Rare coding variation provides insight into the genetic architecture and phenotypic context of autism - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Nature Genetics Year : 2022

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Jack Fu (1, 2) , F. Kyle Satterstrom (2, 1) , Minshi Peng (3) , Harrison Brand (2, 1) , Ryan Collins (4, 2, 1) , Shan Dong (5) , Brie Wamsley (6) , Lambertus Klei (7) , Lily Wang (2, 4) , Stephanie Hao (2, 1) , Christine Stevens (2, 1) , Caroline Cusick (2) , Mehrtash Babadi (2) , Eric Banks (2) , Brett Collins (8) , Sheila Dodge (2) , Stacey Gabriel (2) , Laura Gauthier (2) , Samuel Lee (2) , Lindsay Liang (5) , Alicia Ljungdahl (5) , Behrang Mahjani (8) , Laura Sloofman (8) , Andrey Smirnov (2) , Mafalda Barbosa (8) , Catalina Betancur (9) , Alfredo Brusco (10, 11) , Brian Chung (12) , Edwin Cook (13) , Michael Cuccaro (14) , Enrico Domenici (15) , Giovanni Battista Ferrero (10) , J. Jay Gargus (16) , Gail Herman (17) , Irva Hertz-Picciotto (18) , Patricia Maciel (19) , Dara Manoach (20) , Maria Rita Passos-Bueno (21) , Antonio Persico (22) , Alessandra Renieri (23, 24) , James Sutcliffe (25, 26) , Flora Tassone (18) , Elisabetta Trabetti (27) , Gabriele Campos (21) , Simona Cardaropoli (10) , Diana Carli (10) , Marcus Chan (12) , Chiara Fallerini (23) , Elisa Giorgio (10) , Ana Cristina Girardi (21) , Emily Hansen-Kiss (28) , So Lun Lee (12) , Carla Lintas (29) , Yunin Ludena (18) , Rachel Nguyen (16) , Lisa Pavinato (10) , Margaret Pericak-Vance (14) , Isaac Pessah (18) , Rebecca Schmidt (18) , Moyra Smith (16) , Claudia Costa (21) , Slavica Trajkova (10) , Jaqueline Wang (21) , Mullin Yu (12) , David Cutler (30) , Silvia de Rubeis (8) , Joseph Buxbaum (8) , Mark Daly (1, 2, 4, 31) , Bernie Devlin (7) , Kathryn Roeder (3) , Stephan Sanders (5) , Michael Talkowski (1)
1 Massachusetts General Hospital [Boston]
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 CMU - Carnegie Mellon University [Pittsburgh]
4 HMS - Harvard Medical School [Boston]
5 UC San Francisco - University of California [San Francisco]
6 UCLA - University of California [Los Angeles]
7 University of Pittsburgh School of Medicine
8 MSSM - Icahn School of Medicine at Mount Sinai [New York]
9 NPS - Neuroscience Paris Seine
10 UNITO - Università degli studi di Torino = University of Turin
11 Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino
12 HKU - The University of Hong Kong
13 UIC - University of Illinois [Chicago]
14 UMMSM - University of Miami Leonard M. Miller School of Medicine
15 University of Trento [Trento]
16 UC Irvine - University of California [Irvine]
17 Nationwide Children's Hospital
18 UC Davis - University of California [Davis]
19 Universidade do Minho = University of Minho [Braga]
20 Massachusetts General Hospital [Boston, MA, USA]
21 Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
22 UniMe - Università degli Studi di Messina = University of Messina
23 UNISI - Università degli Studi di Siena = University of Siena
24 Azienda Ospedaliera Universitaria Senese
25 Vanderbilt University [Nashville]
26 Vanderbilt University School of Medicine [Nashville]
27 UNIVR - Università degli studi di Verona = University of Verona
28 University of Texas Health Science Center
29 UCBM - Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
30 Emory University School of Medicine
31 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Jack Fu
  • Function : Author
Massachusetts General Hospital [Boston]
Broad Institute of MIT and Harvard
F. Kyle Satterstrom
Broad Institute of MIT and Harvard
Massachusetts General Hospital [Boston]
Minshi Peng
  • Function : Author
Carnegie Mellon University [Pittsburgh]
Harrison Brand
  • Function : Author
Broad Institute of MIT and Harvard
Massachusetts General Hospital [Boston]
Ryan Collins
  • Function : Author
Harvard Medical School [Boston]
Broad Institute of MIT and Harvard
Massachusetts General Hospital [Boston]
Shan Dong
  • Function : Author
University of California [San Francisco]
Brie Wamsley
  • Function : Author
University of California [Los Angeles]
Lambertus Klei
  • Function : Author
University of Pittsburgh School of Medicine
Lily Wang
  • Function : Author
Broad Institute of MIT and Harvard
Harvard Medical School [Boston]
Stephanie Hao
Broad Institute of MIT and Harvard
Massachusetts General Hospital [Boston]
Christine Stevens
Broad Institute of MIT and Harvard
Massachusetts General Hospital [Boston]
Caroline Cusick
  • Function : Author
Broad Institute of MIT and Harvard
Mehrtash Babadi
  • Function : Author
Broad Institute of MIT and Harvard
Eric Banks
  • Function : Author
Broad Institute of MIT and Harvard
Brett Collins
  • Function : Author
Icahn School of Medicine at Mount Sinai [New York]
Sheila Dodge
  • Function : Author
Broad Institute of MIT and Harvard
Stacey Gabriel
  • Function : Author
Broad Institute of MIT and Harvard
Laura Gauthier
  • Function : Author
Broad Institute of MIT and Harvard
Samuel Lee
Broad Institute of MIT and Harvard
Lindsay Liang
University of California [San Francisco]
Alicia Ljungdahl
  • Function : Author
University of California [San Francisco]
Behrang Mahjani
  • Function : Author
Icahn School of Medicine at Mount Sinai [New York]
Laura Sloofman
  • Function : Author
Icahn School of Medicine at Mount Sinai [New York]
Andrey Smirnov
Broad Institute of MIT and Harvard
Mafalda Barbosa
  • Function : Author
Icahn School of Medicine at Mount Sinai [New York]
Catalina Betancur
Neuroscience Paris Seine
Alfredo Brusco
Università degli studi di Torino = University of Turin
Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino
Brian Chung
The University of Hong Kong
Edwin Cook
University of Illinois [Chicago]
Michael Cuccaro
  • Function : Author
University of Miami Leonard M. Miller School of Medicine
Enrico Domenici
University of Trento [Trento]
Giovanni Battista Ferrero
  • Function : Author
Università degli studi di Torino = University of Turin
J. Jay Gargus
  • Function : Author
University of California [Irvine]
Gail Herman
  • Function : Author
Nationwide Children's Hospital
Irva Hertz-Picciotto
  • Function : Author
University of California [Davis]
Patricia Maciel
Universidade do Minho = University of Minho [Braga]
Dara Manoach
Massachusetts General Hospital [Boston, MA, USA]
Maria Rita Passos-Bueno
  • Function : Author
Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Antonio Persico
  • Function : Author
Università degli Studi di Messina = University of Messina
Alessandra Renieri
  • Function : Author
Università degli Studi di Siena = University of Siena
Azienda Ospedaliera Universitaria Senese
James Sutcliffe
Vanderbilt University [Nashville]
Vanderbilt University School of Medicine [Nashville]
Flora Tassone
  • Function : Author
University of California [Davis]
Elisabetta Trabetti
  • Function : Author
Università degli studi di Verona = University of Verona
Gabriele Campos
Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Simona Cardaropoli
Università degli studi di Torino = University of Turin
Diana Carli
Università degli studi di Torino = University of Turin
Marcus Chan
  • Function : Author
The University of Hong Kong
Chiara Fallerini
  • Function : Author
Università degli Studi di Siena = University of Siena
Elisa Giorgio
  • Function : Author
Università degli studi di Torino = University of Turin
Ana Cristina Girardi
Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Emily Hansen-Kiss
  • Function : Author
University of Texas Health Science Center
So Lun Lee
  • Function : Author
The University of Hong Kong
Carla Lintas
  • Function : Author
Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
Yunin Ludena
  • Function : Author
University of California [Davis]
Rachel Nguyen
  • Function : Author
University of California [Irvine]
Lisa Pavinato
Università degli studi di Torino = University of Turin
Margaret Pericak-Vance
University of Miami Leonard M. Miller School of Medicine
Isaac Pessah
  • Function : Author
University of California [Davis]
Rebecca Schmidt
University of California [Davis]
Moyra Smith
  • Function : Author
University of California [Irvine]
Claudia Costa
  • Function : Author
Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Slavica Trajkova
  • Function : Author
Università degli studi di Torino = University of Turin
Jaqueline Wang
  • Function : Author
Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Mullin Yu
  • Function : Author
The University of Hong Kong
David Cutler
  • Function : Author
Emory University School of Medicine
Silvia de Rubeis
Icahn School of Medicine at Mount Sinai [New York]
Joseph Buxbaum
Icahn School of Medicine at Mount Sinai [New York]
Mark Daly
Massachusetts General Hospital [Boston]
Broad Institute of MIT and Harvard
Harvard Medical School [Boston]
Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Bernie Devlin
University of Pittsburgh School of Medicine
Kathryn Roeder
Carnegie Mellon University [Pittsburgh]
Stephan Sanders
University of California [San Francisco]
Michael Talkowski
Massachusetts General Hospital [Boston]

Abstract

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Domains

Human genetics Neurobiology
Fichier principal
Vignette du fichier
Fu Nat Genet 2022.pdf (18.57 Mo) Télécharger le fichier

Catalina Betancur  : Connect in order to contact the contributor

https://www.hal.inserm.fr/inserm-03949950

Submitted on : Friday, January 20, 2023-11:04:38 PM

Last modification on : Friday, March 24, 2023-2:53:30 PM

Download

Dates and versions

inserm-03949950 , version 1 (20-01-2023)

Identifiers

Cite

Jack Fu, F. Kyle Satterstrom, Minshi Peng, Harrison Brand, Ryan Collins, et al.. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nature Genetics, 2022, 54 (9), pp.1320-1331. ⟨10.1038/s41588-022-01104-0⟩. ⟨inserm-03949950⟩

Export

BibTeX TEI Dublin Core DC Terms EndNote Datacite

Collections

INSERM CNRS NPS IBPS SORBONNE-UNIVERSITE SU-SCIENCES
16 View
20 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More