We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Satterstrom, F. Kyle and Kosmicki, Jack A. and Wang, Jiebiao and Breen, Michael S and De Rubeis, Silvia and An, Joon-Yong and Peng, Minshi and Collins, Ryan L. and Grove, Jakob and Klei, Lambertus and Stevens, Christine and Reichert, Jennifer and Mulhern, Maureen S. and Artomov, Mykyta and Gerges, Sherif and Sheppard, Brooke and Xu, Xinyi and Bhaduri, Aparna and Norman, Utku and Brand, Harrison and Schwartz, Grace and Nguyen, Rachel and Guerrero, Elizabeth E. and Dias, Caroline and Aleksic, Branko and Barbosa, Mafalda and Bishop, Somer and Brusco, Alfredo and Bybjerg-Grauholm, Jonas and Carracedo, Angel and Chan, Marcus C. Y. and Chiocchetti, Andreas G. and Chung, Brian H. Y. and Coon, Hilary and Cuccaro, Michael L. and Currò, Aurora and Bernardina, Bernardo Dalla and Doan, Ryan and Domenici, Enrico and Dong, Shan and Fallerini, Chiara and Fernández-Prieto, Montserrat and Ferrero, Giovanni Battista and Freitag, Christine M. and Fromer, Menachem and Gargus, J. Jay and Giorgio, Elisa and González-Peñas, Javier and Guter, Stephen and Halpern, Danielle and Hansen-Kiss, Emily and He, Xin and Herman, Gail E. and Hertz-Picciotto, Irva and Hougaard, David M. and Hultman, Christina M. and Ionita-Laza, Iuliana and Jacob, Suma and Jamison, Jesslyn and Jugessur, Astanand and Kaartinen, Miia and Knudsen, Gun Peggy and Kolevzon, Alexander and Kushima, Itaru and Lee, So Lun and Lehtimäki, Terho and Lim, Elaine T. and Lintas, Carla and Lipkin, W. Ian and Lopergolo, Diego and Lopes, Fátima and Ludena, Yunin and Maciel, Patricia and Magnus, Per and Mahjani, Behrang and Maltman, Nell and Manoach, Dara S. and Meiri, Gal and Menashe, Idan and Miller, Judith and Minshew, Nancy and de Souza, Eduarda Montenegro M. and Moreira, Danielle and Morrow, Eric M. and Mors, Ole and Mortensen, Preben Bo and Mosconi, Matthew and Muglia, Pierandrea and Neale, Benjamin M. and Nordentoft, Merete and Ozaki, Norio and Palotie, Aarno and Parellada, Mara and Passos-Bueno, Maria Rita and Pericak-Vance, Margaret and Persico, Antonio and Pessah, Isaac and Puura, Kaija and Reichenberg, Abraham and Renieri, Alessandra and Riber, Evelise and Robinson, Elise B. and Samocha, Kaitlin E. and Sandin, Sven and Santangelo, Susan L. and Schellenberg, Gerry and Scherer, Stephen W. and Schlitt, Sabine and Schmidt, Rebecca and Schmitt, Lauren and Silva, Isabela Maya W. and Singh, Tarjinder and Siper, Paige M. and Smith, Moyra and Soares, Gabriela and Stoltenberg, Camilla and Suren, Pål and Susser, Ezra and Sweeney, John and Szatmari, Peter and Tassone, Flora and Teufel, Karoline and Trabetti, Elisabetta and del Pilar Trelles, Maria and Walsh, Christopher and Tang, Lara and Weiss, Lauren A. and Werge, Thomas and Werling, Donna and Wigdor, Emilie M. and Wilkinson, Emma and Willsey, A. Jeremy and Yu, Tim and H.C. Yu, Mullin and Yuen, Ryan and Zachi, Elaine and Group, iPSYCH Consortium and Betancur, Catalina and Cook, Edwin H. and Gallagher, Louise and Gill, Michael and Sutcliffe, James S. and Thurm, Audrey and Zwick, Michael E. and Børglum, Anders D. and State, Matthew W. and Cicek, A. Ercument and Talkowski, Michael E. and Cutler, David J. and Devlin, Bernie and Sanders, Stephan J. and Roeder, Kathryn and Daly, Mark J. and Buxbaum, Joseph, Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (April 13, 2019). Available at SSRN: https://ssrn.com/abstract=3371405
This is a paper under consideration at Cell Press and has not been peer-reviewed.