Abstract
BackgroundAutism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth.MethodsWe quantified neonatal methylomic variation in 1263 infants—of whom ~ 50% went on to subsequently develop ASD—using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings.ResultsWe identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of − 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8.ConclusionsThis study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.
Highlights
Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities
The Integrative Psychiatric Research (iPSYCH) study population comprises all singletons born in Denmark between May 1st 1981 and December 31st 2005, who are still alive and residing in Denmark at their first birthday and with a known mother. iPSYCH ASD cases comprise all children in the study population with an ASD diagnosis reported before December 31st 2012. iPSYCH controls comprise 30,000 persons randomly selected from the study population
Robust epigenetic signatures of gestational age and prenatal tobacco exposure validate DNA methylation data generated from neonatal blood spots Following our stringent QC pipeline our final MINERvA DNA methylation dataset included 1263 samples comprising 629 ASD cases and 634 controls
Summary
Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. Autism spectrum disorder (ASD) defines a group of complex neurodevelopmental disorders marked by deficits in social communication and restricted, repetitive behaviors, interests, or activities [1]. Genetic studies have shown that autism risk is strongly associated with both rare inherited and de novo DNA sequence variants [8,9,10,11]. Previous studies of other neurodevelopmental disorders have reported an enrichment of disease-associated variation in regulatory domains, including enhancers and regions of open chromatin [14]
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