Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
- PMID: 31981491
- PMCID: PMC7250485
- DOI: 10.1016/j.cell.2019.12.036
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
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.
Keywords: autism spectrum disorder; cell type; cytoskeleton; excitatory neurons; excitatory-inhibitory balance; exome sequencing; genetics; inhibitory neurons; liability; neurodevelopment.
Copyright © 2020 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests B.M.N. is a member of the scientific advisory board at Deep Genomics and consults for Biogen, Camp4 Therapeutics Corporation, Takeda Pharmaceutical, and Biogen. During the last 3 years, C.M. Freitag has been consultant to Desitin and Roche and receives royalties for books on ASD, ADHD, and MDD.
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Comment in
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High-Risk, High-Reward Genetics in ASD.Neuron. 2020 Feb 5;105(3):407-410. doi: 10.1016/j.neuron.2020.01.007. Neuron. 2020. PMID: 32027831 Free PMC article.
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Autism Genetics: Over 100 Risk Genes and Counting.Pediatr Neurol Briefs. 2020 Dec 4;34:13. doi: 10.15844/pedneurbriefs-34-13. Pediatr Neurol Briefs. 2020. PMID: 33304087 Free PMC article.
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References
-
- Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, Kurzius-Spencer M, Zahorodny W, Robinson Rosenberg C, White T, et al. (2018). Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 67, 1–23. - PMC - PubMed
-
- Battle A, Brown CD, Engelhardt BE, and Montgomery SB; GTEx Consortium; Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group; Statistical Methods groups—Analysis Working Group; Enhancing GTEx (eGTEx) groups; NIH Common Fund; NIH/NCI; NIH/NHGRI; NIH/NIMH; NIH/NIDA; Biospecimen Collection Source Site—NDRI; Biospecimen Collection Source Site—RPCI; Biospecimen Core Resource—VARI; Brain Bank Repository—University of Miami Brain Endowment Bank; Leidos Biomedical—Project Management; ELSI Study; Genome Browser Data Integration &Visualization — EBI; Genome Browser Data Integration &Visualization — UCSC Genomics Institute, University of California Santa Cruz; Lead analysts; Laboratory, Data Analysis &Coordinating Center (LDACC); NIH program management; Biospecimen collection; Pathology; eQTL manuscript working group (2017). Genetic effects on gene expression across human tissues. Nature 550, 204–213. - PubMed
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