Journal
BIOLOGICAL PSYCHIATRY
Volume 86, Issue 8, Pages 599-607Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.02.016
Keywords
ADHD; CAARS; DNA methylation; Epigenetic; EWAS; Meta-analysis
Categories
Funding
- Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL)
- Netherlands Organisation for Scientific Research (NWO) [480-15-001/674]
- Netherlands Twin Registry Repository: researching the interplay between genome and environment [NWO 184.021.007]
- Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION)
- European Union Seventh Framework Program (FP7/2007-2013) [602768]
- Royal Netherlands Academy of Science Professor Award [PAH/6635]
- Netherlands Organization for Scientific Research [016-130-669]
- Dutch National Science Agenda for the NWANeurolabNL project [400 17 602]
- European Community FP7 [602805]
- European Community Horizon 2020 Program (H2020/2014-2020) [728018]
- NewZealandHealth Research Council
- NewZealand Ministry of Business, Innovation andEmployment
- National Institutes of Health National Institute of Aging [R01AG032282]
- Medical Research Council [MR/P005918, G1002190]
- Jacobs Foundation
- North Carolina Biotechnology Center [2016-IDG-1013, 2016IDG-1013]
- National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD077482]
- American Asthma Foundation Distinguished Investigator Award
- Avielle Foundation
- Economic and Social Research Council Mental Health Leadership Fellowship
- Medical Research Council Skills Development Fellowship
- ESRC [ES/P010113/1] Funding Source: UKRI
- MRC [MR/P014100/1, G1002190, MR/P005918/1] Funding Source: UKRI
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BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HunnanMethylation450K array) in three population-based adult cohorts. METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed. RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia. CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.
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