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 analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most 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 cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Brusco A;Ferrero GB;Giorgio E;Riberi E;
2020

Abstract

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 analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most 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 cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
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https://reader.elsevier.com/reader/sd/pii/S0092867419313984?token=EAA90CCE0ABC0AE67233253117D81C84F6DF5263501B3016AE08F81BD02952F3C809D6EF68403A794937CD6394758C34
autism spectrum disorder; cell type; cytoskeleton; excitatory neurons; excitatory-inhibitory balance; exome sequencing; genetics; inhibitory neurons; liability; neurodevelopment
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 B; Anney R; Barbosa M; Bishop S; Brusco A; Bybjerg-Grauholm J; Carracedo A; Chan MCY; Chiocchetti AG; Chung BHY; Coon H; Cuccaro ML; Curró A; Dalla Bernardina B; Doan R; Domenici E; Dong S; Fallerini C; Fernández-Prieto M; Ferrero GB; Freitag CM; Fromer M; Gargus JJ; Geschwind D; Giorgio E; González-Peñas J; Guter S; Halpern D; Hansen-Kiss E; He X; Herman GE; Hertz-Picciotto I; Hougaard DM; Hultman CM; Ionita-Laza I; Jacob S; Jamison J; Jugessur A; Kaartinen M; Knudsen GP; Kolevzon A; Kushima I; Lee SL; Lehtimäki T; Lim ET; Lintas C; Lipkin WI; Lopergolo D; Lopes F; Ludena Y; Maciel P; Magnus P; Mahjani B; Maltman N; Manoach DS; Meiri G; Menashe I; Miller J; Minshew N; Montenegro EMS; Moreira D; Morrow EM; Mors O; Mortensen PB; Mosconi M; Muglia P; Neale BM; Nordentoft M; Ozaki N; Palotie A; Parellada M; Passos-Bueno MR; Pericak-Vance M; Persico AM; Pessah I; Puura K; Reichenberg A; Renieri A; Riberi E; Robinson EB; Samocha KE; Sandin S; Santangelo SL; Schellenberg G; Scherer SW; Schlitt S; Schmidt R; Schmitt L; Silva IMW; Singh T; Siper PM; Smith M; Soares G; Stoltenberg C; Suren P; Susser E; Sweeney J; Szatmari P; Tang L; Tassone F; Teufel K; Trabetti E; Trelles MDP; Walsh CA; Weiss LA; Werge T; Werling DM; Wigdor EM; Wilkinson E; Willsey AJ; Yu TW; Yu MHC; Yuen R; Zachi E; Agerbo E; Als TD; Appadurai V; Bækvad-Hansen M; Belliveau R; Buil A; Carey CE; Cerrato F; Chambert K; Churchhouse C; Dalsgaard S; Demontis D; Dumont A; Goldstein J; Hansen CS; Hauberg ME; Hollegaard MV; Howrigan DP; Huang H; Maller J; Martin AR; Martin J; Mattheisen M; Moran J; Pallesen J; Palmer DS; Pedersen CB; Pedersen MG; Poterba T; Poulsen JB; Ripke S; Schork AJ; Thompson WK; Turley P; Walters RK; 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
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