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Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
Jack M. Fu ,
F. Kyle Satterstrom ,
Minshi Peng ,
Harrison Brand ,
Ryan L. Collins ,
Shan Dong ,
Brie Wamsley ,
Lambertus Klei ,
Lily Wang ,
Stephanie P. Hao ,
Christine R. Stevens ,
Caroline Cusick ,
Mehrtash Babadi ,
Eric Banks ,
Brett Collins ,
Sheila Dodge ,
Stacey B. Gabriel ,
Laura Gauthier ,
Samuel K. Lee ,
Lindsay Liang ,
Alicia Ljungdahl ,
Behrang Mahjani ,
Laura Sloofman ,
Andrey N. Smirnov ,
Mafalda Barbosa ,
Catalina Betancur ,
Alfredo Brusco ,
Brian H. Y. Chung ,
Edwin H. Cook ,
Michael L. Cuccaro ,
Enrico Domenici ,
Giovanni Battista Ferrero ,
J. Jay Gargus ,
Gail E. Herman ,
Irva Hertz-Picciotto ,
Patricia Maciel ,
Dara S. Manoach ,
Maria Rita Passos-Bueno ,
Antonio M. Persico ,
Alessandra Renieri ,
James S. Sutcliffe ,
Flora Tassone ,
Elisabetta Trabetti ,
Gabriele Campos ,
Simona Cardaropoli ,
Diana Carli ,
Marcus C. Y. 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 N. Pessah ,
Rebecca J. Schmidt ,
Moyra Smith ,
Claudia I. S. Costa ,
Slavica Trajkova ,
Jaqueline Y. T. Wang ,
Mullin H. C. Yu ,
Branko Aleksic ,
Mykyta Artomov ,
Elisa Benetti ,
Monica Biscaldi-Schafer ,
Anders D. Børglum ,
Angel Carracedo ,
Andreas G. Chiocchetti ,
Hilary Coon ,
Ryan N. Doan ,
Montserrat Fernández-Prieto ,
Christine M. Freitag ,
Sherif Gerges ,
Stephen Guter ,
David M. Hougaard ,
Christina M. Hultman ,
Suma Jacob ,
Miia Kaartinen ,
Alexander Kolevzon ,
Itaru Kushima ,
Terho Lehtimäki ,
Caterina Lo Rizzo ,
Nell Maltman ,
Marianna Manara ,
Gal Meiri ,
Idan Menashe ,
Judith Miller ,
Nancy Minshew ,
Matthew Mosconi ,
Norio Ozaki ,
Aarno Palotie ,
Mara Parellada ,
Kaija Puura ,
Abraham Reichenberg ,
Sven Sandin ,
Stephen W. Scherer ,
Sabine Schlitt ,
Lauren Schmitt ,
Katja Schneider-Momm ,
Paige M. Siper ,
Pål Suren ,
John A. Sweeney ,
Karoline Teufel ,
Maria del Pilar Trelles ,
Lauren A. Weiss ,
Ryan Yuen ,
David J. Cutler ,
Silvia De Rubeis ,
Joseph D. Buxbaum ,
Mark J. Daly ,
Bernie Devlin ,
Kathryn Roeder ,
Stephan J. Sanders ,
Michael E. Talkowski ,
The Autism Sequencing Consortium (ASC),
Broad Institute Center for Common Disease Genomics (Broad-CCDG),
iPSYCH-BROAD Consortium
August 18 2022
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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.