Childhood abuse is associated with methylation of multiple loci in adult DNA.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Associations with early-life socio-economic position in adult DNA methylation.

BACKGROUND: Disadvantaged socio-economic position (SEP) in childhood is associated with increased adult mortality and morbidity. We aimed to establish whether childhood SEP was associated with differential methylation of adult DNA. METHODS: Forty adult males from the 1958 British Birth Cohort Study were selected from SEP extremes in both early childhood and mid-adulthood. We performed genome-wide methylation analysis on blood DNA taken at 45 years using MeDIP (methylated DNA immunoprecipitation). We mapped in triplicate the methylation state of promoters of approximately 20,000 genes and 400 microRNAs. Probe methylation scores were averaged across triplicates and differential methylation between groups of individuals was determined. Differentially methylated promoter sites of selected genes were validated using pyrosequencing of bisulfite-converted DNA. RESULTS: Variably methylated probes (9112 from n = 223,359 on the microarray) corresponded to 6176 gene promoters with at least one variable probe. Unsupervised hierarchical clustering of probes obtained from the 500 most variable promoters revealed a cluster enriched with high SEP individuals confirming that SEP differences contribute to overall epigenetic variation. Methylation levels for 1252 gene promoters were associated with childhood SEP vs 545 promoters for adulthood SEP. Functionally, associations with childhood SEP appear in promoters of genes enriched in key cell signalling pathways. The differentially methylated promoters associated with SEP cluster in megabase-sized regions of the genome. CONCLUSIONS: Adult blood DNA methylation profiles show more associations with childhood SEP than adult SEP. Organization of these associations across the genome suggests a well-defined epigenetic pattern linked to early socio-economic environment.

Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height.

OBJECTIVE: The type 2 insulin-like growth factor receptor (IGF2R) is thought to regulate insulin-like growth factor-II (IGF-II) bioavailability by degrading it in the lysosomes after uptake. We hypothesised that polymorphisms in the IGF2R gene could alter size at birth and childhood growth. DESIGN AND METHODS: The hypothesis was tested in a normal birth cohort (Avon Longitudinal Study of Parents and Children) by genotyping the IGF2R gene gly1619arg polymorphism, which causes a non-conservative amino acid change in the IGF-II binding region, using PCR and restriction fragment length polymorphism analysis. RESULTS: The IGF2R gly1619arg genotype was not associated with any measure of size at birth, but A/A homozygotes grew more slowly, as determined by their change in height standard deviation scores (SDS) over the first three years (-0.70 (0.72); n = 12), than G/G homozygotes (0.00 (1.09); n = 561) (p = 0.03). They remained shorter during childhood and by the age of 7 years respective height SDS were: 0.73 (1.02) (n = 12) and 0.01 (0.99) (n = 634) (p = 0.01). These height differences persisted after adjusting for parental heights and gender. There were no detectable differences in weights at 7 years. CONCLUSION: Allelic variation in the gly1619arg SNP of the IGF2R gene is associated with disparity in childhood stature which could reflect altered binding of IGF-II to its receptor.

Genetic information and testing in insurance and employment: technical, social and ethical issues.

The present paper examines the professional and scientific views on the social, ethical and legal issues that impact on genetic information and testing in insurance and employment in Europe. For this purpose, many aspects have been considered, such as the concerns of medical geneticists, of the insurers and employers, of the public, as well as the regulatory frameworks and unresolved issues. The method used was primarily the review of the technical, social, economical and ethical aspects of advances in genetics and the concerns of parties who are involved, that is, the insurers, the employers and the public. The existing guidelines and legislation on this topic were also reported. Then, the method was to examine the issues debated by these parties in Europe, as well as by 47 experts from 14 European countries invited to an international workshop organized by the European Society of Human Genetics Public and Professional Policy Committee in Manchester, UK, 25-27 February 2000. The result of this was that the most important issues raised by genetic information and testing in insurance and employment in Europe include a need for clear definitions of terms used in genetics, declaring the grounds on which genetic information is or is not used, and promoting confidence between the public and the insurance industry. There is currently very little use of genetic information in relation to employment, but the situation should be kept under review.