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

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 J Brennand; Evan Z Macosko; James T R Walters; Michael O'Donovan; Patrick Sullivan; Psychiatric Genomic Consortium Schizophrenia and CNV workgroup; Brain Somatic Mosaicism Network; Jonathan Sebat; Eunjung A Lee; Christopher A Walsh

doi:10.1016/j.xgen.2023.100356

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

Cell Genom. 2023 Jul 6;3(8):100356. doi: 10.1016/j.xgen.2023.100356. eCollection 2023 Aug 9.

Authors

Eduardo A Maury^{1

2

3}, Maxwell A Sherman⁴, Giulio Genovese^{3

5

6}, Thomas G Gilgenast⁷, Tushar Kamath^{6

8}, S J Burris⁶, Prashanth Rajarajan⁹, Erin Flaherty⁹, Schahram Akbarian⁹, Andrew Chess⁹, Steven A McCarroll^{3

5}, Po-Ru Loh^{3

4}, Jennifer E Phillips-Cremins⁷, Kristen J Brennand^{9

10}, Evan Z Macosko^{6

11}, James T R Walters¹², Michael O'Donovan¹², Patrick Sullivan¹³; Psychiatric Genomic Consortium Schizophrenia and CNV workgroup; Brain Somatic Mosaicism Network; Jonathan Sebat¹⁴, Eunjung A Lee^{1

3}, Christopher A Walsh^{1

3

15}

Collaborators

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 Jr, Sarah E Bergen, Elizabeth Bevilacqua, Kimberley D Chambert, Colm O'Dushlaine, 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 A Holmans, Noa Carrera, Nick Craddock, Valentina Escott-Price, Lyudmila Georgieva, Marian L Hamshere, David Kavanagh, Sophie E Legge, Andrew J Pocklington, Alexander L Richards, Douglas M Ruderfer, Nigel M 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 Qin Wu, Silviu A 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 Ke Magnusson, Christina M Hultman, Marcelo Bertalan, Thomas Hansen, Line Olsen, Henrik B 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 V Jablensky, Brian J Kelly, Dominique Campion, Rita M Cantor, Wei Cheng, C Robert Cloninger, Dragan M Svrakic, 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 P 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 Dinan, Jubao Duan, Alan R Sanders, Pablo V Gejman, Elliot S Gershon, Frank Dudbridge, Peter Eichhammer, Johan 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 M 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 Price, Tõnu Esko, Jacob Gratten, S Hong Lee, Peter M Visscher, Naomi R Wray, Bryan J 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 Lieberman, T Scott Stroup, Jouko Lönnqvist, Jaana Suvisaari, Brion S Maher, Wolfgang Maier, Jacques Mallet, Colm McDonald, Andrew M McIntosh, Douglas Hr Blackwood, Andres Metspalu, Lili Milani, Vihra Milanova, Younes Mokrab, David A Collier, Bertram Müller-Myhsok, Kieran C Murphy, Robin M Murray, John Powell, Inez Myin-Germeys, Jim Van Os, Igor Nenadic, 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 Ca Spencer, Srinivas Thirumalai, Juha Veijola, John Waddington, Dermot Walsh, Dieter B Wildenauer, Elvira Bramon, Ariel Darvasi, Danielle Posthuma, David St Clair, Omar Shanta, Marieke Klein, Peter J Park, Daniel Weinberger, John V Moran, Fred H Gage, Flora M Vaccarino, Joseph Gleeson, Gary Mathern, Eric Courchesne, Subhojit Roy, Sara Bizzotto, Michael Coulter, Caroline Dias, Alissa D'Gama, Javier Ganz, Robert Hill, August Yue Huang, Sattar Khoshkhoo, Sonia Kim, Michael Lodato, Michael Miller, Rebeca Borges-Monroy, Rachel Rodin, Zinan Zhou, Craig Bohrson, Chong Chu, Isidro Cortes-Ciriano, Yanmei Dou, Alon Galor, Doga Gulhan, Minseok Kwon, Joe Luquette, Vinay Viswanadham, Attila Jones, Chaggai Rosenbluh, Sean Cho, Ben Langmead, Jeremy Thorpe, Jennifer Erwin, Andrew Jaffe, Michael McConnell, Rujuta Narurkar, Apua Paquola, Jooheon Shin, Richard Straub, Alexej Abyzov, Taejeong Bae, Yeongjun Jang, Yifan Wang, Fred Gage, Sara Linker, Patrick Reed, Meiyan Wang, Alexander Urban, Bo Zhou, Xiaowei Zhu, Reenal Pattni, Aitor Serres Amero, David Juan, Irene Lobon, Tomas Marques-Bonet, Manuel Solis Moruno, Raquel Garcia Perez, Inna Povolotskaya, Eduardo Soriano, Danny Antaki, Dan Averbuj, Laurel Ball, Martin 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 Sestan

Affiliations

¹ Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children's Hospital, Boston, MA, USA.
² Bioinformatics & Integrative Genomics Program and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Brigham and Women's Hospital, Division of Genetics & Center for Data Sciences, Boston, MA, USA.
⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁶ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA.
⁹ Nash Family Department of Neuroscience, Friedman Brain Institute, Department of Genetics & Genomics, Icahn Institute of Genomics and Multiscale Biology, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine of Mount Sinai, New York, NY, USA.
¹⁰ Departments of Psychiatry and Genetics, Yale School of Medicine, New Haven, CT, USA.
¹¹ Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
¹² MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychiatry and Clinical Neurosciences, Cardiff University, Cardiff, Wales.
¹³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ University of California San Diego, Department of Psychiatry, Department of Cellular & Molecular Medicine, Beyster Center of Psychiatric Genomics, San Diego, CA, USA.
¹⁵ Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.

Abstract

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.

Keywords: ABCB11; NRXN1; genomics; mosaicism; schizophrenia; somatic; structural variants; treatment resistance.

Abstract

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