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

Jack Fu; F. Kyle Satterstrom; Minshi Peng; Harrison Brand; Ryan Collins; Shan Dong; Brie Wamsley; Lambertus Klei; Lily Wang; Stephanie Hao; Christine Stevens; Caroline Cusick; Mehrtash Babadi; Eric Banks; Brett Collins; Sheila Dodge; Stacey Gabriel; Laura Gauthier; Samuel Lee; Lindsay Liang; Alicia Ljungdahl; Behrang Mahjani; Laura Sloofman; Andrey Smirnov; Mafalda Barbosa; Catalina Betancur; Alfredo Brusco; Brian Chung; Edwin Cook; Michael Cuccaro; Enrico Domenici; Giovanni Battista Ferrero; J. Jay Gargus; Gail Herman; Irva Hertz-Picciotto; Patricia Maciel; Dara Manoach; Maria Rita Passos-Bueno; Antonio Persico; Alessandra Renieri; James Sutcliffe; Flora Tassone; Elisabetta Trabetti; Gabriele Campos; Simona Cardaropoli; Diana Carli; Marcus Chan; Chiara Fallerini; Elisa Giorgio; Ana Cristina Girardi; Emily Hansen-Kiss; So Lun Lee; Carla Lintas; Yunin Ludena; Rachel Nguyen; Lisa Pavinato; Margaret Pericak-Vance; Isaac Pessah; Rebecca Schmidt; Moyra Smith; Claudia Costa; Slavica Trajkova; Jaqueline Wang; Mullin Yu; David Cutler; Silvia de Rubeis; Joseph Buxbaum; Mark Daly; Bernie Devlin; Kathryn Roeder; Stephan Sanders; Michael Talkowski

doi:10.1038/s41588-022-01104-0

Journal Articles Nature Genetics Year : 2022

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

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Jack Fu

Function : Author

Massachusetts General Hospital [Boston]

Broad Institute of MIT and Harvard

F. Kyle Satterstrom

Function : Author
PersonId : 1218104
ORCID : 0000-0001-6187-7680

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

Function : Author
PersonId : 1218105
ORCID : 0000-0002-3760-8234

Broad Institute of MIT and Harvard

Massachusetts General Hospital [Boston]

Christine Stevens

Function : Author
PersonId : 1218106
ORCID : 0000-0002-2621-2234

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

Function : Author
PersonId : 1218107
ORCID : 0000-0001-6733-0547

Broad Institute of MIT and Harvard

Lindsay Liang

Function : Author
PersonId : 1218108
ORCID : 0000-0002-9393-2645

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

Function : Author
PersonId : 1218109
ORCID : 0000-0002-4450-0408

Broad Institute of MIT and Harvard

Mafalda Barbosa

Function : Author

Icahn School of Medicine at Mount Sinai [New York]

Catalina Betancur

Function : Author
PersonId : 13320
IdHAL : catalina-betancur
ORCID : 0000-0002-3327-4804
IdRef : 180835750

Génétique de l'autisme = Genetics of Autism

Alfredo Brusco

Function : Author
PersonId : 1218110
ORCID : 0000-0002-8318-7231

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

Function : Author
PersonId : 1218111
ORCID : 0000-0002-7044-5916

The University of Hong Kong

Edwin Cook

Function : Author
PersonId : 1218112
ORCID : 0000-0002-5848-5114

University of Illinois [Chicago]

Michael Cuccaro

Function : Author

University of Miami Leonard M. Miller School of Medicine

Enrico Domenici

Function : Author
PersonId : 1218113
ORCID : 0000-0001-7436-6919

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

Function : Author
PersonId : 1218114
ORCID : 0000-0002-0920-6350

Universidade do Minho = University of Minho [Braga]

Dara Manoach

Function : Author
PersonId : 1218115
ORCID : 0000-0001-9208-1167

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

Function : Author
PersonId : 1218116
ORCID : 0000-0001-5200-6007

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

Function : Author
PersonId : 1218117
ORCID : 0000-0002-0470-3382

Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]

Simona Cardaropoli

Function : Author
PersonId : 1218118
ORCID : 0000-0002-8927-8900

Università degli studi di Torino = University of Turin

Diana Carli

Function : Author
PersonId : 1218119
ORCID : 0000-0001-5690-6504

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

Function : Author
PersonId : 1218120
ORCID : 0000-0001-6531-501X

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

Function : Author
PersonId : 1218121
ORCID : 0000-0002-7630-8365

Università degli studi di Torino = University of Turin

Margaret Pericak-Vance

Function : Author
PersonId : 1218122
ORCID : 0000-0001-7283-8804

University of Miami Leonard M. Miller School of Medicine

Isaac Pessah

Function : Author

University of California [Davis]

Rebecca Schmidt

Function : Author
PersonId : 1218123
ORCID : 0000-0003-1582-2747

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

Function : Author
PersonId : 1218124
ORCID : 0000-0001-9383-6883

Icahn School of Medicine at Mount Sinai [New York]

Joseph Buxbaum

Function : Author
PersonId : 1218125
ORCID : 0000-0001-8898-8313

Icahn School of Medicine at Mount Sinai [New York]

Mark Daly

Function : Author
PersonId : 1218126
ORCID : 0000-0002-0949-8752

Massachusetts General Hospital [Boston]

Broad Institute of MIT and Harvard

Harvard Medical School [Boston]

Helsingin yliopisto = Helsingfors universitet = University of Helsinki

Bernie Devlin

Function : Author
PersonId : 1218127
ORCID : 0000-0003-2524-4290

University of Pittsburgh School of Medicine

Kathryn Roeder

Function : Author
PersonId : 1218128
ORCID : 0000-0002-8869-6254

Carnegie Mellon University [Pittsburgh]

Stephan Sanders

Function : Author
PersonId : 1218129
ORCID : 0000-0001-9112-5148

University of California [San Francisco]

Michael Talkowski

Function : Author
PersonId : 1218130
ORCID : 0000-0003-2889-0992

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

Life Sciences [q-bio] Genetics Human genetics Life Sciences [q-bio] Neurons and Cognition [q-bio.NC] Neurobiology

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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 : Wednesday, January 25, 2023-2:24:29 PM

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

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HAL Id : inserm-03949950 , version 1
DOI : 10.1038/s41588-022-01104-0
PUBMED : 35982160
PUBMEDCENTRAL : PMC9653013

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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⟩

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

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