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

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

Nat Genet. 2022 Sep;54(9):1284-1292. doi: 10.1038/s41588-022-01064-5. Epub 2022 Jun 2.

Authors

Danny Antaki^#^{1

2

3

4

5

6}, James Guevara^#^{2

3}, Adam X Maihofer³, Marieke Klein^{2

3}, Madhusudan Gujral^{2

3}, Jakob Grove^{7

8

9

10}, Caitlin E Carey¹¹, Oanh Hong^{2

3}, Maria J Arranz¹², Amaia Hervas¹³, Christina Corsello¹⁴, Keith K Vaux¹⁵, Alysson R Muotri^{4

5

16}, Lilia M Iakoucheva^{3

5}, Eric Courchesne^{6

17}, Karen Pierce^{6

17}, Joseph G Gleeson^{5

6}, Elise B Robinson¹¹, Caroline M Nievergelt³, Jonathan Sebat^{18

19

20

21}

Affiliations

¹ Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
² Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA.
³ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁴ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
⁵ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
⁶ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁸ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
⁹ Center for Genomics and Personalized Medicine and Center for Integrative Sequencing, iSEQ, Aarhus, Denmark.
¹⁰ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
¹¹ Harvard T.H. Chan School of Public Health, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹² Research Laboratory Unit, Fundacio Docencia i Recerca Mutua, Terrassa, Spain.
¹³ Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
¹⁴ TEACCH Autism Program, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Human Longevity Inc., San Diego, CA, USA.
¹⁶ Department of Pediatrics and Department of Cellular & Molecular Medicine, University of California San Diego, School of Medicine, Center for Academic Research and Training in Anthropogeny, Archealization Center, Kavli Institute for Brain and Mind, La Jolla, CA, USA.
¹⁷ Autism Center of Excellence, University of California San Diego, La Jolla, CA, USA.
¹⁸ Beyster Center for Psychiatric Genomics, University of California San Diego, La Jolla, CA, USA. [email protected].
¹⁹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. [email protected].
²⁰ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
²¹ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
Child
Family
Female
Genetic Predisposition to Disease
Humans
Male
Multifactorial Inheritance / genetics

Abstract

Publication types

MeSH terms

Grants and funding