Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Read full paper →- Authors
- 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, Ãngel 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, Montse 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 Morgana Silva Montenegro, 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
- Journal
- Cell
- Year
- 2020
- Citations
- 2,420
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.