TY - JOUR

T1 - Elevated polygenic burden for autism is associated with differential DNA methylation at birth

AU - Hannon, Eilis

AU - Schendel, Diana

AU - Ladd-Acosta, Christine

AU - Grove, Jakob

AU - Hansen, Christine Soholm

AU - Andrews, Shan V.

AU - Hougaard, David Michael

AU - Bresnahan, Michaeline

AU - Mors, Ole

AU - Hollegaard, Mads Vilhelm

AU - Bækvad-Hansen, Marie

AU - Hornig, Mady

AU - Mortensen, Preben Bo

AU - Børglum, Anders D.

AU - Werge, Thomas

AU - Pedersen, Marianne Giørtz

AU - Nordentoft, Merete

AU - Buxbaum, Joseph

AU - Fallin, M. Daniele

AU - Bybjerg-Grauholm, Jonas

AU - Reichenberg, Abraham

AU - Mill, Jonathan

PY - 2018/3/28

Y1 - 2018/3/28

N2 - 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.

AB - 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.

KW - Autism

KW - DNA methylation

KW - Genetics

KW - Neonatal

KW - Genome-wide association study (GWAS)

KW - Epigenome-wide association study (EWAS)

KW - Birth

KW - DNA methylation quantitative trait loci (mQTL)

KW - Polygenic risk score

KW - Prenatal smoking

U2 - 10.1186/s13073-018-0527-4

DO - 10.1186/s13073-018-0527-4

M3 - Journal article

C2 - 29587883

VL - 10

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

M1 - 19

ER -