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 signalling 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 | 1 Jan 2022 |
| DOIs | |
| Publication status | Published - 22 Mar 2022 |
Keywords
- Bipolar disorder
- Genome-wide association study
- Genotype-by-sex interaction
- Major depressive disorder
- Schizophrenia
- Sex differences
ASJC Scopus subject areas
- Biological Psychiatry
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In: Biological Psychiatry, Vol. 91, No. 1, 22.03.2022, p. 102-117.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
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 - Scott, Laura J.
AU - Adams, Mark J.
AU - McIntosh, Andrew M.
AU - Cohen, David
AU - Moran, Jennifer L.
AU - Donnelly, Peter
AU - Palmer, Colin N.A.
AU - Li, Jun Z.
AU - Davies, Gail
AU - Schulte, Eva C.
AU - Berger, Klaus
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, 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. 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
PY - 2022/3/22
Y1 - 2022/3/22
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 signalling 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 signalling 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
AN - SCOPUS:85108284544
SN - 0006-3223
VL - 91
SP - 102
EP - 117
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 1
ER -