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

• Published in: Cell Vol. 180; no. 3; pp. 568 - 584.e23
• Main Authors: Satterstrom, F. Kyle, Breen, Michael S., Grove, Jakob, Klei, Lambertus, Xu, Xinyi, Norman, Utku, Brand, Harrison, Schwartz, Grace, Barbosa, Mafalda, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chiocchetti, Andreas G., Chung, Brian H.Y., Coon, Hilary, Cuccaro, Michael L., Dalla Bernardina, Bernardo, Domenici, Enrico, Dong, Shan, Freitag, Christine M., González-Peñas, Javier, Guter, Stephen, He, Xin, Herman, Gail E., Hertz-Picciotto, Irva, Hougaard, David M., Ionita-Laza, Iuliana, Jacob, Suma, Jamison, Jesslyn, Jugessur, Astanand, Kolevzon, Alexander, Kushima, Itaru, Lee, So Lun, Lehtimäki, Terho, Lim, Elaine T., Lipkin, W. Ian, Lopergolo, Diego, Lopes, Fátima, Ludena, Yunin, Maciel, Patricia, Meiri, Gal, Menashe, Idan, Miller, Judith, Montenegro, Eduarda M.S., Muglia, Pierandrea, Nordentoft, Merete, Ozaki, Norio, Palotie, Aarno, Parellada, Mara, Passos-Bueno, Maria Rita, Persico, Antonio M., Pessah, Isaac, Puura, Kaija, Renieri, Alessandra, Riberi, Evelise, Robinson, Elise B., Samocha, Kaitlin E., Sandin, Sven, Santangelo, Susan L., Schellenberg, Gerry, Scherer, Stephen W., Schmitt, Lauren, Silva, Isabela M.W., Singh, Tarjinder, Siper, Paige M., Soares, Gabriela, Susser, Ezra, Szatmari, Peter, Tang, Lara, Tassone, Flora, Teufel, Karoline, Trelles, Maria del Pilar, Werge, Thomas, Werling, Donna M., Wigdor, Emilie M., Yu, Mullin H.C., Zachi, Elaine, Agerbo, Esben, Als, Thomas Damm, Bækvad-Hansen, Marie, Belliveau, Rich, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Hansen, Christine S., Hauberg, Mads Engel, Hollegaard, Mads V., Howrigan, Daniel P., Maller, Julian, Mattheisen, Manuel, Moran, Jennifer, Pallesen, Jonatan, Poulsen, Jesper Buchhave, Ripke, Stephan, Gallagher, Louise, Gill, Michael, Zwick, Michael E., State, Matthew W., Daly, Mark J., Buxbaum, Joseph D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.02.2020; Elsevier
• Subjects: autism spectrum disorder; Autistic Disorder; Autistic Disorder - genetics; Case-Control Studies; Cell Lineage; cell type; Cerebral Cortex; Cerebral Cortex - growth & development; Cohort Studies; cytoskeleton; excitatory neurons; excitatory-inhibitory balance; Exome; exome sequencing; Exome Sequencing - methods; Female; Gene Expression Regulation, Developmental; Gene Frequency; Genetic Predisposition to Disease; Genetics; Humans; inhibitory neurons; liability; Life Sciences; Male; Medicin och hälsovetenskap; Mutation, Missense; Neurobiology; Neurobiology - methods; neurodevelopment; Neurons; Neurons - metabolism; Phenotype; Sex Factors; Single-Cell Analysis; Single-Cell Analysis - methods; Whole Exome Sequencing; exome sequencing; genetics; neurodevelopment; cytoskeleton; liability; excitatory-inhibitory balance; excitatory neurons; cell type; autism spectrum disorder; inhibitory neurons
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.12.036

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. [Display omitted] •102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR ≤ 0.1)•Most are expressed and enriched early in excitatory and inhibitory neuronal lineages•Most affect synapses or regulate other genes; how these roles dovetail is unknown•Some ASD genes alter early development broadly, others appear more specific to ASD Large-scale sequencing of patients with autism allows identification of over 100 putative ASD-associated genes, the majority of which are neuronally expressed, and investigation of distinct genetic influences on ASD compared with other neurodevelopmental disorders.