Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Authors: Eduardo A. Maury, Maxwell A. Sherman, Giulio Genovese, Thomas G. Gilgenast, Tushar Kamath, S.J. Burris, Prashanth Rajarajan, Erin Flaherty, Schahram Akbarian, Andrew Chess, Steven A. McCarroll, Po‐Ru Loh, Jennifer E. Phillips‐Cremins, Kristen Brennand, Evan Z. Macosko, James Walters, Michael O‘Donovan, Patrick F. Sullivan, Christian R. Marshall, Daniele Merico, Bhooma Thiruvahindrapuram, Zhouzhi Wang, Stephen W. Scherer, Daniel P. Howrigan, Stephan Ripke, Brendan Bulik‐Sullivan, Kai-How Farh, Menachem Fromer, Jacqueline I. Goldstein, Hailiang Huang, Phil Lee, Mark J. Daly, Benjamin M. Neale, Richard A. Belliveau, Sarah E. Bergen, Elizabeth Bevilacqua, Kimberley D. Chambert, Colm Ó'Dúshláine, Edward M. Scolnick, Jordan W. Smoller, Jennifer L. Moran, Aarno Palotie, Tracey L. Petryshen, Wenting Wu, Douglas S. Greer, Danny Antaki, Aniket Shetty, Madhusudan Gujral, William M. Brandler, Dheeraj Malhotra, Karin V. Fuentes Fajarado, Michelle S. Maile, Peter Holmans, Noa Carrera, Nick Craddock, Valentina Escott‐Price, Lyudmila Georgieva, Marian L. Hamshere, David Kavanagh, Sophie E. Legge, Andrew Pocklington, Alexander Richards, Douglas M. Ruderfer, Nigel Williams, George Kirov, Michael J. Owen, Dalila Pinto, Guiqing Cai, Kenneth L. Davis, Elodie Drapeau, Joseph I. Friedman, Vahram Haroutunian, Elena Parkhomenko, Abraham Reichenberg, Jeremy M. Silverman, Joseph D. Buxbaum, Enrico Domenici, Ingrid Agartz, Srdjan Djurovic, Morten Mattingsdal, Ingrid Melle, Ole A. Andreassen, Erik G. Jönsson, Erik Söderman, Margot Albus, Madeline Alexander, Claudine Laurent, Douglas F. Levinson, Farooq Amin, Joshua Atkins, Murray J. Cairns, Rodney J. Scott, Paul A. Tooney, Jing Wu, Silviu‐Alin Bacanu, Tim B. Bigdeli, Mark A. Reimers, Bradley T. Webb, Aaron R. Wolen, Brandon K. Wormley, Kenneth S. Kendler, Brien P. Riley, Anna K. Kähler, Patrik K. E. Magnusson, Christina M. Hultman, Marcelo Bertalan, Thomas Folkmann Hansen, Line Olsen, Henrik Berg Rasmussen, Thomas Werge, Manuel Mattheisen, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, Joshua L. Roffman, William Byerley, Wiepke Cahn, René S. Kahn, Eric Strengman, Roel A. Ophoff, Vaughan J. Carr, Stanley V. Catts, Frans A. Henskens, Carmel M. Loughland, Patricia T. Michie, Christos Pantelis, Ulrich Schall, Assen Jablensky, Brian Kelly, Dominique Campion, Rita M. Cantor, Wei Cheng, C. Robert Cloninger, Dragan M. Švrakić, David Cohen, Paul Cormican, Gary Donohoe, Derek W. Morris, Aiden Corvin, Michael Gill, Benedicto Crespo‐Facorro, James J. Crowley, Martilias S. Farrell, Paola Giusti‐Rodríguez, Yunjung Kim, Jin Szatkiewicz, Stephanie Williams, David Curtis, Jonathan Pimm, Hugh Gurling, Andrew McQuillin, Michael Davidson, Mark Weiser, Franziska Degenhardt, Andreas J. Forstner, Stefan Herms, Per Hoffmann, Andrea Hofman, Sven Cichon, Markus M. Nöthen, Jurgen Del‐Favero, Lynn E. DeLisi, Robert W. McCarley, Deborah L. Levy, Raquelle I. Mesholam‐Gately, Larry J. Seidman, Dimitris Dikeos, George N. Papadimitriou, Timothy G. Dinan, Jubao Duan, Alan R. Sanders, Pablo V. Gejman, Elliot S. Gershon, Frank Dudbridge, Peter Eichhammer, Johan G. Eriksson, Veikko Salomaa, Laurent Essioux, Ayman H. Fanous, James A. Knowles, Michele T. Pato, Carlos N. Pato, Josef Frank, Sandra Meier, Thomas G. Schulze, Jana Strohmaier, Stephanie H. Witt, Marcella Rietschel, Lude Franke, Juha Karjalainen, Robert Freedman, Ann Olincy, Nelson B. Freimer, Shaun Purcell, Panos Roussos, Eli A. Stahl, Pamela Sklar, Jordan W. Smoller, Ina Giegling, Annette M. Hartmann, Bettina Konte, Dan Rujescu, Stephanie Godard, Joel N. Hirschhorn, Tune H. Pers, Alkes L. Price, Tõnu Esko, Jacob Gratten, S. Hong Lee, Peter M. Visscher, Naomi R. Wray, Bryan Mowry, Lieuwe de Haan, Carin J. Meijer, Mark Hansen, Masashi Ikeda, Nakao Iwata, Inge Joa, Luba Kalaydjieva, Matthew C. Keller, James L. Kennedy, Clement C. Zai, Jo Knight, Bernard Lerer, Kung‐Yee Liang, Jeffrey A. Lieberman, T. Scott Stroup, Jouko Lönnqvist, Jaana Suvisaari, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Colm McDonald, Andrew M. McIntosh, Douglas Blackwood, Andres Metspalu, Lili Milani, Vihra Milanova, Younes Mokrab, David Collier, Bertram Müller‐Myhsok, Kieran C. Murphy, Robin Murray, John Powell, Inez Myin‐Germeys, Jim van Os, Igor Nenadić, Deborah A. Nertney, Gerald Nestadt, Ann E. Pulver, Kristin K. Nicodemus, Laura Nisenbaum, Annelie Nordin, Rolf Adolfsson, Eadbhard O’Callaghan, Sang-Yun Oh, F. Anthony O’Neill, Tiina Paunio, Olli Pietiläinen, Diana O. Perkins, Digby Quested, Adam Savitz, Qingqin S. Li, Sibylle G. Schwab, Jianxin Shi, Chris C. A. Spencer, Srinivas Thirumalai, Juha Veijola, John L. Waddington, Dermot Walsh, Dieter B. Wildenauer, Elvira Bramon, Ariel Darvasi, Daniëlle Posthuma, David St Clair, Omar Shanta, Marieke Klein, Peter J. Park, Daniel R. Weinberger, John V. Moran, Fred H. Gage, Flora M. Vaccarino, Joseph G. Gleeson, Gary W. Mathern, Eric Courchesne, Subhojit Roy, Sara Bizzotto, Michael E. Coulter, Caroline Dias, Alissa M. D’Gama, Javier Ganz, Robert Hill, August Yue Huang, Sattar Khoshkhoo, Sonia Kim, Michael A. Lodato, Michael Miller, Rebeca Borges-Monroy, Rachel E. Rodin, Zinan Zhou, Craig L. Bohrson, Chong Chu, Isidro Cortés‐Ciriano, Yanmei Dou, Alon Galor, D. Gulhan, Min‐Seok Kwon, Joe Luquette, Vinay Viswanadham, Attila Jones, Chaggai Rosenbluh, Sean Cho, Ben Langmead, Jeremy Thorpe, Jennifer A. Erwin, Andrew E. Jaffe, Michael J. McConnell, Rujuta Narurkar, Apuã C.M. Paquola, Jooheon Shin, Richard E. Straub, Alexej Abyzov, Taejeong Bae, Yeongjun Jang, Yifan Wang, Fred H. Gage, Sara B. Linker, Patrick Reed, Meiyan Wang, Alexander E. Urban, Bo Zhou, Xiaowei Zhu, Reenal Pattni, Aitor Serres Amero, David Juan, Irene Lobón, Tomàs Marquès‐Bonet, Manuel Solis Moruno, Raquel García Pérez, Inna Povolotskaya, Eduardo Soriano, Danny Antaki, Dan Averbuj, Laurel Ball, Martin W. Breuss, Xiaoxu Yang, Changuk Chung, Sarah B. Emery, Diane A. Flasch, Jeffrey M. Kidd, Huira C. Kopera, Kenneth Y. Kwan, Ryan E. Mills, John B. Moldovan, Chen Sun, Xuefang Zhao, Weichen Zhou, Trenton J. Frisbie, Adriana Cherskov, Liana Fasching, Alexandre Jourdon, Sirisha Pochareddy, Soraya Scuderi, Nenad Šestan, Jonathan Sebat, Eunjung A. Lee, Christopher A. Walsh - Cell Genomics 2023 cited by 43

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.