Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
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Jack Fu
- Function : Author
F. Kyle Satterstrom
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Stephanie Hao
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Christine Stevens
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Samuel Lee
- Function : Author
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Lindsay Liang
- Function : Author
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Andrey Smirnov
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Catalina Betancur
- Function : Author
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Brian Chung
- Function : Author
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Edwin Cook
- Function : Author
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Enrico Domenici
- Function : Author
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Patricia Maciel
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Dara Manoach
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James Sutcliffe
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Gabriele Campos
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Simona Cardaropoli
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Diana Carli
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Ana Cristina Girardi
- Function : Author
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Lisa Pavinato
- Function : Author
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Margaret Pericak-Vance
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Rebecca Schmidt
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Silvia de Rubeis
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Joseph Buxbaum
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Bernie Devlin
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Kathryn Roeder
- Function : Author
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Stephan Sanders
- Function : Author
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Michael Talkowski
- Function : Author
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- ORCID : 0000-0003-2889-0992
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.
Embargoed file
Embargoed file
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