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.
Original language | English |
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Journal | Biological Psychiatry |
Early online date | 2021 |
DOIs | |
Publication status | E-pub ahead of print - 2021 |
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. / Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium et al.
In: Biological Psychiatry, 2021.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
AU - Blokland, Gabriëlla A. M.
AU - Grove, Jakob
AU - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
AU - Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU - Chen, Chia-Yen
AU - Cotsapas, Chris
AU - Tobet, Stuart
AU - Handa, Robert
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Ripke, Stephan
AU - Neale, Benjamin M.
AU - Corvin, Aiden
AU - Walters, James T. R.
AU - Farh, Kai-How
AU - Holmans, Peter A.
AU - Lee, Phil
AU - Bulik-Sullivan, Brendan
AU - Collier, David A.
AU - Huang, Hailiang
AU - Pers, Tune H.
AU - Agartz, Ingrid
AU - Agerbo, Esben
AU - Albus, Margot
AU - Alexander, Madeline
AU - Amin, Farooq
AU - Bacanu, Silviu A.
AU - Begemann, Martin
AU - Belliveau, Richard A.
AU - Bene, Judit
AU - Bergen, Sarah E.
AU - Bevilacqua, Elizabeth
AU - Bigdeli, Tim B.
AU - Black, Donald W.
AU - Bruggeman, Richard
AU - Buccola, Nancy G.
AU - Buckner, Randy L.
AU - Byerley, William
AU - Cahn, Wiepke
AU - Cai, Guiqing
AU - Campion, Dominique
AU - Cantor, Rita M.
AU - Carr, Vaughan J.
AU - Carrera, Noa
AU - Catts, Stanley V.
AU - Chambert, Kimberly D.
AU - Chan, Raymond C. K.
AU - Chen, Ronald Y. L.
AU - Chen, Eric Y. H.
AU - Cheng, Wei
AU - Cheung, Eric F. C.
AU - Chong, Siow Ann
AU - Cloninger, C. Robert
AU - Cohen, David
AU - Cohen, Nadine
AU - Cormican, Paul
AU - Craddock, Nick
AU - Crowley, James J.
AU - Curtis, David
AU - Davidson, Michael
AU - Davis, Kenneth L.
AU - Degenhardt, Franziska
AU - del Favero, Jurgen
AU - Demontis, Ditte
AU - Dikeos, Dimitris
AU - Dinan, Timothy
AU - Djurovic, Srdjan
AU - Donohoe, Gary
AU - Drapeau, Elodie
AU - Duan, Jubao
AU - Dudbridge, Frank
AU - Durmishi, Naser
AU - Eichhammer, Peter
AU - Eriksson, Johan
AU - Escott-Price, Valentina
AU - Essioux, Laurent
AU - Fanous, Ayman H.
AU - Farrell, Martilias S.
AU - Frank, Josef
AU - Franke, Lude
AU - Freedman, Robert
AU - Freimer, Nelson B.
AU - Friedl, Marion
AU - Friedman, Joseph I.
AU - Fromer, Menachem
AU - Genovese, Giulio
AU - Georgieva, Lyudmila
AU - Giegling, Ina
AU - Giusti-Rodríguez, Paola
AU - Godard, Stephanie
AU - Goldstein, Jacqueline I.
AU - Golimbet, Vera
AU - Gopal, Srihari
AU - Gratten, Jacob
AU - de Haan, Lieuwe
AU - Hammer, Christian
AU - Hamshere, Marian L.
AU - Hansen, Mark
AU - Hansen, Thomas
AU - Haroutunian, Vahram
AU - Hartmann, Annette M.
AU - Henskens, Frans A.
AU - Herms, Stefan
AU - Hirschhorn, Joel N.
AU - Hoffmann, Per
AU - Hofman, Andrea
AU - Hollegaard, Mads V.
AU - iPSYCH
AU - Hougaard, David M.
AU - Ikeda, Masashi
AU - Joa, Inge
AU - Julià, Antonio
AU - Kahn, René S.
AU - Kalaydjieva, Luba
AU - Karachanak-Yankova, Sena
AU - Karjalainen, Juha
AU - Kavanagh, David
AU - Keller, Matthew C.
AU - Kennedy, James L.
AU - Khrunin, Andrey
AU - Kim, Yunjung
AU - Klovins, Janis
AU - Knowles, James A.
AU - Konte, Bettina
AU - Kucinskas, Vaidutis
AU - Kucinskiene, Zita Ausrele
AU - Kuzelova-Ptackova, Hana
AU - Kähler, Anna K.
AU - Laurent, Claudine
AU - Lee Chee Keong, Jimmy
AU - Lee, S. Hong
AU - Legge, Sophie E.
AU - Lerer, Bernard
AU - Li, Miaoxin
AU - Li, Tao
AU - Liang, Kung-Yee
AU - Lieberman, Jeffrey
AU - Limborska, Svetlana
AU - Loughland, Carmel M.
AU - Lubinski, Jan
AU - Lönnqvist, Jouko
AU - Macek, Milan
AU - Magnusson, Patrik K. E.
AU - Maher, Brion S.
AU - Maier, Wolfgang
AU - Mallet, Jacques
AU - Marsal, Sara
AU - Mattheisen, Manuel
AU - Mattingsdal, Morten
AU - McCarley, Robert W.
AU - McDonald, Colm
AU - McIntosh, Andrew M.
AU - Meier, Sandra
AU - Meijer, Carin J.
AU - Melegh, Bela
AU - Melle, Ingrid
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T.
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mokrab, Younes
AU - Morris, Derek W.
AU - Mors, Ole
AU - Murphy, Kieran C.
AU - Murray, Robin M.
AU - Myin-Germeys, Inez
AU - Müller-Myhsok, Bertram
AU - Nelis, Mari
AU - Nenadic, Igor
AU - Nertney, Deborah A.
AU - Nestadt, Gerald
AU - Nicodemus, Kristin K.
AU - Nikitina-Zake, Liene
AU - Nisenbaum, Laura
AU - Nordin, Annelie
AU - O'Callaghan, Eadbhard
AU - O'Dushlaine, Colm
AU - O'Neill, F. Anthony
AU - Oh, Sang-Yun
AU - Olincy, Ann
AU - Olsen, Line
AU - van Os, Jim
AU - St Clair, David
AU - Lencz, Todd
AU - Mowry, Bryan J.
AU - Periyasamy, Sathish
AU - Cairns, Murray J.
AU - Tooney, Paul A.
AU - Wu, Jing Qin
AU - Kelly, Brian
AU - Kirov, George
AU - Sullivan, Patrick F.
AU - Riley, Brien P.
AU - Esko, T. nu
AU - Jönsson, Erik G.
AU - Palotie, Aarno
AU - Ehrenreich, Hannelore
AU - Steixner-Kumar, Agnes
AU - Sham, Pak C.
AU - Iwata, Nakao
AU - Weinberger, Daniel R.
AU - Gejman, Pablo V.
AU - Sanders, Alan R.
AU - Buxbaum, Joseph D.
AU - Rujescu, Dan
AU - Bramon, Elvira
AU - Pato, Michele T.
AU - Lee, Jimmy
AU - Molden, Espen
AU - Ophoff, Roel A.
AU - McQuillin, Andrew
AU - Bass, Nicholas J.
AU - Adolfsson, Rolf
AU - Malhotra, Anil K.
AU - Stahl, Eli A.
AU - Breen, Gerome
AU - Forstner, Andreas J.
AU - Trubetskoy, Vassily
AU - Wang, Yunpeng
AU - Coleman, Jonathan R. I.
AU - Gaspar, H. léna A.
AU - de Leeuw, Christiaan A.
AU - Steinberg, Stacy
AU - Whitehead Pavlides, Jennifer M.
AU - Trzaskowski, Maciej
AU - Byrne, Enda M.
AU - Richards, Alexander L.
AU - Abbott, Liam
AU - Akil, Huda
AU - Albani, Diego
AU - Alliey-Rodriguez, Ney
AU - Als, Thomas D.
AU - Anjorin, Adebayo
AU - Antilla, Verneri
AU - Awasthi, Swapnil
AU - Badner, Judith A.
AU - Bækvad-Hansen, Marie
AU - Barchas, Jack D.
AU - Bass, Nicholas
AU - Bauer, Michael
AU - Belliveau, Richard
AU - Pedersen, Carsten B. cker
AU - Bøen, Erlend
AU - Boks, Marco P.
AU - Boocock, James
AU - Budde, Monika
AU - Bunney, William
AU - Burmeister, Margit
AU - Bybjerg-Grauholm, Jonas
AU - Casas, Miquel
AU - Cerrato, Felecia
AU - Cervantes, Pablo
AU - Chambert, Kimberly
AU - Charney, Alexander W.
AU - Chen, Danfeng
AU - Churchhouse, Claire
AU - Clarke, Toni-Kim
AU - Coryell, William
AU - Craig, David W.
AU - Cruceanu, Cristiana
AU - Czerski, Piotr M.
AU - Dale, Anders M.
AU - de Jong, Simone
AU - del-Favero, Jurgen
AU - DePaulo, J. Raymond
AU - Dobbyn, Amanda L.
AU - Dumont, Ashley
AU - Elvsåshagen, Torbjørn
AU - Fan, Chun Chieh
AU - Fischer, Sascha B.
AU - Flickinger, Matthew
AU - Foroud, Tatiana M.
AU - Forty, Liz
AU - Fraser, Christine
AU - Gade, Katrin
AU - Gage, Diane
AU - Garnham, Julie
AU - Giambartolomei, Claudia
AU - Pedersen, Marianne Giørtz
AU - Goldstein, Jaqueline
AU - Gordon, Scott D.
AU - Gordon-Smith, Katherine
AU - Green, Elaine K.
AU - Green, Melissa J.
AU - Greenwood, Tiffany A.
AU - Guan, Weihua
AU - Guzman-Parra, José
AU - Hautzinger, Martin
AU - Heilbronner, Urs
AU - Hipolito, Maria
AU - Holland, Dominic
AU - Huckins, Laura
AU - Jamain, Stéphane
AU - Johnson, Jessica S.
AU - Kandaswamy, Radhika
AU - Karlsson, Robert
AU - Kittel-Schneider, Sarah
AU - Kogevinas, Manolis
AU - Koller, Anna C.
AU - Kupka, Ralph
AU - Lavebratt, Catharina
AU - Lawrence, Jacob
AU - Lawson, William B.
AU - Leber, Markus
AU - Lee, Phil H.
AU - Levy, Shawn E.
AU - Li, Jun Z.
AU - Liu, Chunyu
AU - Lucae, Susanne
AU - Maaser, Anna
AU - MacIntyre, Donald J.
AU - Mahon, Pamela B.
AU - Martinsson, Lina
AU - McCarroll, Steve
AU - McGuffin, Peter
AU - McInnis, Melvin G.
AU - McKay, James D.
AU - Medeiros, Helena
AU - Medland, Sarah E.
AU - Meng, Fan
AU - Montgomery, Grant W.
AU - Mühleisen, Thomas W.
AU - Mullins, Niamh
AU - Nguyen, Hoang
AU - Nievergelt, Caroline M.
AU - Adolfsson, Annelie Nordin
AU - Nwulia, Evaristus A.
AU - O'Donovan, Claire
AU - Olde Loohuis, Loes M.
AU - Ori, Anil P. S.
AU - Oruc, Lilijana
AU - Ösby, Urban
AU - Perlis, Roy H.
AU - Perry, Amy
AU - Pfennig, Andrea
AU - Potash, James B.
AU - Purcell, Shaun M.
AU - Regeer, Eline J.
AU - Reif, Andreas
AU - Reinbold, C. line S.
AU - Rice, John P.
AU - Rivas, Fabio
AU - Rivera, Margarita
AU - Roussos, Panos
AU - Ruderfer, Douglas M.
AU - Ryu, Euijung
AU - Sánchez-Mora, Cristina
AU - Schatzberg, Alan F.
AU - Scheftner, William A.
AU - Schork, Nicholas J.
AU - Weickert, Cynthia Shannon
AU - Shehktman, Tatyana
AU - Shilling, Paul D.
AU - Sigurdsson, Engilbert
AU - Slaney, Claire
AU - Smeland, Olav B.
AU - Sobell, Janet L.
AU - Hansen, Christine S. holm
AU - Spijker, Anne T.
AU - Steffens, Michael
AU - Strauss, John S.
AU - Streit, Fabian
AU - Strohmaier, Jana
AU - Szelinger, Szabolcs
AU - Thompson, Robert C.
AU - Thorgeirsson, Thorgeir E.
AU - Treutlein, Jens
AU - Vedder, Helmut
AU - Wang, Weiqing
AU - Watson, Stanley J.
AU - Weickert, Thomas W.
AU - Witt, Stephanie H.
AU - Xi, Simon
AU - Xu, Wei
AU - Young, Allan H.
AU - Zandi, Peter
AU - Zhang, Peng
AU - Zöllner, Sebastian
AU - Martin, Nicholas G.
AU - Fullerton, Janice M.
AU - Mitchell, Philip B.
AU - Schofield, Peter R.
AU - Schaupp, Sabrina
AU - Comes, Ashley L.
AU - Sirignano, Lea
AU - Cichon, Sven
AU - Grigoroiu-Serbanescu, Maria
AU - Hauser, Joanna
AU - Lissowska, Jolanta
AU - Mayoral, Fermin
AU - Świątkowska, Beata
AU - Schulze, Thomas G.
AU - Nöthen, Markus M.
AU - Rietschel, Marcella
AU - Kelsoe, John
AU - Leboyer, Marion
AU - Etain, Bruno
AU - Bellivier, Frank
AU - Vincent, John B.
AU - Alda, Martin
AU - O'Donovan, Claire
AU - Biernacka, Joanna M.
AU - Frye, Mark
AU - McElroy, Susan L.
AU - Scott, Laura J.
AU - Landén, Mikael
AU - Vaaler, Arne E.
AU - Andreassen, Ole A.
AU - Wray, Naomi R.
AU - Abdellaoui, Abdel
AU - Adams, Mark J.
AU - Air, Tracy M.
AU - Andlauer, Till F. M.
AU - Bacanu, Silviu-Alin
AU - Beekman, Aartjan T. F.
AU - Binder, Elisabeth B.
AU - Bryois, Julien
AU - Buttenschøn, Henriette N.
AU - Cai, Na
AU - Castelao, Enrique
AU - Christensen, Jane Hvarregaard
AU - Colodro-Conde, Lucía
AU - Couvy-Duchesne, Baptiste
AU - Crawford, Gregory E.
AU - Davies, Gail
AU - Deary, Ian J.
AU - Derks, Eske M.
AU - Direk, Nese
AU - Dolan, Conor V.
AU - Dunn, Erin C.
AU - Eley, Thalia C.
AU - Hassan Kiadeh, Farnush Farhadi
AU - Finucane, Hilary K.
AU - Foo, Jerome C.
AU - Gill, Michael
AU - Goes, Fernando S.
AU - Hall, Lynsey S.
AU - Hansen, Thomas F.
AU - Hickie, Ian B.
AU - Homuth, Georg
AU - Horn, Carsten
AU - Hottenga, Jouke-Jan
AU - Howard, David M.
AU - Ising, Marcus
AU - Jansen, Rick
AU - Jones, Ian
AU - Jones, Lisa A.
AU - Jorgenson, Eric
AU - Kohane, Isaac S.
AU - Kraft, Julia
AU - Kretzschmar, Warren W.
AU - Kutalik, Zoltán
AU - Li, Yihan
AU - Lind, Penelope A.
AU - MacKinnon, Dean F.
AU - Maier, Robert M.
AU - Marchini, Jonathan
AU - Mbarek, Hamdi
AU - McGrath, Patrick
AU - Mehta, Divya
AU - Middeldorp, Christel M.
AU - Mihailov, Evelin
AU - Milaneschi, Yuri
AU - Mondimore, Francis M.
AU - Mostafavi, Sara
AU - Nauck, Matthias
AU - Ng, Bernard
AU - Nivard, Michel G.
AU - Nyholt, Dale R.
AU - O'Reilly, Paul F.
AU - Oskarsson, Hogni
AU - Owen, Michael J.
AU - Painter, Jodie N.
AU - Peterson, Roseann E.
AU - Peyrot, Wouter J.
AU - Pistis, Giorgio
AU - Posthuma, Danielle
AU - Quiroz, Jorge A.
AU - Qvist, Per
AU - Mirza, Saira Saeed
AU - Schoevers, Robert
AU - Schulte, Eva C.
AU - Shen, Ling
AU - Shi, Jianxin
AU - Shyn, Stanley I.
AU - Sinnamon, Grant C. B.
AU - Smit, Johannes H.
AU - Smith, Daniel J.
AU - Stefansson, Hreinn
AU - Tansey, Katherine E.
AU - Teismann, Henning
AU - Teumer, Alexander
AU - Thompson, Wesley
AU - Thomson, Pippa A.
AU - Traylor, Matthew
AU - Uitterlinden, André G.
AU - Umbricht, Daniel
AU - van der Auwera, Sandra
AU - van Hemert, Albert M.
AU - Viktorin, Alexander
AU - Visscher, Peter M.
AU - Webb, Bradley T.
AU - Weinsheimer, Shantel Marie
AU - Wellmann, J. rgen
AU - Willemsen, Gonneke
AU - Wu, Yang
AU - Xi, Hualin S.
AU - Yang, Jian
AU - Zhang, Futao
AU - Arolt, Volker
AU - Baune, Bernhard T.
AU - Berger, Klaus
AU - Boomsma, Dorret I.
AU - Dannlowski, Udo
AU - de Geus, Eco J. C.
AU - Domenici, Enrico
AU - Domschke, Katharina
AU - Grabe, Hans J.
AU - Hamilton, Steven P.
AU - Hayward, Caroline
AU - Heath, Andrew C.
AU - Kendler, Kenneth S.
AU - Kloiber, Stefan
AU - Lewis, Glyn
AU - Li, Qingqin S.
AU - Madden, Pamela A. F.
AU - Magnusson, Patrik K.
AU - Mortensen, Preben Bo
AU - Nordentoft, Merete
AU - O'Donovan, Michael C.
AU - Paciga, Sara A.
AU - Pedersen, Nancy L.
AU - Penninx, Brenda W. J. H.
AU - Porteous, David J.
AU - Preisig, Martin
AU - Schaefer, Catherine
AU - Smoller, Jordan W.
AU - Stefansson, Kari
AU - Tiemeier, Henning
AU - Uher, Rudolf
AU - Völzke, Henry
AU - Weissman, Myrna M.
AU - Werge, Thomas
AU - Lewis, Cathryn M.
AU - Levinson, Douglas F.
AU - Børglum, Anders D.
AU - Air, Tracy
AU - Völker, Uwe
AU - Bortolato, Marco
AU - Bralten, Janita
AU - Bulik, Cynthia M.
AU - Burton, Christie L.
AU - Carey, Caitlin E.
AU - Davis, Lea K.
AU - Duncan, Laramie E.
AU - Edenberg, Howard J.
AU - Erdman, Lauren
AU - Faraone, Stephen V.
AU - Goldstein, Jill M.
AU - Goleva, Slavina B.
AU - Guo, Wei
AU - Hübel, Christopher
AU - Huckins, Laura M.
AU - Khramtsova, Ekaterina A.
AU - Martin, Joanna
AU - Mathews, Carol A.
AU - Petryshen, Tracey L.
AU - Robinson, Elise
AU - Stahl, Eli
AU - Stranger, Barbara E.
AU - Traglia, Michela
AU - Walters, Raymond K.
AU - Weiss, Lauren A.
AU - Winham, Stacey J.
AU - Yao, Yin
AU - Skajaa, Kristjar
AU - Nöthen, Markus
AU - Owen, Michael
AU - Yolken, Robert H.
AU - Plath, Niels
AU - Mill, Jonathan
AU - Geschwind, Daniel
AU - Mortensen, Preben B.
N1 - Funding Information: These analyses were supported by a private donor, Ms. Gwill York (to JMG) and, in part, by the National Institute of Mental Health (NIMH) and Office of Research on Women's Health (Grant No. ORWH-NIMH U54 MH118919 [to JMG, ST, and RH; JMG and RH, multi?principal investigators] and Grant No. NIMH R01 MH092380 [to TLP, principal investigator]). Funding sources for individual cohorts are provided in reference numbers ( 35?37). Summary statistics are available for download from https://www.med.unc.edu/pgc/ upon publication. JMG is on the scientific advisory board for and has equity in Cala Health, a neuromodulation company, although this is unrelated to the topic in this study; TLP is an employee of Concert Pharmaceuticals, also unrelated to this study. JWS is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. All other authors report no biomedical financial interests or potential conflicts of interest. Bipolar Disorder Working Group of the Psychiatric Genomics Consortium: Eli A. Stahl, Gerome Breen, Andreas J. Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R.I. Coleman, H?l?na A. Gaspar, Christiaan A. de Leeuw, Stacy Steinberg, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Tune H. Pers, Peter A. Holmans, Alexander L. Richards, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie B?kvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E. Bergen, Carsten B?cker Pedersen, Erlend B?en, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, David Curtis, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J. Raymond DePaulo, Srdjan Djurovic, Amanda L. Dobbyn, Ashley Dumont, Torbj?rn Elvs?shagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Gi?rtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Jos? Guzman-Parra, Marian L. Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, St?phane Jamain, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Lili Milani, Grant W. Montgomery, Derek W. Morris, Thomas W. M?hleisen, Niamh Mullins, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban ?sby, Roy H. Perlis, Amy Perry, Andrea Pfennig, James B. Potash, Shaun M. Purcell, Eline J. Regeer, Andreas Reif, C?line S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina S?nchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Christine S?holm Hansen, Anne T. Spijker, David St Clair, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Stephanie H. Witt, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Z?llner, eQTLGen Consortium, BIOS Consortium, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Anders D. B?rglum, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, T?nu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, Ren? S. Kahn, George Kirov, Mikael Land?n, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram M?ller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. N?then, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribas?s, Marcella Rietschel, Guy A. Rouleau, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Thomas Werge, John I. Nurnberger, Naomi R. Wray, Arianna Di Florio, Howard J. Edenberg, Sven Cichon, Roel A. Ophoff, Laura J. Scott, Ole A. Andreassen, John Kelsoe, Pamela Sklar?. Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium: Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Esben Agerbo, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie B?kvad-Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttensch?n, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Jonathan R.I. Coleman, Luc?a Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Josef Frank, H?l?na A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine S?holm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zolt?n Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Michael J. Owen, Jodie N. Painter, Carsten B?cker Pedersen, Marianne Gi?rtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Jianxin Shi, Stanley I. Shyn, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, Andr? G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Shantel Marie Weinsheimer, J?rgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, Eco J.C. de Geus, J. Raymond DePaulo, Enrico Domenici, Katharina Domschke, T?nu Esko, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Kenneth S. Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S. Li, Susanne Lucae, Pamela AF Madden, Patrik K. Magnusson, Nicholas G. Martin, Andrew M. McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram M?ller-Myhsok, Merete Nordentoft, Markus M. N?then, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, Roy H. Perlis, David J. Porteous, James B. Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G. Schulze, Jordan W. Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry V?lzke, Myrna M. Weissman, Thomas Werge, Cathryn M. Lewis, Douglas F. Levinson, Gerome Breen, Anders D. B?rglum, Patrick F. Sullivan. Funding Information: These analyses were supported by a private donor, Ms. Gwill York (to JMG) and, in part, by the National Institute of Mental Health (NIMH) and Office of Research on Women's Health (Grant No. ORWH-NIMH U54 MH118919 [to JMG, ST, and RH; JMG and RH, multi–principal investigators] and Grant No. NIMH R01 MH092380 [to TLP, principal investigator]). Funding sources for individual cohorts are provided in reference numbers ( 35–37 ). Publisher Copyright: © 2021 Society of Biological Psychiatry Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
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 (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.
KW - Bipolar disorder
KW - Genome-wide association study
KW - Genotype-by-sex interaction
KW - Major depressive disorder
KW - Schizophrenia
KW - Sex differences
UR - http://www.scopus.com/inward/record.url?scp=85108284544&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2021.02.972
DO - 10.1016/j.biopsych.2021.02.972
M3 - Article
C2 - 34099189
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
ER -