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

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  • Danny Antaki, University of California at San Diego
  • ,
  • James Guevara, University of California at San Diego
  • ,
  • Adam X. Maihofer, University of California at San Diego
  • ,
  • Marieke Klein, University of California at San Diego
  • ,
  • Madhusudan Gujral, University of California at San Diego
  • ,
  • Jakob Grove
  • Caitlin E. Carey, Massachusetts Institute of Technology
  • ,
  • Oanh Hong, University of California at San Diego
  • ,
  • Maria J. Arranz, Fundació Docència i Recerca Mutua Terrassa
  • ,
  • Amaia Hervas, University of Barcelona
  • ,
  • Christina Corsello, University of North Carolina
  • ,
  • Keith K. Vaux, Human Longevity, Inc.
  • ,
  • Alysson R. Muotri, University of California at San Diego
  • ,
  • Lilia M. Iakoucheva, University of California at San Diego
  • ,
  • Eric Courchesne, University of California at San Diego
  • ,
  • Karen Pierce, University of California at San Diego
  • ,
  • Joseph G. Gleeson, University of California at San Diego
  • ,
  • Elise B. Robinson, Massachusetts Institute of Technology
  • ,
  • Caroline M. Nievergelt, University of California at San Diego
  • ,
  • Jonathan Sebat, University of California at San Diego

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 - Sep 2022

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Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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