A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex
- PMID: 35654974
- PMCID: PMC9474668
- DOI: 10.1038/s41588-022-01064-5
A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex
Erratum in
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Publisher Correction: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex.Nat Genet. 2022 Aug;54(8):1259. doi: 10.1038/s41588-022-01145-5. Nat Genet. 2022. PMID: 35768728 No abstract available.
Abstract
The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Conflict of interest statement
Competing Interests
A.R.M. is a co-founder and has an equity interest in TISMOO, a company focusing on applications of genetics and human brain organoids to personalized medicine. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. The remaining authors declare no competing interests.
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