Rare coding variation illuminates the allelic architecture, risk genes, cellular expression patterns, and phenotypic context of autism
Authors: Fu Jack M. , Satterstrom F. Kyle , Peng Minshi , Brand Harrison , Collins Ryan L. , Dong Shan , Klei Lambertus , Stevens Christine R. , Cusick Caroline , Babadi Mehrtash , Banks Eric , Collins Brett , Dodge Sheila , Gabriel Stacey B. , Gauthier Laura , Lee Samuel K. , Liang Lindsay , Ljungdahl Alicia , Mahjani Behrang , Sloofman Laura , Smirnov Andrey , Barbosa Mafalda , Brusco Alfredo , Chung Brian H.Y. , Cuccaro Michael L. , Domenici Enrico , Ferrero Giovanni Battista , Gargus Jay J. , Herman Gail E. , Hertz-Picciotto Irva , Maciel Patricia , Manoach Dara S. , Passos-Bueno Maria Rita , Persico Antonio M. , Renieri Alessandra , Tassone Flora , Trabetti Elisabetta , Campos Gabriele , Chan Marcus C.Y. , Fallerini Chiara , Giorgio Elisa , Girard Ana Cristina , Hansen-Kiss Emily , Lee So Lun , Lintas Carla , Ludena Yunin , Nguyen Rachel , Pavinato Lisa , Pericak-Vance Margaret , Pessah Isaac , Riberi Evelise , Schmidt Rebecca , Smith Moyra , Souza Claudia I.C. , Trajkova Slavica , Wang Jaqueline Y.T. , Yu Mullin H.C. ,   The Autism Sequencing Consoritum (ASC),   Broad Institute Center for Common Disease Genomics (Broad-CCDG),   iPSYCH-BROAD Consortium, Cutler David J. , De Rubeis Silvia , Buxbaum Joseph D. , Daly Mark J. , Devlin Bernie , Roeder Kathryn , Sanders Stephan J. , Talkowski Michael E. 
Published: December 2021

Individuals with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDDs) often carry disruptive mutations in genes that are depleted of functional variation in the broader population. We build upon this observation and exome sequencing from 154,842 individuals to explore the allelic diversity of rare protein-coding variation contributing risk for ASD and related NDDs. Using an integrative statistical model, we jointly analyzed rare protein-truncating variants (PTVs), damaging missense variants, and copy number variants (CNVs) derived from exome sequencing of 63,237 individuals from ASD cohorts. We discovered 71 genes associated with ASD at a false discovery rate (FDR) ≤ 0.001, a threshold approximately equivalent to exome-wide significance, and 183 genes at FDR ≤ 0.05. Associations were predominantly driven by de novo PTVs, damaging missense variants, and CNVs: 57.4%, 21.2%, and 8.32% of evidence, respectively. Though fewer in number, CNVs conferred greater relative risk than PTVs, and repeat-mediated de novo CNVs exhibited strong maternal bias in parent-of-origin (e.g., 92.3% of 16p11.2 CNVs), whereas all other CNVs showed a paternal bias. To explore how genes associated with ASD and NDD overlap or differ, we analyzed our ASD cohort alongside a developmental delay (DD) cohort from the deciphering developmental disorders study (DDD; n=91,605 samples). We first reanalyzed the DDD dataset using the same models as the ASD cohorts, then performed joint analyses of both cohorts and identified 373 genes contributing to NDD risk at FDR ≤ 0.001 and 662 NDD risk genes at FDR ≤ 0.05. Of these NDD risk genes, 54 genes (125 genes at FDR ≤ 0.05) were unique to the joint analyses and not significant in either cohort alone. Our results confirm overlap of most ASD and DD risk genes, although many differ significantly in frequency of mutation. Analyses of single-cell transcriptome datasets showed that genes associated predominantly with DD were strongly enriched for earlier neurodevelopmental cell types, whereas genes displaying stronger evidence for association in ASD cohorts were more enriched for maturing neurons. The ASD risk genes were also enriched for genes associated with schizophrenia from a separate rare coding variant analysis of 121,570 individuals, emphasizing that these neuropsychiatric disorders share common pathways to risk.