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      Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

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      Embargo Lift Date: 2021-02-06
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      Author(s)
      Satterstrom, F. K.
      Kosmicki, J. A.
      Wang, J.
      Breen, M. S.
      De Rubeis, S.
      An, J. - Y.
      Peng, M.
      Collins, R.
      Grove, J.
      Klei, L.
      Stevens, C.
      Reichert, J.
      Mulhern, M. S.
      Artomov, M.
      Gerges, S.
      Sheppard, B.
      Xu, X.
      Bhaduri, A.
      Norman, Utku
      Brand, H.
      Schwartz, G.
      Nguyen, R.
      Guerrero, E. E.
      Dias, C.
      Autism Sequencing Consortium
      iPSYCH-Broad Consortium
      Betancur, C
      Cook, E
      Gallagher, L
      Gill, M
      Sutcliffe, J
      Thurm, A
      Zwick, M
      State, M
      Çicek, A. Ercüment
      Talkowski, M
      Cutler, D
      Devlin, B.
      Sanders, S
      Roeder, K.
      Daly, M
      Buxbaum, J.
      Date
      2020-02-06
      Source Title
      Cell
      Print ISSN
      0092-8674
      Publisher
      Elsevier
      Volume
      180
      Issue
      3
      Pages
      568 - 5.84E+025
      Language
      English
      Type
      Article
      Item Usage Stats
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      263
      downloads
      Abstract
      We present the largest exome sequencing study ofautism spectrum disorder (ASD) to date (n = 35,584total samples, 11,986 with ASD). Using an enhancedanalytical framework to integratedenovoand case-control rare variation, we identify 102 risk genes at afalse discovery rate of 0.1 or less. Of these genes, 49show higher frequencies of disruptivedenovovari-ants in individuals ascertained to have severe neuro-developmental delay, whereas 53 show higher fre-quencies in individuals ascertained to have ASD;comparing ASD cases with mutations in thesegroups reveals phenotypic differences. Expressedearly in brain development, most risk genes haveroles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelop-mental and neurophysiological changes), and 13 fallwithin loci recurrently hit by copy number variants.In cells from the human cortex, expression of riskgenes is enriched in excitatory and inhibitoryneuronal lineages, consistent with multiple paths toan excitatory-inhibitory imbalance underlying ASD.
      Keywords
      Autism spectrum disorder
      Cell type
      Cytoskeleton
      Excitatory neurons
      Excitatory-inhibitory balance
      Exome sequencing
      Genetics
      Inhibitory neurons
      Liability
      Permalink
      http://hdl.handle.net/11693/75461
      Published Version (Please cite this version)
      https://dx.doi.org/10.1016/j.cell.2019.12.036
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      • Department of Computer Engineering 1561
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