PT  - JOURNAL ARTICLE
AU  - Eilis Hannon
AU  - Diana Schendel
AU  - Christine Ladd-Acosta
AU  - Jakob Grove
AU  - iPSYCH-Broad ASD Group
AU  - Christine Søholm Hansen
AU  - Shan V. Andrews
AU  - David Michael Hougaard
AU  - Michaeline Bresnahan
AU  - Ole Mors
AU  - Mads Vilhelm Hollegaard
AU  - Marie Bækvad-Hansen
AU  - Mady Hornig
AU  - Preben Bo Mortensen
AU  - Anders D. Børglum
AU  - Thomas Werge
AU  - Marianne Giørtz Pedersen
AU  - Merete Nordentoft
AU  - Joseph Buxbaum
AU  - M Daniele Fallin
AU  - Jonas Bybjerg-Grauholm
AU  - Abraham Reichenberg
AU  - Jonathan Mill
TI  - Elevated polygenic burden for autism is associated with differential DNA methylation at birth
AID  - 10.1101/225193
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 225193
4099  - http://biorxiv.org/content/early/2017/11/26/225193.short
4100  - http://biorxiv.org/content/early/2017/11/26/225193.full
AB  - Background 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.Methods We quantified neonatal methylomic variation in 1,263 infants - of whom ~50% went on to subsequently develop ASD – using DNA isolated from a unique collection of archived blood spots taken shortly after birth. We used matched genetic data from the same individuals to examine the molecular consequences of ASD 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.Results Although we did not identify specific loci showing consistent changes in neonatal DNA methylation associated with later ASD, we found a significant association between increased polygenic burden for autism and methylomic variation at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8.Conclusions This study is the largest analysis of DNA methylation in ASD yet undertaken and the first to integrate both genetic and epigenetic variation at birth in ASD. 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.