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A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex.
Antaki, Danny; Guevara, James; Maihofer, Adam X; Klein, Marieke; Gujral, Madhusudan; Grove, Jakob; Carey, Caitlin E; Hong, Oanh; Arranz, Maria J; Hervas, Amaia; Corsello, Christina; Vaux, Keith K; Muotri, Alysson R; Iakoucheva, Lilia M; Courchesne, Eric; Pierce, Karen; Gleeson, Joseph G; Robinson, Elise B; Nievergelt, Caroline M; Sebat, Jonathan.
Afiliación
  • Antaki D; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
  • Guevara J; Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA.
  • Maihofer AX; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
  • Klein M; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Gujral M; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
  • Grove J; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Carey CE; Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA.
  • Hong O; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
  • Arranz MJ; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
  • Hervas A; Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA.
  • Corsello C; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
  • Vaux KK; Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA.
  • Muotri AR; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
  • Iakoucheva LM; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • Courchesne E; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
  • Pierce K; Center for Genomics and Personalized Medicine and Center for Integrative Sequencing, iSEQ, Aarhus, Denmark.
  • Gleeson JG; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
  • Robinson EB; Harvard T.H. Chan School of Public Health, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Nievergelt CM; Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA.
  • Sebat J; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Nat Genet ; 54(9): 1284-1292, 2022 09.
Article en En | MEDLINE | ID: mdl-35654974
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastorno Autístico / Trastorno del Espectro Autista Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Child / Female / Humans / Male Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastorno Autístico / Trastorno del Espectro Autista Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Child / Female / Humans / Male Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos