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

TitleLarge-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Authors
Sattterstrom, FKKosmicki, JAWang, JBreen, MSDe Rubeis, SAn, JYPeng, MCollins, RGrove, JKlei, LStevens, CPedersen, CBPedersen, MGPoterba, TPoulsen, JBRipke, SSchork, AJThompson, WKTurley, PWalters, RKBrand, HMontenegro, EMSSchwartz, GNguyen, RGuerrero, EEDias, CBetancur, CCook, EHGallagher, LGill, MSutcliffe, JSThurm, AMoreira, DZwick, MEBorglum, ADState, MWCicek, AETalkowski, MECutler, DJDevlin, BSanders, SJRoeder, KDaly, MJMorrow, EMBuxbaum, JDAleksic, BAnney, RBarbosa, MBishop, SBrusco, ABybjerg-Grauholm, JCarracedo, AChan, MCYChiocchetti, AGMors, OChung, BHYCoon, HCuccaro, MLCurro, ADalla Bernardina, BDoan, RDomenici, EDong, SFallerini, CFernandez-Prieto, MMortensen, PBFerrero, GMFreitag, CMFromer, MGargus, JJGeschwind, DGiorgio, EGonzalez-Perias, JGuter, SHalpern, DHansen-Kiss, EMosconi, MHe, XHerman, GEHertz-Piccfiotto, IHougaard, DMHultman, CMIonita-Laza, LJacob, SJamison, JJugessur, AKaartinen, MMuglia, PKnudsen, GPKolevzon, AKushima, ILee, SLLehtimaki, TLim, ETLintas, CLipkin, WILopergolo, DLopes, FNeale, BMLudena, YMaciel, PMagnus, PMahjani, BMaltman, NManoach, DSMeiri, GMenashe, IMiller, JMinshew, NNordentoft, MOzaki, NReichert, JPalotie, AParellada, MPassos-Bueno, MRPericak-Vance, MPersico, AMPessah, IPuura, KReichenberg, ARenien, ARiberi, EMulhern, MSRobinson, EBSamocha, KESandin, SSantangelo, SISchellenberg, GScherer, SWSchlitt, SSchmidt, RSchmitt, LSilva, IMWArtomov, MSingh, TSiper, PMSmith, MSoares, GStoltenberg, CSuren, PSusser, ESweeney, JSzatmari, PTang, LGerges, STassone, FTeufel, KTrabetti, ETrelles, MDPWalsh, CAWeiss, LAWerge, TWerling, DMWigdor, EMWilkinson, ESheppard, SWillsey, AJYu, TWYU, HCYuen, RZachi, EAgerbo, EAls, TDAppadurai, VBaekvad-Hansen, MBelliveau, RXu, XBuil, ACarey, CECerrato, FChambert, KChurchhouse, CDalsgaard, SDemontis, DDumont, AGoldstein, JHansen, CSBhaduri, AHauberg, MEHollegaard, MVHowrigan, DPHuang, HMaller, JMartin, ARMartin, JMattheisen, MMoran, JPallesen, JNorman, UPalmer, DS
Keywordsautism spectrum disorder
cell type
cytoskeleton
excitatory neurons
excitatory-inhibitory balance
Issue Date2020
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/cell
Citation
Cell, 2020, v. 180 n. 3, p. 568-584.e23 How to Cite?
AbstractWe 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.
Persistent Identifierhttp://hdl.handle.net/10722/281228
ISSN
2017 Impact Factor: 31.398
2015 SCImago Journal Rankings: 28.188

 

DC FieldValueLanguage
dc.contributor.authorSattterstrom, FK-
dc.contributor.authorKosmicki, JA-
dc.contributor.authorWang, J-
dc.contributor.authorBreen, MS-
dc.contributor.authorDe Rubeis, S-
dc.contributor.authorAn, JY-
dc.contributor.authorPeng, M-
dc.contributor.authorCollins, R-
dc.contributor.authorGrove, J-
dc.contributor.authorKlei, L-
dc.contributor.authorStevens, C-
dc.contributor.authorPedersen, CB-
dc.contributor.authorPedersen, MG-
dc.contributor.authorPoterba, T-
dc.contributor.authorPoulsen, JB-
dc.contributor.authorRipke, S-
dc.contributor.authorSchork, AJ-
dc.contributor.authorThompson, WK-
dc.contributor.authorTurley, P-
dc.contributor.authorWalters, RK-
dc.contributor.authorBrand, H-
dc.contributor.authorMontenegro, EMS-
dc.contributor.authorSchwartz, G-
dc.contributor.authorNguyen, R-
dc.contributor.authorGuerrero, EE-
dc.contributor.authorDias, C-
dc.contributor.authorBetancur, C-
dc.contributor.authorCook, EH-
dc.contributor.authorGallagher, L-
dc.contributor.authorGill, M-
dc.contributor.authorSutcliffe, JS-
dc.contributor.authorThurm, A-
dc.contributor.authorMoreira, D-
dc.contributor.authorZwick, ME-
dc.contributor.authorBorglum, AD-
dc.contributor.authorState, MW-
dc.contributor.authorCicek, AE-
dc.contributor.authorTalkowski, ME-
dc.contributor.authorCutler, DJ-
dc.contributor.authorDevlin, B-
dc.contributor.authorSanders, SJ-
dc.contributor.authorRoeder, K-
dc.contributor.authorDaly, MJ-
dc.contributor.authorMorrow, EM-
dc.contributor.authorBuxbaum, JD-
dc.contributor.authorAleksic, B-
dc.contributor.authorAnney, R-
dc.contributor.authorBarbosa, M-
dc.contributor.authorBishop, S-
dc.contributor.authorBrusco, A-
dc.contributor.authorBybjerg-Grauholm, J-
dc.contributor.authorCarracedo, A-
dc.contributor.authorChan, MCY-
dc.contributor.authorChiocchetti, AG-
dc.contributor.authorMors, O-
dc.contributor.authorChung, BHY-
dc.contributor.authorCoon, H-
dc.contributor.authorCuccaro, ML-
dc.contributor.authorCurro, A-
dc.contributor.authorDalla Bernardina, B-
dc.contributor.authorDoan, R-
dc.contributor.authorDomenici, E-
dc.contributor.authorDong, S-
dc.contributor.authorFallerini, C-
dc.contributor.authorFernandez-Prieto, M-
dc.contributor.authorMortensen, PB-
dc.contributor.authorFerrero, GM-
dc.contributor.authorFreitag, CM-
dc.contributor.authorFromer, M-
dc.contributor.authorGargus, JJ-
dc.contributor.authorGeschwind, D-
dc.contributor.authorGiorgio, E-
dc.contributor.authorGonzalez-Perias, J-
dc.contributor.authorGuter, S-
dc.contributor.authorHalpern, D-
dc.contributor.authorHansen-Kiss, E-
dc.contributor.authorMosconi, M-
dc.contributor.authorHe, X-
dc.contributor.authorHerman, GE-
dc.contributor.authorHertz-Piccfiotto, I-
dc.contributor.authorHougaard, DM-
dc.contributor.authorHultman, CM-
dc.contributor.authorIonita-Laza, L-
dc.contributor.authorJacob, S-
dc.contributor.authorJamison, J-
dc.contributor.authorJugessur, A-
dc.contributor.authorKaartinen, M-
dc.contributor.authorMuglia, P-
dc.contributor.authorKnudsen, GP-
dc.contributor.authorKolevzon, A-
dc.contributor.authorKushima, I-
dc.contributor.authorLee, SL-
dc.contributor.authorLehtimaki, T-
dc.contributor.authorLim, ET-
dc.contributor.authorLintas, C-
dc.contributor.authorLipkin, WI-
dc.contributor.authorLopergolo, D-
dc.contributor.authorLopes, F-
dc.contributor.authorNeale, BM-
dc.contributor.authorLudena, Y-
dc.contributor.authorMaciel, P-
dc.contributor.authorMagnus, P-
dc.contributor.authorMahjani, B-
dc.contributor.authorMaltman, N-
dc.contributor.authorManoach, DS-
dc.contributor.authorMeiri, G-
dc.contributor.authorMenashe, I-
dc.contributor.authorMiller, J-
dc.contributor.authorMinshew, N-
dc.contributor.authorNordentoft, M-
dc.contributor.authorOzaki, N-
dc.contributor.authorReichert, J-
dc.contributor.authorPalotie, A-
dc.contributor.authorParellada, M-
dc.contributor.authorPassos-Bueno, MR-
dc.contributor.authorPericak-Vance, M-
dc.contributor.authorPersico, AM-
dc.contributor.authorPessah, I-
dc.contributor.authorPuura, K-
dc.contributor.authorReichenberg, A-
dc.contributor.authorRenien, A-
dc.contributor.authorRiberi, E-
dc.contributor.authorMulhern, MS-
dc.contributor.authorRobinson, EB-
dc.contributor.authorSamocha, KE-
dc.contributor.authorSandin, S-
dc.contributor.authorSantangelo, SI-
dc.contributor.authorSchellenberg, G-
dc.contributor.authorScherer, SW-
dc.contributor.authorSchlitt, S-
dc.contributor.authorSchmidt, R-
dc.contributor.authorSchmitt, L-
dc.contributor.authorSilva, IMW-
dc.contributor.authorArtomov, M-
dc.contributor.authorSingh, T-
dc.contributor.authorSiper, PM-
dc.contributor.authorSmith, M-
dc.contributor.authorSoares, G-
dc.contributor.authorStoltenberg, C-
dc.contributor.authorSuren, P-
dc.contributor.authorSusser, E-
dc.contributor.authorSweeney, J-
dc.contributor.authorSzatmari, P-
dc.contributor.authorTang, L-
dc.contributor.authorGerges, S-
dc.contributor.authorTassone, F-
dc.contributor.authorTeufel, K-
dc.contributor.authorTrabetti, E-
dc.contributor.authorTrelles, MDP-
dc.contributor.authorWalsh, CA-
dc.contributor.authorWeiss, LA-
dc.contributor.authorWerge, T-
dc.contributor.authorWerling, DM-
dc.contributor.authorWigdor, EM-
dc.contributor.authorWilkinson, E-
dc.contributor.authorSheppard, S-
dc.contributor.authorWillsey, AJ-
dc.contributor.authorYu, TW-
dc.contributor.authorYU, HC-
dc.contributor.authorYuen, R-
dc.contributor.authorZachi, E-
dc.contributor.authorAgerbo, E-
dc.contributor.authorAls, TD-
dc.contributor.authorAppadurai, V-
dc.contributor.authorBaekvad-Hansen, M-
dc.contributor.authorBelliveau, R-
dc.contributor.authorXu, X-
dc.contributor.authorBuil, A-
dc.contributor.authorCarey, CE-
dc.contributor.authorCerrato, F-
dc.contributor.authorChambert, K-
dc.contributor.authorChurchhouse, C-
dc.contributor.authorDalsgaard, S-
dc.contributor.authorDemontis, D-
dc.contributor.authorDumont, A-
dc.contributor.authorGoldstein, J-
dc.contributor.authorHansen, CS-
dc.contributor.authorBhaduri, A-
dc.contributor.authorHauberg, ME-
dc.contributor.authorHollegaard, MV-
dc.contributor.authorHowrigan, DP-
dc.contributor.authorHuang, H-
dc.contributor.authorMaller, J-
dc.contributor.authorMartin, AR-
dc.contributor.authorMartin, J-
dc.contributor.authorMattheisen, M-
dc.contributor.authorMoran, J-
dc.contributor.authorPallesen, J-
dc.contributor.authorNorman, U-
dc.contributor.authorPalmer, DS-
dc.date.accessioned2020-03-09T09:51:52Z-
dc.date.available2020-03-09T09:51:52Z-
dc.date.issued2020-
dc.identifier.citationCell, 2020, v. 180 n. 3, p. 568-584.e23-
dc.identifier.issn0092-8674-
dc.identifier.urihttp://hdl.handle.net/10722/281228-
dc.description.abstractWe 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.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/cell-
dc.relation.ispartofCell-
dc.subjectautism spectrum disorder-
dc.subjectcell type-
dc.subjectcytoskeleton-
dc.subjectexcitatory neurons-
dc.subjectexcitatory-inhibitory balance-
dc.titleLarge-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.emailLee, SL: slleem@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.cell.2019.12.036-
dc.identifier.pmid31981491-
dc.identifier.scopuseid_2-s2.0-85078664833-
dc.identifier.hkuros309266-
dc.identifier.volume180-
dc.identifier.issue3-
dc.identifier.spage568-
dc.identifier.epage584.e23-
dc.publisher.placeUnited States-

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