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Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
- Source :
- Nature genetics, vol 54, iss 9, Nature Genetics, Nature Genetics, 2022, 54 (9), pp.1320-1331. ⟨10.1038/s41588-022-01104-0⟩, Nat Genet, Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Publication Year :
- 2022
-
Abstract
- International audience; 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.
- Subjects :
- Broad Institute Center for Common Disease Genomics
Autism Sequencing Consortium
DNA Copy Number Variations
Autism Spectrum Disorder
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Autism
Intellectual and Developmental Disabilities (IDD)
iPSYCH-BROAD Consortium
autism spectrum disorders
disease gene
copy number variants
neuropsychiatric disorders
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
GENOMAS
Medical and Health Sciences
Article
Clinical Research
Genetics
Humans
2.1 Biological and endogenous factors
Genetic Predisposition to Disease
Autistic Disorder
Aetiology
Genetic association study
Pediatric
Human Genome
Neurodevelopmental disorders
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Biological Sciences
Autism spectrum disorders
Brain Disorders
Mental Health
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Mutation
Gene expression
Biotechnology
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 10614036 and 15461718
- Database :
- OpenAIRE
- Journal :
- Nature genetics, vol 54, iss 9, Nature Genetics, Nature Genetics, 2022, 54 (9), pp.1320-1331. ⟨10.1038/s41588-022-01104-0⟩, Nat Genet, Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Accession number :
- edsair.doi.dedup.....e272fcce2991b63297b66fd9e9849ad8