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Novel genes for autism implicate both excitatory and inhibitory cell lineages in risk

2018; Cold Spring Harbor Laboratory; Linguagem: Inglês

F. Kyle Satterstrom, Jack A. Kosmicki, Jiebiao Wang, Michael S. Breen, Silvia De Rubeis, Joon‐Yong An, Minshi Peng, Ryan L. Collins, Jakob Grove, Lambertus Klei, Christine Stevens, Jennifer Reichert, Maureen Mulhern, Mykyta Artomov, Sherif Gerges, Brooke Sheppard, Xinyi Xu, Aparna Bhaduri, Utku Norman, Harrison Brand, Grace Schwartz, Rachel Nguyen, Elizabeth E. Guerrero, Caroline Dias, Branko Aleksić, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg‐Grauholm, Ángel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian Hon‐Yin Chung, Hilary Coon, Michael L. Cuccaro, Aurora Currò, Bernardo Dalla Bernardina, Ryan N. Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Fernández Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel H. Geschwind, Elisa Giorgio, Javier González‐Peñas, Stephen J. Guter, Danielle Halpern, Emily Hansen‐Kiss, Xin He, Gail E. Herman, Irva Hertz‐Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita‐Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtimäki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fátima Lopes, Yunin Ludeña, Patrı́cia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy J. Minshew, Eduarda Montenegro M. de Souza, Danielle de Paula Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew W. Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos‐Bueno, Margaret A. Pericak‐Vance, Antonio M. Persico, Isaac N. Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca J. Schmidt, Lauren Schmitt, Isabela Maya W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pål Surén, Ezra Susser, John A. Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, M. Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, Jeremy A. Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan K. C. Yuen, Elaine Cristina Zachi, Catalina Betancur, Edwin H. Cook, Louise Gallagher, Michael Gill, Thomas Lehner, Geetha Senthil, James S. Sutcliffe, Audrey Thurm, Michael E. Zwick, Anders D. Børglum, Matthew W. State, A. Ercüment Çiçek, Michael E. Talkowski, David J. Cutler, Bernie Devlin, Stephan Sanders, Kathryn Roeder, Joseph D. Buxbaum, Mark J. Daly,

Genomics and Rare Diseases

Abstract We present the largest exome sequencing study to date focused on rare variation in autism spectrum disorder (ASD) (n=35,584). Integrating de novo and case-control variation with an enhanced Bayesian framework incorporating evolutionary constraint against mutation, we implicate 99 genes in ASD risk at a false discovery rate (FDR) ≤ 0.1. Of these 99 risk genes, 46 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 50 show higher frequencies in individuals ascertained for ASD, and comparing ASD cases with disruptive mutations in the two groups shows differences in phenotypic presentation. Expressed early in brain development, most of the risk genes have roles in neuronal communication or regulation of gene expression, and 12 fall within recurrent copy number variant loci. In human cortex single-cell gene expression data, expression of the 99 risk genes is also enriched in both excitatory and inhibitory neuronal lineages, implying that disruption of these genes alters the development of both neuron types. Together, these insights broaden our understanding of the neurobiology of ASD.