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; The Autism Sequencing Consortium (ASC)

doi:10.1038/s41588-022-01104-0

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

Journal article

Peer reviewed

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, …

Nature genetics, Vol.54(9), pp.1320-1331

2022-09-01

DOI: https://doi.org/10.1038/s41588-022-01104-0

PMID: 35982160

Appears in Miller School of Medicine - Latest Publications

Abstract

Genetics

Human genetics

Life Sciences

Neurobiology

Neurons and Cognition

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.

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Title: Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
Creators: Jack Fu - Massachusetts General Hospital
F. Kyle Satterstrom - Broad Institute
Minshi Peng - Carnegie Mellon University
Harrison Brand - Massachusetts General Hospital
Ryan Collins - Massachusetts General Hospital
Shan Dong - University of California, San Francisco
Brie Wamsley - University of California, Los Angeles
Lambertus Klei - University of Pittsburgh
Lily Wang - Broad Institute
Stephanie Hao - Massachusetts General Hospital
Christine Stevens - Broad Institute
Caroline Cusick - Broad Institute
Mehrtash Babadi - Broad Institute
Eric Banks - Broad Institute
Brett Collins - Icahn School of Medicine at Mount Sinai
Sheila Dodge - Broad Institute
Stacey Gabriel - Broad Institute
Laura Gauthier - Broad Institute
Samuel Lee - Broad Institute
Lindsay Liang - University of California, San Francisco
Alicia Ljungdahl - University of California, San Francisco
Behrang Mahjani - Icahn School of Medicine at Mount Sinai
Laura Sloofman - Icahn School of Medicine at Mount Sinai
Andrey Smirnov - Broad Institute
Mafalda Barbosa - Child Health and Development Institute
Catalina Betancur - Institut de Biologie Paris-Seine
Alfredo Brusco - University of Turin
Brian Chung - University of Hong Kong
Edwin Cook - University of Illinois Chicago
Michael Cuccaro - University of Miami
Enrico Domenici - University of Trento
Giovanni Battista Ferrero - University of Turin
J. Jay Gargus - Center for Autism and Related Disorders
Gail Herman - Nationwide Children's Hospital
Irva Hertz-Picciotto - University of California, Davis
Patricia Maciel - University of Minho
Dara Manoach - Massachusetts General Hospital
Maria Rita Passos-Bueno - Universidade de São Paulo
Antonio Persico - University of Messina
Alessandra Renieri - University of Siena
James Sutcliffe - Vanderbilt University
Flora Tassone - University of California, Davis
Elisabetta Trabetti - University of Verona
Gabriele Campos - Universidade de São Paulo
Simona Cardaropoli - University of Turin
Diana Carli - University of Turin
Marcus Chan - University of Hong Kong
Chiara Fallerini - University of Siena
Elisa Giorgio - University of Turin
Ana Cristina Girardi - Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Emily Hansen-Kiss - The University of Texas Health Science Center at Houston
So Lun Lee - Duchess of Kent Children's Hospital
Carla Lintas - Università Campus Bio-Medico
Yunin Ludena - University of California, Davis
Rachel Nguyen - Center for Autism and Related Disorders
Lisa Pavinato - University of Turin
Margaret Pericak-Vance - University of Miami
Isaac Pessah - University of California, Davis
Rebecca Schmidt - University of California, Davis
Moyra Smith - Center for Autism and Related Disorders
Claudia Costa - Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Slavica Trajkova - University of Turin
Jaqueline Wang - Escola Politecnica da Universidade de Sao Paulo [Sao Paulo]
Mullin Yu - University of Hong Kong
David Cutler - Emory University
Silvia de Rubeis - Icahn School of Medicine at Mount Sinai
Joseph Buxbaum - Icahn School of Medicine at Mount Sinai
Mark Daly - Harvard University
Bernie Devlin - University of Pittsburgh
Kathryn Roeder - Carnegie Mellon University
Stephan Sanders - University of California, San Francisco
Michael Talkowski - Harvard University
The Autism Sequencing Consortium (ASC)
Publication Details: Nature genetics, Vol.54(9), pp.1320-1331
Publisher: Nature Publishing Group
Number of pages: 12
Academic Unit: Miller School of Medicine; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 35982160
Record Identifier: 991032796335702976