Article open access publication

Elevated polygenic burden for autism is associated with differential DNA methylation at birth

Genome Medicine, Springer Nature, ISSN 1756-994X

Volume 10, 1, 2018

DOI:10.1186/s13073-018-0527-4, Dimensions: pub.1101785475, PMC: PMC5872584, PMID: 29587883,



  1. (1) University of Exeter, grid.8391.3
  2. (2) Aarhus University, grid.7048.b, AU
  3. (3) Johns Hopkins University, grid.21107.35
  4. (4) Lundbeck Foundation, grid.452548.a
  5. (5) Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
  6. (6) State Serum Institute, grid.6203.7
  7. (7) Columbia University, grid.21729.3f
  8. (8) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  9. (9) Department of Clinical Medicine, Aarhus University; Aarhus University Hospital, Risskov, Denmark
  10. (10) University of Copenhagen, grid.5254.6, KU
  11. (11) Icahn School of Medicine at Mount Sinai, grid.59734.3c


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. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: This 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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Times Cited: 33

Field Citation Ratio (FCR): 10.65

Relative Citation ratio (RCR): 3.42

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