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

Gabriëlla A.M. Blokland; Jakob Grove; Chia-yen Chen; Chris Cotsapas; Stuart Tobet; Patrick F. Sullivan; Dorret I. Boomsma; Brenda W.J.H. Penninx; Jouke-Jan Hottenga; Eco J.C. de Geus; Gonneke Willemsen; Yuri Milaneschi; Thomas D. Als; Anders D. Børglum; Tracey L. Petryshen; Jordan W. Smoller; Jill M. Goldstein; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Sex Differences Cross-Disorder Analysis 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

Gabriëlla A.M. Blokland, Jakob Grove, Chia-yen Chen, Chris Cotsapas, Stuart Tobet, Patrick F. Sullivan, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics ConsortiumSex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH

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

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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
Pages (from-to)	102-117
Number of pages	16
Journal	Biological Psychiatry
Volume	91
Issue number	1
Early online date	23 Mar 2021
DOIs	https://doi.org/10.1016/j.biopsych.2021.02.972
Publication status	Published - 1 Jan 2022

Funding

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, Héléna 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 Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E. Bergen, Carsten Bøcker Pedersen, Erlend Bøen, 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, Torbjørn Elvsåshagen, 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 Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, José Guzman-Parra, Marian L. Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane 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. Mühleisen, 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 Ösby, Roy H. Perlis, Amy Perry, Andrea Pfennig, James B. Potash, Shaun M. Purcell, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-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 Søholm 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 Zöllner, 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. Børglum, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Tõnu 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, René S. Kahn, George Kirov, Mikael Landén, 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 Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, 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 Ribasés, 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 Bækvad-Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Jonathan R.I. Coleman, Lucía 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, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm 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, Zoltán 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 Bøcker Pedersen, Marianne Giørtz 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, André 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, Jürgen 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, Tõnu 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 Müller-Myhsok, Merete Nordentoft, Markus M. Nöthen, 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 Völzke, Myrna M. Weissman, Thomas Werge, Cathryn M. Lewis, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, Patrick F. Sullivan. 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 ).

Funders	Funder number
Hualin S. Xi
National Institute of Mental Health	U54MH118919
Office of Research on Women's Health	R01 MH092380, 35–37
Concert Pharmaceuticals

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10.1016/j.biopsych.2021.02.972

SexDependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic DisordersFinal published version, 966 KBLicence: Article 25fa Dutch Copyright Act

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Blokland, G. A. M., Grove, J., Chen, C., Cotsapas, C., Tobet, S., Sullivan, P. F., Boomsma, D. I., Penninx, B. W. J. H., Hottenga, J.-J., de Geus, E. J. C., Willemsen, G., Milaneschi, Y., Als, T. D., Børglum, A. D., Petryshen, T. L., Smoller, J. W., Goldstein, J. M., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, ... iPSYCH (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

@article{e1888d4f181d4946aaec9dd838cda2c2,

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

abstract = "BackgroundSex 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.MethodsWe 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.ResultsAcross 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).ConclusionsIn 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.",

author = "Blokland, {Gabri{\"e}lla A.M.} and Jakob Grove and Chia-yen Chen and Chris Cotsapas and Stuart Tobet and Robert Handa 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 Aiden Corvin and Riley, {Brien P.} and T{\~o}nu Esko and Lili Milani and J{\"o}nsson, {Erik G.} and Aarno Palotie and Hannelore Ehrenreich and Martin Begemann 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 Ina Giegling and Bettina Konte and Hartmann, {Annette M.} and Elvira Bramon and Murray, {Robin M.} and Pato, {Michele T.} and Jimmy Lee and Ingrid Melle and Espen Molden and Ophoff, {Roel A.} and Andrew Mcquillin and Bass, {Nicholas J.} and Rolf Adolfsson and Malhotra, {Anil K.} and Martin, {Nicholas G.} and Fullerton, {Janice M.} and Mitchell, {Philip B.} and Schofield, {Peter R.} and Forstner, {Andreas J.} and Franziska Degenhardt and Sabrina Schaupp and Comes, {Ashley L.} and Manolis Kogevinas and Jos{\'e} Guzman-parra and Andreas Reif and Fabian Streit and Lea Sirignano and Sven Cichon and Maria Grigoroiu-serbanescu and Joanna Hauser and Jolanta Lissowska and Fermin Mayoral and Bertram M{\"u}ller-myhsok and Beata {\'S}wi{\c a}tkowska and Schulze, {Thomas G.} and Markus N{\"o}then and Marcella Rietschel and John Kelsoe and Marion Leboyer and St{\'e}phane Jamain and Bruno Etain and Frank Bellivier and Vincent, {John B.} and Martin Alda and Claire O{\textquoteright}donovan and Pablo Cervantes and Biernacka, {Joanna M.} and Mark Frye and Mcelroy, {Susan L.} and Scott, {Laura J.} and Eli Stahl and Mikael Land{\'e}n and Hamshere, {Marian L.} and Smeland, {Olav B.} and Srdjan Djurovic and Vaaler, {Arne E.} and Andreassen, {Ole A.} and Baune, {Bernhard T.} and Tracy Air and Martin Preisig and Rudolf Uher and Levinson, {Douglas F.} and Weissman, {Myrna M.} and Potash, {James B.} and Jianxin Shi and Knowles, {James A.} and Perlis, {Roy H.} and Susanne Lucae and Boomsma, {Dorret I.} and Penninx, {Brenda W.J.H.} and Jouke-Jan Hottenga and {de Geus}, {Eco J.C.} and Gonneke Willemsen and Yuri Milaneschi and Henning Tiemeier and Grabe, {Hans J.} and Alexander Teumer and {Van Der Auwera}, Sandra and Uwe V{\"o}lker and Hamilton, {Steven P.} and Magnusson, {Patrik K.e.} and Alexander Viktorin and Divya Mehta and Niamh Mullins and Adams, {Mark J.} and Gerome Breen and Mcintosh, {Andrew M.} and Lewis, {Cathryn M.} and Hougaard, {David M.} and Merete Nordentoft and Ole Mors and Mortensen, {Preben Bo} and Thomas Werge and Als, {Thomas D.} and B{\o}rglum, {Anders D.} and Petryshen, {Tracey L.} and Smoller, {Jordan W.} and Goldstein, {Jill M.} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and {Bipolar Disorder Working Group of the Psychiatric Genomics Consortium} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and {Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium} and iPSYCH",

year = "2022",

month = jan,

day = "1",

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

language = "English",

volume = "91",

pages = "102--117",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "1",

}

Blokland, GAM, Grove, J, Chen, C, Cotsapas, C, Tobet, S, Sullivan, PF, Boomsma, DI, Penninx, BWJH, Hottenga, J-J , de Geus, EJC , Willemsen, G, Milaneschi, Y, Als, TD, Børglum, AD, Petryshen, TL, Smoller, JW, Goldstein, JM, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium & iPSYCH 2022, 'Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders', Biological Psychiatry, vol. 91, no. 1, pp. 102-117. https://doi.org/10.1016/j.biopsych.2021.02.972

TY - JOUR

T1 - Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

AU - Blokland, Gabriëlla A.M.

AU - Grove, Jakob

AU - Chen, Chia-yen

AU - Cotsapas, Chris

AU - Tobet, Stuart

AU - Handa, Robert

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 - Corvin, Aiden

AU - Riley, Brien P.

AU - Esko, Tõnu

AU - Milani, Lili

AU - Jönsson, Erik G.

AU - Palotie, Aarno

AU - Ehrenreich, Hannelore

AU - Begemann, Martin

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 - Giegling, Ina

AU - Konte, Bettina

AU - Hartmann, Annette M.

AU - Bramon, Elvira

AU - Murray, Robin M.

AU - Pato, Michele T.

AU - Lee, Jimmy

AU - Melle, Ingrid

AU - Molden, Espen

AU - Ophoff, Roel A.

AU - Mcquillin, Andrew

AU - Bass, Nicholas J.

AU - Adolfsson, Rolf

AU - Malhotra, Anil K.

AU - Martin, Nicholas G.

AU - Fullerton, Janice M.

AU - Mitchell, Philip B.

AU - Schofield, Peter R.

AU - Forstner, Andreas J.

AU - Degenhardt, Franziska

AU - Schaupp, Sabrina

AU - Comes, Ashley L.

AU - Kogevinas, Manolis

AU - Guzman-parra, José

AU - Reif, Andreas

AU - Streit, Fabian

AU - Sirignano, Lea

AU - Cichon, Sven

AU - Grigoroiu-serbanescu, Maria

AU - Hauser, Joanna

AU - Lissowska, Jolanta

AU - Mayoral, Fermin

AU - Müller-myhsok, Bertram

AU - Świątkowska, Beata

AU - Schulze, Thomas G.

AU - Nöthen, Markus

AU - Rietschel, Marcella

AU - Kelsoe, John

AU - Leboyer, Marion

AU - Jamain, Stéphane

AU - Etain, Bruno

AU - Bellivier, Frank

AU - Vincent, John B.

AU - Alda, Martin

AU - O’donovan, Claire

AU - Cervantes, Pablo

AU - Biernacka, Joanna M.

AU - Frye, Mark

AU - Mcelroy, Susan L.

AU - Scott, Laura J.

AU - Stahl, Eli

AU - Landén, Mikael

AU - Hamshere, Marian L.

AU - Smeland, Olav B.

AU - Djurovic, Srdjan

AU - Vaaler, Arne E.

AU - Andreassen, Ole A.

AU - Baune, Bernhard T.

AU - Air, Tracy

AU - Preisig, Martin

AU - Uher, Rudolf

AU - Levinson, Douglas F.

AU - Weissman, Myrna M.

AU - Potash, James B.

AU - Shi, Jianxin

AU - Knowles, James A.

AU - Perlis, Roy H.

AU - Lucae, Susanne

AU - Boomsma, Dorret I.

AU - Penninx, Brenda W.J.H.

AU - Hottenga, Jouke-Jan

AU - de Geus, Eco J.C.

AU - Willemsen, Gonneke

AU - Milaneschi, Yuri

AU - Tiemeier, Henning

AU - Grabe, Hans J.

AU - Teumer, Alexander

AU - Van Der Auwera, Sandra

AU - Völker, Uwe

AU - Hamilton, Steven P.

AU - Magnusson, Patrik K.e.

AU - Viktorin, Alexander

AU - Mehta, Divya

AU - Mullins, Niamh

AU - Adams, Mark J.

AU - Breen, Gerome

AU - Mcintosh, Andrew M.

AU - Lewis, Cathryn M.

AU - Hougaard, David M.

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Werge, Thomas

AU - Als, Thomas D.

AU - Børglum, Anders D.

AU - Petryshen, Tracey L.

AU - Smoller, Jordan W.

AU - Goldstein, Jill M.

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

AU - iPSYCH

PY - 2022/1/1

Y1 - 2022/1/1

N2 - BackgroundSex 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.MethodsWe 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.ResultsAcross 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).ConclusionsIn 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 - BackgroundSex 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.MethodsWe 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.ResultsAcross 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).ConclusionsIn 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.

U2 - 10.1016/j.biopsych.2021.02.972

DO - 10.1016/j.biopsych.2021.02.972

M3 - Article

SN - 0006-3223

VL - 91

SP - 102

EP - 117

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 1

ER -

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

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