Thus, a possible epigenomic mechanism connecting ageing-specific changes with a late-onset disease indicates this type of pathogenic pathway may exist in other adult-onset illnesses. An epigenetic role may assist in explaining the progressive and quantitative nature of most common diseases [54
]. Chronic diseases such as psychiatric illness, which have been predominately intractable to genomic analysis, not withstanding precise phenotyping difficulties, may be model cases for environmental influences affecting the epigenome. Adverse early life events are considerable risk factors for later onset psychiatric morbidity and murine models have identified DNA methylation changes that affect long-term hormonal alterations together with features mimicking depression [55
]. These epigenetic modulations induced by these experiences appear to become hardwired, with lasting effects on established neurons indicating their possible role in behavioural and psychiatric disorders [56
]. The critical role of histone modification in neuronal morphology has also been demonstrated by further murine work into addiction [57
]. Specifically cocaine-induced structural changes within the Nucleus Accumbens, in the striatum of the basal ganglia, were identified, which is known to play an important role in reward and pleasure systems. Reduced global levels of H3K9 dimethylation due to repression of the lysine dimethyltransferase G9a within this brain region, regulated by a cocaine-induced transcription factor, subsequently led to addictive-like behaviour. In humans DNA methylation differences have been identified in the frontal cortex of those diagnosed with major psychotic symptoms, in regions linked to the disease aetiology, and additionally were also discerned due to long-term anti-psychotic treatment [58
]. Any common complex diseases with strong genetic and environmental aspects would be excellent targets for in-depth epigenomic analysis.
Monozygotic twins reduce genetic heterogeneity to an almost negligible level. These models have been ideal in the past for heritability studies, utilising concordance, but also have obvious great benefit in focusing on pure epigenetic changes, especially in those rare sets that are discordant for disease status. This form of analysis in the autoimmune disease systemic lupus erythematosus (SLE) [59
] identified a decrease in methylation across a number of genes associated with the phenotype. These were enriched for those with a known role in immune function, thus characterizing this disease, but not excluding the possibility of their involvement in the pathogenesis.
The re-examination of GWA study SNP data with respect to parent of origin effects has facilitated the identification of a common susceptibility type 1 diabetes SNP within an imprinted region [60
]. In an Icelandic cohort, this analysis found breast cancer, basal-cell carcinoma and type 2 diabetes (T2D) SNP associations [61
], with one of the latter showing a differentially methylated CTCF-binding site and decreased methylation.
The integration of epigenomic information in complex trait genomic analysis can help to reveal further functional insights within an associated locus. This is shown in a study of open chromatin sites in T2D by DNA-seq of formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) in pancreatic islets [62
]. An open location was mapped to a T2D associated SNP in the TCFL2
gene and was identified to be allele-specific and to alter enhancer activity. Analysis of common histone marks, also in human pancreatic islets, detected regulatory elements in the location of known T2D SNP associations [63
]. Within regions of strong linkage disequilibrium, allele-specific histone modifications or methylation data may enable narrowing down of critical regions and formulation of novel functional hypotheses.