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Journal Articles Nature Genetics Year : 2022

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

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Samuel Lee
Lindsay Liang
Andrey Smirnov
Brian Chung
Edwin Cook
Enrico Domenici
Rebecca Schmidt
Kathryn Roeder

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

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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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