Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.
Autistic Disorder
/ genetics
Case-Control Studies
Cell Lineage
Cerebral Cortex
/ growth & development
Cohort Studies
Exome
Female
Gene Expression Regulation, Developmental
Gene Frequency
Genetic Predisposition to Disease
Humans
Male
Mutation, Missense
Neurobiology
/ methods
Neurons
/ metabolism
Phenotype
Sex Factors
Single-Cell Analysis
/ methods
Exome Sequencing
/ methods
autism spectrum disorder
cell type
cytoskeleton
excitatory neurons
excitatory-inhibitory balance
exome sequencing
genetics
inhibitory neurons
liability
neurodevelopment
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
06 02 2020
06 02 2020
Historique:
received:
20
03
2019
revised:
08
07
2019
accepted:
24
12
2019
pubmed:
26
1
2020
medline:
22
8
2020
entrez:
26
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31981491
pii: S0092-8674(19)31398-4
doi: 10.1016/j.cell.2019.12.036
pmc: PMC7250485
mid: NIHMS1569306
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
568-584.e23Subventions
Organisme : NIMH NIH HHS
ID : R01 MH110928
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106910
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008895
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111660
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH057881
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111658
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111661
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH111662
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH095797
Pays : United States
Organisme : NIEHS NIH HHS
ID : R24 ES028533
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH113362
Pays : United States
Organisme : NIMH NIH HHS
ID : R37 MH057881
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH097849
Pays : United States
Investigateurs
Branko Aleksic
(B)
Richard Anney
(R)
Mafalda Barbosa
(M)
Somer Bishop
(S)
Alfredo Brusco
(A)
Jonas Bybjerg-Grauholm
(J)
Angel Carracedo
(A)
Marcus C Y Chan
(MCY)
Andreas G Chiocchetti
(AG)
Brian H Y Chung
(BHY)
Hilary Coon
(H)
Michael L Cuccaro
(ML)
Aurora Curró
(A)
Bernardo Dalla Bernardina
(B)
Ryan Doan
(R)
Enrico Domenici
(E)
Shan Dong
(S)
Chiara Fallerini
(C)
Montserrat Fernández-Prieto
(M)
Giovanni Battista Ferrero
(GB)
Christine M Freitag
(CM)
Menachem Fromer
(M)
J Jay Gargus
(JJ)
Daniel Geschwind
(D)
Elisa Giorgio
(E)
Javier González-Peñas
(J)
Stephen Guter
(S)
Danielle Halpern
(D)
Emily Hansen-Kiss
(E)
Xin He
(X)
Gail E Herman
(GE)
Irva Hertz-Picciotto
(I)
David M Hougaard
(DM)
Christina M Hultman
(CM)
Iuliana Ionita-Laza
(I)
Suma Jacob
(S)
Jesslyn Jamison
(J)
Astanand Jugessur
(A)
Miia Kaartinen
(M)
Gun Peggy Knudsen
(GP)
Alexander Kolevzon
(A)
Itaru Kushima
(I)
So Lun Lee
(SL)
Terho Lehtimäki
(T)
Elaine T Lim
(ET)
Carla Lintas
(C)
W Ian Lipkin
(WI)
Diego Lopergolo
(D)
Fátima Lopes
(F)
Yunin Ludena
(Y)
Patricia Maciel
(P)
Per Magnus
(P)
Behrang Mahjani
(B)
Nell Maltman
(N)
Dara S Manoach
(DS)
Gal Meiri
(G)
Idan Menashe
(I)
Judith Miller
(J)
Nancy Minshew
(N)
Eduarda M S Montenegro
(EMS)
Danielle Moreira
(D)
Eric M Morrow
(EM)
Ole Mors
(O)
Preben Bo Mortensen
(PB)
Matthew Mosconi
(M)
Pierandrea Muglia
(P)
Benjamin M Neale
(BM)
Merete Nordentoft
(M)
Norio Ozaki
(N)
Aarno Palotie
(A)
Mara Parellada
(M)
Maria Rita Passos-Bueno
(MR)
Margaret Pericak-Vance
(M)
Antonio M Persico
(AM)
Isaac Pessah
(I)
Kaija Puura
(K)
Abraham Reichenberg
(A)
Alessandra Renieri
(A)
Evelise Riberi
(E)
Elise B Robinson
(EB)
Kaitlin E Samocha
(KE)
Sven Sandin
(S)
Susan L Santangelo
(SL)
Gerry Schellenberg
(G)
Stephen W Scherer
(SW)
Sabine Schlitt
(S)
Rebecca Schmidt
(R)
Lauren Schmitt
(L)
Isabela M W Silva
(IMW)
Tarjinder Singh
(T)
Paige M Siper
(PM)
Moyra Smith
(M)
Gabriela Soares
(G)
Camilla Stoltenberg
(C)
Pål Suren
(P)
Ezra Susser
(E)
John Sweeney
(J)
Peter Szatmari
(P)
Lara Tang
(L)
Flora Tassone
(F)
Karoline Teufel
(K)
Elisabetta Trabetti
(E)
Maria Del Pilar Trelles
(MDP)
Christopher A Walsh
(CA)
Lauren A Weiss
(LA)
Thomas Werge
(T)
Donna M Werling
(DM)
Emilie M Wigdor
(EM)
Emma Wilkinson
(E)
A Jeremy Willsey
(AJ)
Timothy W Yu
(TW)
Mullin H C Yu
(MHC)
Ryan Yuen
(R)
Elaine Zachi
(E)
Esben Agerbo
(E)
Thomas Damm Als
(TD)
Vivek Appadurai
(V)
Marie Bækvad-Hansen
(M)
Rich Belliveau
(R)
Alfonso Buil
(A)
Caitlin E Carey
(CE)
Felecia Cerrato
(F)
Kimberly Chambert
(K)
Claire Churchhouse
(C)
Søren Dalsgaard
(S)
Ditte Demontis
(D)
Ashley Dumont
(A)
Jacqueline Goldstein
(J)
Christine S Hansen
(CS)
Mads Engel Hauberg
(ME)
Mads V Hollegaard
(MV)
Daniel P Howrigan
(DP)
Hailiang Huang
(H)
Julian Maller
(J)
Alicia R Martin
(AR)
Joanna Martin
(J)
Manuel Mattheisen
(M)
Jennifer Moran
(J)
Jonatan Pallesen
(J)
Duncan S Palmer
(DS)
Carsten Bøcker Pedersen
(CB)
Marianne Giørtz Pedersen
(MG)
Timothy Poterba
(T)
Jesper Buchhave Poulsen
(JB)
Stephan Ripke
(S)
Andrew J Schork
(AJ)
Wesley K Thompson
(WK)
Patrick Turley
(P)
Raymond K Walters
(RK)
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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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