Journal article
Elevated polygenic burden for autism is associated with differential DNA methylation at birth
Genome medicine, v 10(1), pp 19-19
28 Mar 2018
PMID: 29587883
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 similar to 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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Details
- Title
- Elevated polygenic burden for autism is associated with differential DNA methylation at birth
- Creators
- Eilis Hannon - University of ExeterDiana Schendel - Aarhus UniversityChristine Ladd-Acosta - Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USAJakob Grove - Aarhus UniversityChristine Soholm Hansen - Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, DenmarkShan V. Andrews - Bloomberg (United States)David Michael Hougaard - Statens Serum InstitutMichaeline Bresnahan - Columbia UniversityOle Mors - Lundbeck FoundationMads Vilhelm Hollegaard - Lundbeck FoundationMarie Baekvad-Hansen - Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, DenmarkMady Hornig - Columbia UniversityPreben Bo Mortensen - Lundbeck FoundationAnders D. Borglum - Aarhus UniversityThomas Werge - Lundbeck FoundationMarianne Giortz Pedersen - Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, DenmarkMerete Nordentoft - Lundbeck FoundationJoseph Buxbaum - Icahn School of Medicine at Mount SinaiM. Daniele Fallin - Columbia UniversityJonas Bybjerg-Grauholm - Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, DenmarkAbraham Reichenberg - Icahn School of Medicine at Mount SinaiJonathan Mill - University of ExeteriPSYCH-Broad ASD Grp
- Publication Details
- Genome medicine, v 10(1), pp 19-19
- Publisher
- Springer Nature
- Number of pages
- 13
- Grant note
- MR/K013807/1 / UK Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 294838 / European Research Council; European Research Council (ERC) RFAs 01086; 02199; DD11-002; DD06-003; DD04-001; DD09-002 / Centers for Disease Control and Prevention (CDC); United States Department of Health & Human Services; Centers for Disease Control & Prevention - USA HD073978 / Eunice Kennedy Shriver National Institute of Child Health and Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) HD073978 / National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Lundbeck Foundation; Lundbeckfonden Novo Nordisk Foundation; Novocure Limited Aarhus University Hospital R102-A9118; R155-2014-1724 / Lundbeck Foundation; Lundbeckfonden Stanley Medical Research Institute Distinguished Investigator Award from the Brain & Behavior Research Foundation HD073978 / National Institute of Environmental Health Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) Beatrice and Samuel A. Seaver Foundation R155-2014-1724; R248-2017-2003 / Lundbeck Foundation; Lundbeckfonden Simons Foundation (SFARI) award MH089606 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Copenhagen University Hospital MR/K013807/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Burroughs-Wellcome Trust training grant: Maryland, Genetics, Epidemiology and Medicine (MD-GEM) 7659 / Autism Speaks Award iPSYCH Copenhagen University MR/K013807/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Aarhus University
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000428906200001
- Scopus ID
- 2-s2.0-85044353251
- Other Identifier
- 991021463714504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity