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
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.
#1Aojie Lian (UCSD: University of California, San Diego)H-Index: 1
#2James GuevaraH-Index: 1
Last. Jonathan Sebat (UCSD: University of California, San Diego)H-Index: 47
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MotivationAs sequencing technologies and analysis pipelines evolve, DNM calling tools must be adapted. Therefore, a flexible approach is needed that can accurately identify de novo mutations from genome or exome sequences from a variety of datasets and variant calling pipelines. ResultsHere, we describe SynthDNM, a random-forest based classifier that can be readily adapted to new sequencing or variant-calling pipelines by applying a flexible approach to constructing simulated training examples f...
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#1Maxwell A Sherman (MIT: Massachusetts Institute of Technology)H-Index: 1
#1Maxwell A. Sherman (MIT: Massachusetts Institute of Technology)H-Index: 8
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Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings. We detected 46 mCNVs in probands and 19 mCNVs in siblings, affecting 2.8-73.8% of cells. Probands carried a significa...
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#1Ileena Mitra (UCSD: University of California, San Diego)H-Index: 5
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Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants3,4. It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), defined here as sequ...
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#1Robert W. Davies (University of Oxford)H-Index: 18
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The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for indivi...
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#1Celia J. Fulco (CSU: Colorado State University)H-Index: 3
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Advanced parental age is a well-replicated risk factor for autism spectrum disorder (ASD), a neurodevelopmental condition with a complex and not well-defined etiology. We sought to determine parental age associations with ASD-related outcomes in subjects at high familial risk for ASD. A total of 397 younger siblings of a child with ASD, drawn from existing prospective high familial risk cohorts, were included in these analyses. Overall, we did not observe significant associations of advanced par...
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Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 300,000 participants from the UK Biobank to examine asso...
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Summary We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; com...
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Cited By0
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...