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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, Robert J. Handa, James Walters, Kai-How Farh, Peter Holmans, Phil Lee, Brendan Bulik‐Sullivan, David Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Margot Albus, Madeline Alexander, Farooq Amin, Silviu‐Alin Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C. K. Chan, Ronald Y.L. Chen, Eric Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del‐Favero, Ditte Demontis, Dimitris Dikeos, Timothy G. Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan G. Eriksson, Valentina Escott‐Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti‐Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, В. Е. Голимбет, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Thomas Folkmann Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Andrey Khrunin, Yunjung Kim, Jānis Kloviņš, James A. Knowles, Bettina Konte, Vaidutis Kučinskas, Zita Aušrelė Kučinskienė, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, Sang Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung‐Yee Liang, Jeffrey A. Lieberman, Limborskaia Sa, Carmel M. Loughland, Jan Lubiński, Jouko Lönnqvist, Milan Maçek, Patrik K. E. Magnusson, Brion S. Maher, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Béla Melegh, Raquelle I. Mesholam‐Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Kieran C. Murphy, Robin Murray, Inez Myin‐Germeys, Bertram Müller‐Myhsok, Mari Nelis, Igor Nenadić, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Ņikitina-Zaķe, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejović-Milovančević, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew Pocklington, Alkes L. Price, Ann E. Pulver, Shaun Purcell, Digby Quested, Henrik Berg Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurðsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, P. A. Slominsky, Hon‐Cheong So, Chris C. A. Spencer, Eli A. Stahl, Elisabeth Stögmann, Richard E. Straub, Eric Strengman, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Švrakić, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Драга Тончева, Sarah Tosato, Juha Veijola, John L. Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kāri Stefánsson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas Blackwood, Joseph D. Buxbaum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Pablo V. Gejman, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen Jablensky, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Wu, Brian Kelly, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Daniëlle Posthuma, Brien P. Riley, Pak C. Sham, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Patrick F. Sullivan, Michael O‘Donovan, Inês Barroso, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Robert Plomin, Anna Rautanen, Stephen Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard D. Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T McCann, Simon Potter, Rathi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul A. Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, María J. Arranz, Steven C. Bakker, Stephan Bender, Benedicto Crespo‐Facorro, Jérémy Hall, Conrad Iyegbe, Stephen M. Lawrie, Cathryn M. Lewis, Kuang Lin, Don Linszen, Ignácio F. Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Agnes Steixner-Kumar, Espen Molden, Nicholas Bass, Gerome Breen, Vassily Trubetskoy, Yunpeng Wang, Jonathan R. I. Coleman, Héléna A. Gaspar, Christiaan de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, 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, Michael Bauer, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William E. Bunney, Margit Burmeister, Jonas Bybjerg‐Grauholm, Miguel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Amanda Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon‐Smith, Elaine Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, José Guzmán‐Parra, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura M. Huckins, Jessica Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel‐Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William Lawson, Markus Leber, Phil H. Lee, Shawn Levy, Jun Z. Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Thomas W. Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus Nwulia, Claire O’Donovan, Loes M. Olde Loohuis, Anil P. S. Ori, Lilijana Oruč, Urban Ösby, Roy H. Perlis, Amy Perry, Andrea Pfennig, James B. Potash, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez‐Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter P. Zandi, Peng Zhang, Sebastian Zöllner, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Sabrina K. Schaupp, Ashley L. Comes, Lea Sirignano, Maria Grigoroiu‐Serbânescu, Joanna Hauser, Jolanta Lissowska, Fermín Mayoral, Beata Świątkowska, John R. Kelsoe, Marion Leboyer, Bruno Étain, Frank Bellivier, John B. Vincent, Martin Alda, Joanna M. Biernacka, Mark A. Frye, Susan L. McElroy, Laura J. Scott, Mikael Landén, Stephan Ripke, Abdel Abdellaoui, Mark J. Adams, Tracy Air, Till F. M. Andlauer, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Christensen, Lucía Colodro‐Conde, Baptiste Couvy‐Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Neşe Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert Maier, Jonathan Marchini, Hamdi Mbarek, Patrick J. McGrath, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Högni Óskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert A. Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant Sinnamon, Johannes H. Smit, Daniel J. Smıth, Stacy Steinberg, Fabian Streit, Katherine E. Tansey, Henning Teismann, Wesley K. Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Shantel Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T. Baune, Udo Dannlowski, Eco J. C. de Geus, Katharina Domschke, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, P.A. Madden, Merete Nordentoft, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, David J. Porteous, Martin Preisig, Catherine Schaefer, Jordan W. Smoller, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M. Weissman, Uwe Völker, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Jill M. Goldstein, Slavina B. Goleva, Wei Guo, Christopher Hübel, Ekaterina Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Thomas Werge, Kristjar Skajaa, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel H. Geschwind, Preben Bo Mortensen
Bibliographic record
VenueBiological Psychiatry · 2021
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsMcGill University Health CentreDalhousie UniversityCentre for Addiction and Mental Health
FundersMedical Research CouncilGillings School of Public HealthH. Lundbeck A/SLundbeckfondenGGZ inGeestOffice of Research on Women's HealthMassachusetts General HospitalNational Institute for Health and Care ResearchCancer Research UKAmsterdam University Medical CentersNational Institute of Mental HealthConcert PharmaceuticalsVrije Universiteit AmsterdamWellcome TrustAarhus UniversitetErasmus Medisch CentrumStanley Center for Psychiatric Research, Broad InstituteUniversiteit Maastricht
KeywordsPsychologyGenetic architectureMood disordersMoodDevelopmental psychologyClinical psychologyPsychiatryGeneticsBiologyPhenotype
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: ) 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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.002
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.006
Threshold uncertainty score0.019
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.013
GPT teacher head0.275
Teacher spread0.262 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations139
Published2021
Admission routes1
Has abstractno