Department of Economics and Business Economics

Case-control meta-analysis of blood DNA methylation and autism spectrum disorder

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  • Shan V Andrews, 2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, W6509, Baltimore, MD 21205 USA.
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  • Brooke Sheppard, 2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, W6509, Baltimore, MD 21205 USA.
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  • Gayle C Windham, 3California Department of Public Health, Environmental Health Investigations Branch, 850 Marina Bay Parkway, Richmond, CA 94804 USA.
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  • Laura A Schieve, 4National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, MS E-86, 1600 Clifton Road, Atlanta, GA 30333 USA.
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  • Diana E Schendel
  • Lisa A Croen, 8Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA 94612 USA.
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  • Pankaj Chopra, 9Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322 USA.
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  • Reid S Alisch, 10Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Blvd, Madison, WI 53719 USA.
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  • Craig J Newschaffer, A.J. Drexel Autism Institute, 3020 Market Street Suite 560, Philadelphia, PA 19104 USA.
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  • Stephen T Warren, 14Department of Pediatrics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322 USA.
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  • Andrew P Feinberg, 16Department of Medicine, Johns Hopkins School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205 USA.
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  • M Daniele Fallin, 17Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway, HH850, Baltimore, MD 21205 USA.
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  • Christine Ladd-Acosta, 2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, W6509, Baltimore, MD 21205 USA.

Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies.

Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample.

Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 × 10- 7. Seven CpGs showed differences at p < 1 × 10- 5 and 48 at 1 × 10- 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds.

Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

Original languageEnglish
Article number40
JournalMolecular Autism
Volume9
Issue1
Number of pages11
ISSN2040-2392
DOIs
Publication statusPublished - 2018

    Research areas

  • Autism spectrum disorders, CONVERGENCE, DIAGNOSTIC OBSERVATION SCHEDULE, DNA methylation, EXPLORE EARLY DEVELOPMENT, Epigenome, FRAGILE-X-SYNDROME, GENE, GENOME-WIDE ASSOCIATION, HETEROGENEITY, INDIVIDUALS, MUTATIONS, Peripheral blood, RETT-SYNDROME, Simons Simplex Collection, Study to Explore Early Development

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