Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
Authors: Satterstrom F. Kyle , Kosmicki Jack A. , Wang Jiebiao , Breen Michael S. , De Rubeis Silvia , An Joon-Yong , Peng Minshi , Collins Ryan , Grove Jakob , Klei Lambertus , Stevens Christine , Reichert Jennifer , Mulhern Maureen S. , Artomov Mykyta , Gerges Sherif , Sheppard Brooke , Xu Xinyi , Bhaduri Aparna , Norman Utku , Brand Harrison , Schwartz Grace , Nguyen Rachel , Guerrero Elizabeth E. , Dias Caroline , Aleksic Branko , Anney Richard , Barbosa Mafalda , Bishop Somer , Brusco Alfredo , Bybjerg-Grauholm Jonas , Carracedo Angel , Chan Marcus C.Y. , Chiocchetti Andreas G. , Chung Brian H. Y. , Coon Hilary , Cuccaro Michael L. , Currò Aurora , Bernardina Bernardo Dalla , Doan Ryan , Domenici Enrico , Dong Shan , Fallerini Chiara , Fernández-Prieto Montserrat , Ferrero Giovanni Battista , Freitag Christine M. , Fromer Menachem , Gargus J. Jay , Geschwind Daniel , Giorgio Elisa , González-Peñas Javier , Guter Stephen , Halpern Danielle , Hansen-Kiss Emily , He Xin , Herman Gail E. , Hertz-Picciotto Irva , Hougaard David M. , Hultman Christina M. , Ionita-Laza Iuliana , Jacob Suma , Jamison Jesslyn , Jugessur Astanand , Kaartinen Miia , Knudsen Gun Peggy , Kolevzon Alexander , Kushima Itaru , Lee So Lun , Lehtimäki Terho , Lim Elaine T. , Lintas Carla , Lipkin W. Ian , Lopergolo Diego , Lopes Fátima , Ludena Yunin , Maciel Patricia , Magnus Per , Mahjani Behrang , Maltman Nell , Manoach Dara S. , Meiri Gal , Menashe Idan , Miller Judith , Minshew Nancy , de Souza Eduarda Montenegro M. , Moreira Danielle , Morrow Eric M. , Mors Ole , Mortensen Preben Bo , Mosconi Matthew , Muglia Pierandrea , Neale Benjamin , Nordentoft Merete , Ozaki Norio , Palotie Aarno , Parellada Mara , Passos-Bueno Maria Rita , Pericak-Vance Margaret , Persico Antonio , Pessah Isaac , Puura Kaija , Reichenberg Abraham , Renieri Alessandra , Riberi Evelise , Robinson Elise B. , Samocha Kaitlin E. , Sandin Sven , Santangelo Susan L. , Schellenberg Gerry , Scherer Stephen W. , Schlitt Sabine , Schmidt Rebecca , Schmitt Lauren , Silva Isabela Maya W. , Singh Tarjinder , Siper Paige M. , Smith Moyra , Soares Gabriela , Stoltenberg Camilla , Suren Pål , Susser Ezra , Sweeney John , Szatmari Peter , Tang Lara , Tassone Flora , Teufel Karoline , Trabetti Elisabetta , Trelles Maria del Pilar , Walsh Christopher , Weiss Lauren A. , Werge Thomas , Werling Donna , Wigdor Emilie M. , Wilkinson Emma , Willsey Jeremy A. , Yu Tim , Yu Mullin H.C. , Yuen Ryan , Zachi Elaine ,   iPSYCH consortium, Betancur Catalina , Cook Edwin H. , Gallagher Louise , Gill Michael , Sutcliffe James S. , Thurm Audrey , Zwick Michael E. , Børglum Anders D. , State Matthew W. , Cicek A. Ercument , Talkowski Michael E. , Cutler David J. , Devlin Bernie , Sanders Stephan J. , Roeder Kathryn , Daly Mark J. , Buxbaum Joseph D. 
Published: December 2018

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.