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

Published on Apr 4, 2021in medRxiv
· DOI :10.1101/2021.03.30.21254657
Danny Antaki10
Estimated H-index: 10
(UCSD: University of California, San Diego),
Adam X. Maihofer22
Estimated H-index: 22
(UCSD: University of California, San Diego)
+ 15 AuthorsJonathan Sebat47
Estimated H-index: 47
Sources
Abstract
The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable to de novo mutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.
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Abstract null null Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. Recently developed genomic technologies, including microarray and next-generation sequencing (NGS), have enabled researchers to genetic analyses aimed at identifying genetic variations associated with ASD and to elucidate the genetic architecture of the disorder. Large-scale microarray, exome sequencing analyses, and robust statistical methods have resulted in successful gene disco...
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