A cross-disorder analysis of CNVs finds novel loci and dose-dependent relationships of genes to psychiatric traits

作者：Omar Shanta, Marieke Klein, M Sacks, Jeffrey R. MacDonald, Adam X. Maihofer, Mohammad Ahangari, Worrawat Engchuan, Bhooma Thiruvahindrapuram, James P. Guevara, Oanh Hong, Guillaume Huguet, Ida E. Sønderby, Maria Kalyuzhny, Mark J. Adams, Rolf Adolfsson, Ingrid Agartz, Allison E. Aiello, Martin Alda, Judith Allardyce, Ananda B. Amstadter, Till F. M. Andlauer, Ole A. Andreassen, María S. Artigas, S. Bryn Austin, Muhammad Ayub, Dewleen G. Baker, Nick Bass, Bernhard T. Baune, Maximilian Bayas, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Jonathan I. Bisson, D. Blackwood, Marco P. Boks, David Braff, Elvira Bramon, Gerome Breen, T. Brueckl, Richard A. Bryant, Cynthia M. Bulik, Joseph D. Buxbaum, Murray J. Cairns, José Miguel Caldas‐de‐Almeida, Megan Campbell, Dominique Campion, Vaughan J. Carr, Enrique Castelao, Boris Chaumette, Sven Cichon, David Cohen, Aiden Corvin, Nicholas Craddock, Jennifer Crosbie, Darrina Czamara, Udo Dannlowski, Franziska Degenhardt, Douglas L. Delahanty, Astrid Dempfle, Guillaume Desachy, Arianna Di Florio, Faith Dickerson, Srdjan Djurovic, Katharina Domschke, Lisa Douglas, Ole Kristian Drange, Laramie E. Duncan, Howard J. Edenberg, Tõnu Esko, Stephen V. Faraone, Norah C. Feeny, Andreas J. Forstner, Barbara Franke, Mark A. Frye, Dong‐Jing Fu, Janice M. Fullerton, А. Э. Гареева, Linda Garvert, Justine M. Gatt, Pablo V. Gejman, Daniel H. Geschwind, Ina Giegling, Stephen J. Glatt, Joe Glessner, Fernando S. Goes, Katherine Gordon‐Smith, Hans J. Grabe, Melissa J. Green, Michael F. Green, Tiffany A. Greenwood, Maria Grigoroiu‐Serbânescu, Raquel E. Gur, Ruben C. Gur, José Guzmán‐Parra, Jan Haavik, Tim Hahn, Håkon Håkonarson, Joachim Hallmayer, Marian L. Hamshere, Annette M. Hartmann, Arsalan Hassan, Caroline Hayward, Johannes Hebebrand, Sian Hemmings, Stefan Herms, Marisol Herrera-Rivero, Anke Hinney, Georg Homuth, Andrés Ingason, Lucas Toshio Ito, Nakao Iwata, Ian Jones, Lisa Jones, Lina Jönsson, Erik G. Jönsson, René S. Kahn, Robert Karlsson, Milissa L. Kaufman, John R. Kelsoe, James L. Kennedy, Anthony P. King, Tilo Kircher, George Kirov, Per M. Knappskog, James A. Knowles, Nene Kobayashi, Karestan C. Koenen, Bettina Konte, Mayuresh S. Korgaonkar, Kaarina Kowalec, Marie‐Odile Krebs, Mikael Landén, Claudine Laurent‐Levinson, Lauren A. M. Lebois, Doug Levinson, Cathryn M. Lewis, Qingqin S. Li, Israel Liberzon, Greg Light, Sandra K. Loo, Yi Lu, Susanne Lucae, Charles R. Marmar, Nick Martin, Fermín Mayoral, Andrew M. McIntosh, Katie A. McLaughlin, Samuel A. McLean, Andrew McQuillin, Sarah E. Medland, Andreas Meyer‐Lindenberg, Vihra Milanova, Philip B. Mitchell, Esther Molina, Bryan Mowry, Bertram Müller‐Myhsok, Niamh Mullins, Robin Murray, Markus M. Nöthen, John I. Nürnberger, Kevin S. O’Connell, Roel A. Ophoff, Holly K. Orcutt, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Michele T. Pato, Joanna Pawlak, Triinu Peters, Tracey L. Petryshen, Giorgio Pistis, James B. Potash, John Powell, Martin Preisig, Digby Quested, Josep Antoni Ramos‐Quiroga, Andreas Reif, Kerry J. Ressler, Marta Ribasés, Marcella Rietschel, Victoria B. Risbrough, Margarita Rivera, Alex O. Rothbaum, Barbara O. Rothbaum, Dan Rujescu, Takeo Saito, Alan R. Sanders, Russell Schachar, Peter R. Schofield, Eva C. Schulte, Thomas G. Schulze, Laura J. Scott, Soraya Seedat, Christina M. Sheerin, Jianxin Shi, Pamela Sklar, Susan L. Smalley, Olav B. Smeland, Jordan W. Smoller, Edmund Sonuga‐Barke, David St Clair, Nils Eiel Steen, Dan J. Stein, Frederike Stein, Murray B. Stein, Fabian Streit, Neal R. Swerdlow, Florence Thibaut, Johan H. Thygesen, И. Ф. Тимербулатов, Claudio Toma, Edward Trapido, Micheline Tremblay, Ming T. Tsuang, Monica Uddin, Marquis P. Vawter, John B. Vincent, Henry Völzke, James Walters, Cynthia Shannon Weickert, Lauren A. Weiss, Myrna M. Weissman, Thomas Werge, Stephanie H. Witt, Miguel Xavier, Robert H. Yolken, Ross McD. Young, Tetyana Zayats, Lori A. Zoellner, Kimberley Kendall, Brien P. Riley, Naomi R. Wray, Michael O‘Donovan, Patrick F. Sullivan, Sandra Sanchez‐Roige, Caroline M. Nievergelt, Sébastien Jacquemont, Stephen W. Scherer, Jonathan Sebat · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.07.11.25331310 · 被引用次数：6 · 研究领域：Genomic variations and chromosomal abnormalities、Genetics and Neurodevelopmental Disorders、Genetic Associations and Epidemiology

Abstract Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( SMYD3, USP7 - HAPSTR1 ) and in the combined cross-disorder analysis ( ASTN2 ). Rare CNVs accounted for 1–3% of heritability across diagnoses. In ASD, associations were uniformly positive, consistent with autism having diverse etiologies and clinical presentations. By contrast, CNVs showed a dose-dependent relationship for other diagnoses, including SCZ and PTSD, with reciprocal deletions and duplications having inversely correlated effects and distinct genotype-phenotype relationships. Our findings suggest that genes have effects that are both dose-dependent and pleiotropic, such that a positive influence on one dimension of psychopathology may be accompanied by positive or negative effects on others.