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

F Kyle Satterstrom (1, 2) , Jack Kosmicki (1, 2, 3) , Jiebiao Wang (4) , Michael Breen (5) , Silvia de Rubeis (5) , Joon-Yong An (6, 7) , Minshi Peng (4) , Ryan Collins (2, 3) , Jakob Grove (8, 9, 10) , Lambertus Klei (11) , Christine Stevens (1, 3, 2) , Jennifer Reichert (5) , Maureen Mulhern (5) , Mykyta Artomov (1, 3, 2) , Sherif Gerges (1, 3, 2) , Brooke Sheppard (6) , Xinyi Xu (5) , Aparna Bhaduri (6, 12) , Utku Norman (13) , Harrison Brand (2) , Grace Schwartz (6) , Rachel Nguyen (14) , Elizabeth Guerrero (15) , Caroline Dias (16) , Catalina Betancur (17) , Edwin Cook (18) , Louise Gallagher (19) , Michael Gill (19) , James Sutcliffe (20) , Audrey Thurm (21) , Michael Zwick (22) , Anders Børglum (8, 10, 9) , Matthew State (6) , A. Ercument Cicek (4, 13) , Michael Talkowski (2) , David Cutler (22) , Bernie Devlin (11) , Stephan Sanders (6) , Kathryn Roeder (4) , Mark Daly (1, 2, 3, 23) , Joseph Buxbaum (5)

1 BROAD INSTITUTE - Broad Institute of MIT and Harvard
2 Massachusetts General Hospital [Boston]
3 HMS - Harvard Medical School [Boston]
4 CMU - Carnegie Mellon University [Pittsburgh]
5 MSSM - Icahn School of Medicine at Mount Sinai [New York]
6 UC San Francisco - University of California [San Francisco]
7 Korea University [Seoul]
8 iPSYCH - The Lundbeck Foundation Initiative for Integrative Psychiatric Research
9 Aarhus University [Aarhus]
10 CGPM - Center for Genomics and Personalized Medicine [Aarhus, Denmark]
11 University of Pittsburgh School of Medicine
12 Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA]
13 Bilkent University [Ankara]
14 UC Irvine - University of California [Irvine]
15 MIND - Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA]
16 Boston Children's Hospital
17 NPS - Neuroscience Paris Seine
18 UIC - University of Illinois [Chicago]
19 Trinity College Dublin
20 Vanderbilt University School of Medicine [Nashville]
21 NIMH - National Institute of Mental Health
22 Emory University School of Medicine
23 FIMM - Institute for Molecular Medicine Finland [Helsinki]

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.

Mots clés: autism spectrum disorder; cell type; cytoskeleton; excitatory neurons; excitatory-inhibitory balance; exome sequencing; genetics; inhibitory neurons; liability; neurodevelopment

Domaines: Génétique

F Kyle Satterstrom, Jack Kosmicki, Jiebiao Wang, Michael Breen, Silvia de Rubeis, et al.. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell, 2020, 180 (3), pp.568-584.e23. ⟨10.1016/j.cell.2019.12.036⟩. ⟨inserm-03135343⟩