• Eilis Hannon, Diana Schendel, Christine Ladd-Acosta, Jakob Grove, iPSYCH-Broad ASD Group, Christine Søholm Hansen, Shan V Andrews, David Michael Hougaard, Michaeline Bresnahan, Ole Mors, Mads Vilhelm Hollegaard, Marie Bækvad-Hansen, Mady Hornig, Preben Bo Mortensen, Anders D Børglum, Thomas Werge, Marianne Giørtz Pedersen, Merete Nordentoft, Joseph Buxbaum, Daniele Fallin M M Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. , Jonas Bybjerg-Grauholm, Abraham Reichenberg, and Jonathan Mill.
• University of Exeter Medical School, University of Exeter, RILD Building, Level 4, Barrack Rd, Exeter, EX2 5DW, UK.
• Genome Med. 2018 Mar 28; 10 (1): 19.

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.

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