Michie PT, Milanova V, Mokrab Y, Morris DW, Murphy KC, Myin-Germeys I, Nelis M, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nikitina-Zake L, Nisenbaum L, Nordin A, O'Callaghan E, O'Dushlaine C, O'Neill FA, Oh SY, Olincy A, Olsen L, Van Os J, Pantelis C, Papadimitriou GN, Papiol S, Parkhomenko E, Paunio T, Pejovic-Milovancevic M, Perkins DO, Pietiläinen O, Pimm J, Pocklington AJ, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Reichenberg A, Reimers MA, Richards AL, Roffman JL, Roussos P, Ruderfer DM, Salomaa V, Schall U, Schubert CR, Schwab SG, Scolnick EM, Scott RJ, Seidman LJ, Sigurdsson E, Silagadze T, Silverman JM, Sim K, Slominsky P, So HC, Spencer CC, Stefansson H, Steinberg S, Stogmann E, Straub RE, Strengman E, Strohmaier J, Stroup TS, Subramaniam M, Suvisaari J, Svrakic DM, Szatkiewicz JP, Söderman E, Thirumalai S, Toncheva D, Tosato S, Veijola J, Waddington J, Walsh D, Wang D, Wang Q, Webb BT, Weiser M, Wildenauer DB, Williams NM, Williams S, Witt SH, Wolen AR, Wong EH, Wormley BK, Xi HS, Zai CC, Zheng X, Zimprich F, Wray NR, Stefansson K, Visscher PM, Blackwood DH, Darvasi A, Domenici E, Gill M, Gurling H, Hultman CM, Jablensky AV, Kendler KS, Knight J, Li QS, Liu J, McCarroll SA, Moran JL, Owen MJ, Pato CN, Posthuma D, Sklar P, Wendland JR, Daly MJ, Donnelly P, Barroso I, Blackwell JM, Brown MA, Casas JP, Deloukas P, Duncan-Son A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Band G, Bellenguez C, Freeman C, Giannoulatou E, Hellenthal G, Pearson R, Pirinen M, Strange A, Su Z, Vukcevic D, Langford C, Blackburn H, Bumpstead SJ, Dronov S, Edkins S, Gillman M, Gray E, Gwilliam R, Hammond N, Hunt SE, Jayakumar A, Liddle J, McCann OT, Potter SC, Ravindrarajah R, Ricketts M, Tashakkori-Ghanbaria A, Waller M, Weston P, Whittaker P, Widaa S, McCarthy MI, Arranz MJ, Bakker S, Bender S, Crespo-Facorro B, Hall J, Iyegbe C, Lawrie S, Lin K, Linszen DH, Mata I, Walshe M, Weisbrod M, Wiersma D, Trubetskoy V, Mattheisen M, Wang Y, Coleman JR, Gaspar HA, de Leeuw CA, Pavlides JM, Trzaskowski M, Byrne EM, Abbott L, Akil H, Albani D, Alliey-Rodriguez N, Anjorin A, Antilla V, Awasthi S, Badner JA, Bækvad-Hansen M, Barchas JD, Bauer M, Belliveau R, Pedersen CB, Bøen E, Boks MP, Boocock J, Budde M, Bunney W, Burmeister M, Bybjerg-Grauholm J, Casas M, Cerrato F, Charney AW, Chen D, Churchhouse C, Clarke TK, Coryell W, Craig DW, Cruceanu C, Czerski PM, Dale AM, de Jong S, Del-Favero J, DePaulo JR, Dobbyn AL, Dumont A, Elvsåshagen T, Fan CC, Fischer SB, Flickinger M, Foroud TM, Forty L, Fraser C, Gade K, Gage D, Garnham J, Giambartolomei C, Pedersen MG, Gordon SD, Gordon-Smith K, Green EK, Green MJ, Greenwood TA, Guan W, Hautzinger M, Heilbronner U, Hipolito M, Holland D, Huckins LM, Johnson JS, Kandaswamy R, Karlsson R, Kittel-Schneider S, Koller AC, Kupka R, Lavebratt C, Lawrence J, Lawson WB, Leber M, Levy SE, Li JZ, Liu C, Maaser A, MacIntyre DJ, Mahon PB, Martinsson L, McGuffin P, McInnis MG, McKay JD, Medeiros H, Medland SE, Meng F, Montgomery GW, Mühleisen TW, Nguyen H, Nievergelt CM, Adolfsson AN, Nwulia EA, Olde Loohuis LM, Ori AP, Oruc L, Ösby U, Perry A, Pfennig A, Regeer EJ, Reinbold CS, Rice JP, Rivas F, Rivera M, Ryu E, Sánchez-Mora C, Schatzberg AF, Scheftner WA, Weickert CS, Shehktman T, Shilling PD, Slaney C, Sobell JL, Hansen CS, Spijker AT, Steffens M, Strauss JS, Szelinger S, Thompson RC, Thorgeirsson TE, Treutlein J, Vedder H, Wang W, Watson SJ, Weickert TW, Xu W, Young AH, Zandi P, Zhang P, Zöllner S, Backlund L, Berrettini WH, Boehnke M, Craddock N, Dannlowski U, Gershon ES, Goes FS, Jones I, Jones LA, McMahon FJ, Morken G, Myers RM, Nimgaonkar V, Oedegaard KJ, Paciga SA, Ramos-Quiroga JA, Ribasés M, Rouleau GA, Schalling M, Serretti A, Stordal E, Turecki G, Vieta E, Nurnberger JI, Di Florio A, Edenberg HJ, Abdellaoui A, Andlauer TF, Beekman AT, Binder EB, Bryois J, Buttenschøn HN, Cai N, Castelao E, Christensen JH, Colodro-Conde L, Couvy-Duchesne B, Crawford GE, Davies G, Deary IJ, Derks EM, Direk N, Dolan CV, Dunn EC, Eley TC, Kiadeh FFH, Finucane HK, Foo JC, Hall LS, Hickie IB, Homuth G, Horn C, Howard DM, Ising M, Jansen R, Jorgenson E, Kohane IS, Kraft J, Kretzschmar WW, Kutalik Z, Li Y, Lind PA, MacKinnon DF, Maier RM, Marchini J, Mbarek H, McGrath P, Middeldorp CM, Mihailov E, Mondimore FM, Mostafavi S, Nauck M, Ng B, Nivard MG, Nyholt DR, O'Reilly PF, Oskarsson H, Painter JN, Peterson RE, Peyrot WJ, Pistis G, Quiroz JA, Qvist P, Mirza SS, Schoevers R, Schulte EC, Shen L, Shyn SI, Sinnamon GC, Smit JH, Smith DJ, Tansey KE, Teismann H, Thompson W, Thomson PA, Traylor M, Uitterlinden AG, Umbricht D, van Hemert AM, Weinsheimer SM, Wellmann J, Wu Y, Yang J, Zhang F, Arolt V, Berger K, Domschke K, Hayward C, Heath AC, Kloiber S, Lewis G, Madden PA, Metspelu A, Pedersen NL, Porteous DJ, Schaefer C, Völzke H, Bortolato M, Bralten J, Bulik CM, Burton CL, Carey CE, Davis LK, Duncan LE, Erdman L, Faraone SV, Goleva SB, Guo W, Hübel C, Khramtsova EA, Martin J, Mathews CA, Robinson E, Stranger BE, Traglia M, Walters RK, Weiss LA, Winham SJ, Yao Y, Skajaa K, Yolken RH, Plath N, Mill J, Geschwind D (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 91

Pages Range: 102-117

Journal Issue: 1

DOI: 10.1016/j.biopsych.2021.02.972

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.

Involved external institutions

Maastricht University Medical Center (UMC+) Netherlands (NL) Massachusetts General Hospital United States (USA) (US) University of Aberdeen United Kingdom (GB) Feinstein Institute for Medical Research United States (USA) (US) University of Queensland Australia (AU) Schizophrenia Research Institute Australia (AU) University of Newcastle (UoN) Australia (AU) Cardiff University United Kingdom (GB) University of North Carolina at Chapel Hill United States (USA) (US) Trinity College Dublin Ireland (IE) Virginia Commonwealth University (VCU) United States (USA) (US) Max-Planck-Institut für Experimentelle Medizin Germany (DE) The University of Hong Kong (HKU) / 香港大學 Hong Kong (HK) Aarhus University Denmark (DK) Fujita Health University Japan (JP) Lieber Institute for Brain Development United States (USA) (US) University of Chicago United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) Martin-Luther-Universität Halle-Wittenberg (MLU) Germany (DE) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) Karolinska Institute Sweden (SE) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) University of Copenhagen Denmark (DK) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) University of New South Wales (UNSW) Australia (AU) Klinikum der Universität München (LMU Klinikum) Germany (DE) Instituto de Salud Global de Barcelona (ISGlobal) Spain (ES) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Universitätsklinikum Bonn Germany (DE) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) The University of Liverpool United Kingdom (GB) Nofer Institute of Occupational Medicine (NIOM) Poland (PL) State University of New York Upstate Medical University (SUNY) United States (USA) (US) Université Paris Cité France (FR) King’s College London United Kingdom (GB) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Stanford University United States (USA) (US) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) University of Oslo Norway (NO) University of Iowa United States (USA) (US) University of Adelaide Australia (AU) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) University of Edinburgh United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) University of Southern California (USC) United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Kaiser Permanente United States (USA) (US) University College London (UCL) United Kingdom (GB) Queensland University of Technology (QUT) Australia (AU) Umeå University Sweden (SE) Neuroscience Research Australia NeuRA Australia (AU) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Dalhousie University Canada (CA) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Mayo Clinic United States (USA) (US) Lindner Center of HOPE United States (USA) (US) University of Michigan United States (USA) (US) Erasmus University Medical Center (MC) Netherlands (NL) Institute of Mental Health Singapore (SG) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Diakonhjemmet Hospital Norway (NO) Philipps-Universität Marburg Germany (DE)

How to cite

APA:

Blokland, G.A., Grove, J., Chen, C.Y., Cotsapas, C., Tobet, S., Handa, R.,... Geschwind, D. (2022). Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry, 91(1), 102-117. https://doi.org/10.1016/j.biopsych.2021.02.972

MLA:

Blokland, Gabriëlla A.M., et al. "Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders." Biological Psychiatry 91.1 (2022): 102-117.

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