Childhood abuse is associated with methylation of multiple loci in adult DNA
- Equal contributors
1 Sackler Program for Epigenetics & Developmental Psychobiology, McGill University, 3655 Promenade Sir William Osler, Montreal H3G 1Y6, QC, Canada
2 Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal H3G 1Y6, QC, Canada
3 McGill Centre for Bioinformatics, McGill University, 3649 Promenade Sir William Osler, Montreal H3G 0B1, QC, Canada
4 MRC Centre of Epidemiology for Child Health/ Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
5 Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
6 Human Early Learning Partnership, University of British Columbia, Suite 440, 2206 East Mall, Vancouver V6T 1Z3, BC, Canada
BMC Medical Genomics 2014, 7:13 doi:10.1186/1755-8794-7-13Published: 11 March 2014
Childhood abuse is associated with increased adult disease risk, suggesting that processes acting over the long-term, such as epigenetic regulation of gene activity, may be involved. DNA methylation is a critical mechanism in epigenetic regulation. We aimed to establish whether childhood abuse was associated with adult DNA methylation profiles.
In 40 males from the 1958 British Birth Cohort we compared genome-wide promoter DNA methylation in blood taken at 45y for those with, versus those without, childhood abuse (n = 12 vs 28). We analysed the promoter methylation of over 20,000 genes and 489 microRNAs, using MeDIP (methylated DNA immunoprecipitation) in triplicate.
We found 997 differentially methylated gene promoters (311 hypermethylated and 686 hypomethylated) in association with childhood abuse and these promoters were enriched for genes involved in key cell signaling pathways related to transcriptional regulation and development. Using bisulfite-pyrosequencing, abuse-associated methylation (MeDIP) at the metalloproteinase gene, PM20D1, was validated and then replicated in an additional 27 males. Abuse-associated methylation was observed in 39 microRNAs; in 6 of these, the hypermethylated state was consistent with the hypomethylation of their downstream gene targets. Although distributed across the genome, the differentially methylated promoters associated with child abuse clustered in genome regions of at least one megabase. The observations for child abuse showed little overlap with methylation patterns associated with socioeconomic position.
Our observed genome-wide methylation profiles in adult DNA associated with childhood abuse justify the further exploration of epigenetic regulation as a mediating mechanism for long-term health outcomes.