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; Schizophrenia Working Group of the Psychiatric Genomics Consortium; iPSYCH

doi:10.1016/j.biopsych.2021.02.972

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, Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH

Research output: Contribution to journal › Article › Academic › peer-review

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
Journal	Biological Psychiatry
Early online date	2021
DOIs	https://doi.org/10.1016/j.biopsych.2021.02.972
Publication status	E-pub ahead of print - 2021

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10.1016/j.biopsych.2021.02.972

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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, Schizophrenia Working Group of the Psychiatric Genomics Consortium, & iPSYCH (2021). Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2021.02.972

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. / Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. In: Biological Psychiatry. 2021.

@article{ebe55d9e24ae4c1098c5cdffe48e2a89,

title = "Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders",

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. ",

keywords = "Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences",

author = "Blokland, {Gabri{\"e}lla A. M.} and Jakob Grove and {Bipolar Disorder Working Group of the Psychiatric Genomics Consortium} and {Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Chia-Yen Chen and Chris Cotsapas and Stuart Tobet and Robert Handa and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and Stephan Ripke and Neale, {Benjamin M.} and Aiden Corvin and Walters, {James T. R.} and Kai-How Farh and Holmans, {Peter A.} and Phil Lee and Brendan Bulik-Sullivan and Collier, {David A.} and Hailiang Huang and Pers, {Tune H.} and Ingrid Agartz and Esben Agerbo and Margot Albus and Madeline Alexander and Farooq Amin and Bacanu, {Silviu A.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and William Byerley and Wiepke Cahn and Guiqing Cai and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Catts, {Stanley V.} and Chambert, {Kimberly D.} and Chan, {Raymond C. K.} and Chen, {Ronald Y. L.} and Chen, {Eric Y. H.} and Wei Cheng and Cheung, {Eric F. C.} and Chong, {Siow Ann} and Cloninger, {C. Robert} and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and Crowley, {James J.} and David Curtis and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and {del Favero}, Jurgen and Ditte Demontis and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Naser Durmishi and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Laurent Essioux and Fanous, {Ayman H.} and Farrell, {Martilias S.} and Josef Frank and Lude Franke and Robert Freedman and Freimer, {Nelson B.} and Marion Friedl and Friedman, {Joseph I.} and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Ina Giegling and Paola Giusti-Rodr{\'i}guez and Stephanie Godard and Goldstein, {Jacqueline I.} and Vera Golimbet and Srihari Gopal and Jacob Gratten and {de Haan}, Lieuwe and Christian Hammer and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian and Hartmann, {Annette M.} and Henskens, {Frans A.} and Stefan Herms and Hirschhorn, {Joel N.} and Per Hoffmann and Andrea Hofman and Hollegaard, {Mads V.} and iPSYCH and Hougaard, {David M.} and Masashi Ikeda and Inge Joa and Antonio Juli{\`a} and Kahn, {Ren{\'e} S.} and Luba Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kennedy, {James L.} and Andrey Khrunin and Yunjung Kim and Janis Klovins and Knowles, {James A.} and Bettina Konte and Vaidutis Kucinskas and Kucinskiene, {Zita Ausrele} and Hana Kuzelova-Ptackova and K{\"a}hler, {Anna K.} and Claudine Laurent and {Lee Chee Keong}, Jimmy and Lee, {S. Hong} and Legge, {Sophie E.} and Bernard Lerer and Miaoxin Li and Tao Li and Kung-Yee Liang and Jeffrey Lieberman and Svetlana Limborska and Loughland, {Carmel M.} and Jan Lubinski and Jouko L{\"o}nnqvist and Milan Macek and Magnusson, {Patrik K. E.} and Maher, {Brion S.} and Wolfgang Maier and Jacques Mallet and Sara Marsal and Manuel Mattheisen and Morten Mattingsdal and McCarley, {Robert W.} and Colm McDonald and McIntosh, {Andrew M.} and Sandra Meier and Meijer, {Carin J.} and Bela Melegh and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Younes Mokrab and Morris, {Derek W.} and Ole Mors and Murphy, {Kieran C.} and Murray, {Robin M.} and Inez Myin-Germeys and Bertram M{\"u}ller-Myhsok and Mari Nelis and Igor Nenadic and Nertney, {Deborah A.} and Gerald Nestadt and Nicodemus, {Kristin K.} and Liene Nikitina-Zake and Laura Nisenbaum and Annelie Nordin and Eadbhard O'Callaghan and Colm O'Dushlaine and O'Neill, {F. Anthony} and Sang-Yun Oh and Ann Olincy and Line Olsen and {van Os}, Jim and {St Clair}, David and Todd Lencz and Mowry, {Bryan J.} and Sathish Periyasamy and Cairns, {Murray J.} and Tooney, {Paul A.} and Wu, {Jing Qin} and Brian Kelly and George Kirov and Sullivan, {Patrick F.} and Riley, {Brien P.} and Esko, {T. nu} and J{\"o}nsson, {Erik G.} and Aarno Palotie and Hannelore Ehrenreich and Agnes Steixner-Kumar and Sham, {Pak C.} and Nakao Iwata and Weinberger, {Daniel R.} and Gejman, {Pablo V.} and Sanders, {Alan R.} and Buxbaum, {Joseph D.} and Dan Rujescu and Elvira Bramon and Pato, {Michele T.} and Jimmy Lee and Espen Molden and Ophoff, {Roel A.} and Andrew McQuillin and Bass, {Nicholas J.} and Rolf Adolfsson and Malhotra, {Anil K.} and Stahl, {Eli A.} and Gerome Breen and Forstner, {Andreas J.} and Vassily Trubetskoy and Yunpeng Wang and Coleman, {Jonathan R. I.} and Gaspar, {H. l{\'e}na A.} and {de Leeuw}, {Christiaan A.} and Stacy Steinberg and {Whitehead Pavlides}, {Jennifer M.} and Maciej Trzaskowski and Byrne, {Enda M.} and Richards, {Alexander L.} and Liam Abbott and Huda Akil and Diego Albani and Ney Alliey-Rodriguez and Als, {Thomas D.} and Adebayo Anjorin and Verneri Antilla and Swapnil Awasthi and Badner, {Judith A.} and Marie B{\ae}kvad-Hansen and Barchas, {Jack D.} and Nicholas Bass and Michael Bauer and Richard Belliveau and Pedersen, {Carsten B. cker} and Erlend B{\o}en and Boks, {Marco P.} and James Boocock and Monika Budde and William Bunney and Margit Burmeister and Jonas Bybjerg-Grauholm and Miquel Casas and Felecia Cerrato and Pablo Cervantes and Kimberly Chambert and Charney, {Alexander W.} and Danfeng Chen and Claire Churchhouse and Toni-Kim Clarke and William Coryell and Craig, {David W.} and Cristiana Cruceanu and Czerski, {Piotr M.} and Dale, {Anders M.} and {de Jong}, Simone and Jurgen del-Favero and DePaulo, {J. Raymond} and Dobbyn, {Amanda L.} and Ashley Dumont and Torbj{\o}rn Elvs{\aa}shagen and Fan, {Chun Chieh} and Fischer, {Sascha B.} and Matthew Flickinger and Foroud, {Tatiana M.} and Liz Forty and Christine Fraser and Katrin Gade and Diane Gage and Julie Garnham and Claudia Giambartolomei and Pedersen, {Marianne Gi{\o}rtz} and Jaqueline Goldstein and Gordon, {Scott D.} and Katherine Gordon-Smith and Green, {Elaine K.} and Green, {Melissa J.} and Greenwood, {Tiffany A.} and Weihua Guan and Jos{\'e} Guzman-Parra and Martin Hautzinger and Urs Heilbronner and Maria Hipolito and Dominic Holland and Laura Huckins and St{\'e}phane Jamain and Johnson, {Jessica S.} and Radhika Kandaswamy and Robert Karlsson and Sarah Kittel-Schneider and Manolis Kogevinas and Koller, {Anna C.} and Ralph Kupka and Catharina Lavebratt and Jacob Lawrence and Lawson, {William B.} and Markus Leber and Lee, {Phil H.} and Levy, {Shawn E.} and Li, {Jun Z.} and Chunyu Liu and Susanne Lucae and Anna Maaser and MacIntyre, {Donald J.} and Mahon, {Pamela B.} and Lina Martinsson and Steve McCarroll and Peter McGuffin and McInnis, {Melvin G.} and McKay, {James D.} and Helena Medeiros and Medland, {Sarah E.} and Fan Meng and Montgomery, {Grant W.} and M{\"u}hleisen, {Thomas W.} and Niamh Mullins and Hoang Nguyen and Nievergelt, {Caroline M.} and Adolfsson, {Annelie Nordin} and Nwulia, {Evaristus A.} and Claire O'Donovan and {Olde Loohuis}, {Loes M.} and Ori, {Anil P. S.} and Lilijana Oruc and Urban {\"O}sby and Perlis, {Roy H.} and Amy Perry and Andrea Pfennig and Potash, {James B.} and Purcell, {Shaun M.} and Regeer, {Eline J.} and Andreas Reif and Reinbold, {C. line S.} and Rice, {John P.} and Fabio Rivas and Margarita Rivera and Panos Roussos and Ruderfer, {Douglas M.} and Euijung Ryu and Cristina S{\'a}nchez-Mora and Schatzberg, {Alan F.} and Scheftner, {William A.} and Schork, {Nicholas J.} and Weickert, {Cynthia Shannon} and Tatyana Shehktman and Shilling, {Paul D.} and Engilbert Sigurdsson and Claire Slaney and Smeland, {Olav B.} and Sobell, {Janet L.} and Hansen, {Christine S. holm} and Spijker, {Anne T.} and Michael Steffens and Strauss, {John S.} and Fabian Streit and Jana Strohmaier and Szabolcs Szelinger and Thompson, {Robert C.} and Thorgeirsson, {Thorgeir E.} and Jens Treutlein and Helmut Vedder and Weiqing Wang and Watson, {Stanley J.} and Weickert, {Thomas W.} and Witt, {Stephanie H.} and Simon Xi and Wei Xu and Young, {Allan H.} and Peter Zandi and Peng Zhang and Sebastian Z{\"o}llner and Martin, {Nicholas G.} and Fullerton, {Janice M.} and Mitchell, {Philip B.} and Schofield, {Peter R.} and Sabrina Schaupp and Comes, {Ashley L.} and Lea Sirignano and Sven Cichon and Maria Grigoroiu-Serbanescu and Joanna Hauser and Jolanta Lissowska and Fermin Mayoral and Beata {\'S}wi{\c a}tkowska and Schulze, {Thomas G.} and N{\"o}then, {Markus M.} and Marcella Rietschel and John Kelsoe and Marion Leboyer and Bruno Etain and Frank Bellivier and Vincent, {John B.} and Martin Alda and Claire O'Donovan and Biernacka, {Joanna M.} and Mark Frye and McElroy, {Susan L.} and Scott, {Laura J.} and Mikael Land{\'e}n and Vaaler, {Arne E.} and Andreassen, {Ole A.} and Wray, {Naomi R.} and Abdel Abdellaoui and Adams, {Mark J.} and Air, {Tracy M.} and Andlauer, {Till F. M.} and Silviu-Alin Bacanu and Beekman, {Aartjan T. F.} and Binder, {Elisabeth B.} and Julien Bryois and Buttensch{\o}n, {Henriette N.} and Na Cai and Enrique Castelao and Christensen, {Jane Hvarregaard} and Luc{\'i}a Colodro-Conde and Baptiste Couvy-Duchesne and Crawford, {Gregory E.} and Gail Davies and Deary, {Ian J.} and Derks, {Eske M.} and Nese Direk and Dolan, {Conor V.} and Dunn, {Erin C.} and Eley, {Thalia C.} and {Hassan Kiadeh}, {Farnush Farhadi} and Finucane, {Hilary K.} and Foo, {Jerome C.} and Michael Gill and Goes, {Fernando S.} and Hall, {Lynsey S.} and Hansen, {Thomas F.} and Hickie, {Ian B.} and Georg Homuth and Carsten Horn and Jouke-Jan Hottenga and Howard, {David M.} and Marcus Ising and Rick Jansen and Ian Jones and Jones, {Lisa A.} and Eric Jorgenson and Kohane, {Isaac S.} and Julia Kraft and Kretzschmar, {Warren W.} and Zolt{\'a}n Kutalik and Yihan Li and Lind, {Penelope A.} and MacKinnon, {Dean F.} and Maier, {Robert M.} and Jonathan Marchini and Hamdi Mbarek and Patrick McGrath and Divya Mehta and Middeldorp, {Christel M.} and Evelin Mihailov and Yuri Milaneschi and Mondimore, {Francis M.} and Sara Mostafavi and Matthias Nauck and Bernard Ng and Nivard, {Michel G.} and Nyholt, {Dale R.} and O'Reilly, {Paul F.} and Hogni Oskarsson and Owen, {Michael J.} and Painter, {Jodie N.} and Peterson, {Roseann E.} and Peyrot, {Wouter J.} and Giorgio Pistis and Danielle Posthuma and Quiroz, {Jorge A.} and Per Qvist and Mirza, {Saira Saeed} and Robert Schoevers and Schulte, {Eva C.} and Ling Shen and Jianxin Shi and Shyn, {Stanley I.} and Sinnamon, {Grant C. B.} and Smit, {Johannes H.} and Smith, {Daniel J.} and Hreinn Stefansson and Tansey, {Katherine E.} and Henning Teismann and Alexander Teumer and Wesley Thompson and Thomson, {Pippa A.} and Matthew Traylor and Uitterlinden, {Andr{\'e} G.} and Daniel Umbricht and {van der Auwera}, Sandra and {van Hemert}, {Albert M.} and Alexander Viktorin and Visscher, {Peter M.} and Webb, {Bradley T.} and Weinsheimer, {Shantel Marie} and Wellmann, {J. rgen} and Gonneke Willemsen and Yang Wu and Xi, {Hualin S.} and Jian Yang and Futao Zhang and Volker Arolt and Baune, {Bernhard T.} and Klaus Berger and Boomsma, {Dorret I.} and Udo Dannlowski and {de Geus}, {Eco J. C.} and Enrico Domenici and Katharina Domschke and Grabe, {Hans J.} and Hamilton, {Steven P.} and Caroline Hayward and Heath, {Andrew C.} and Kendler, {Kenneth S.} and Stefan Kloiber and Glyn Lewis and Li, {Qingqin S.} and Madden, {Pamela A. F.} and Magnusson, {Patrik K.} and Mortensen, {Preben Bo} and Merete Nordentoft and O'Donovan, {Michael C.} and Paciga, {Sara A.} and Pedersen, {Nancy L.} and Penninx, {Brenda W. J. H.} and Porteous, {David J.} and Martin Preisig and Catherine Schaefer and Smoller, {Jordan W.} and Kari Stefansson and Henning Tiemeier and Rudolf Uher and Henry V{\"o}lzke and Weissman, {Myrna M.} and Thomas Werge and Lewis, {Cathryn M.} and Levinson, {Douglas F.} and B{\o}rglum, {Anders D.} and Tracy Air and Uwe V{\"o}lker and Marco Bortolato and Janita Bralten and Bulik, {Cynthia M.} and Burton, {Christie L.} and Carey, {Caitlin E.} and Davis, {Lea K.} and Duncan, {Laramie E.} and Edenberg, {Howard J.} and Lauren Erdman and Faraone, {Stephen V.} and Goldstein, {Jill M.} and Goleva, {Slavina B.} and Wei Guo and Christopher H{\"u}bel and Huckins, {Laura M.} and Khramtsova, {Ekaterina A.} and Joanna Martin and Mathews, {Carol A.} and Petryshen, {Tracey L.} and Elise Robinson and Eli Stahl and Stranger, {Barbara E.} and Michela Traglia and Walters, {Raymond K.} and Weiss, {Lauren A.} and Winham, {Stacey J.} and Yin Yao and Kristjar Skajaa and Markus N{\"o}then and Michael Owen and Yolken, {Robert H.} and Niels Plath and Jonathan Mill and Daniel Geschwind and Mortensen, {Preben B.}",

note = "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: {\textcopyright} 2021 Society of Biological Psychiatry Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

doi = "10.1016/j.biopsych.2021.02.972",

language = "English",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

}

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, Schizophrenia Working Group of the Psychiatric Genomics Consortium & iPSYCH 2021, 'Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2021.02.972

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

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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

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AU - Eriksson, Johan

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AU - Fanous, Ayman H.

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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 -

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, Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry. 2021. Epub 2021. doi: 10.1016/j.biopsych.2021.02.972

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

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