A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Danny Antaki, James Guevara, Adam X. Maihofer, Marieke Klein, Madhusudan Gujral, Jakob Grove, Caitlin E. Carey, Oanh Hong, Maria J. Arranz, Amaia Hervas, Christina Corsello, Keith K. Vaux, Alysson R. Muotri, Lilia M. Iakoucheva, Eric Courchesne, Karen Pierce, Joseph G. Gleeson, Elise B. Robinson, Caroline M. Nievergelt, Jonathan Sebat*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

7 Citations (Scopus)

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.

Original languageEnglish
JournalNature Genetics
Volume54
Issue9
Pages (from-to)1284-1292
Number of pages9
ISSN1061-4036
DOIs
Publication statusPublished - Sept 2022

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