Epigenetic outlier profiles in depression: A genome-wide DNA methylation analysis of monozygotic twins

Abstract

Recent discoveries highlight the importance of stochastic epigenetic changes, as indexed by epigenetic outlier DNA methylation signatures, as a valuable tool to understand aberrant cell function and subsequent human pathology. There is evidence of such changes in different complex disorders as diverse as cancer, obesity and, to a lesser extent, depression. The current study was aimed at identifying outlying DNA methylation signatures of depressive psychopathology. Here, genome-wide DNA methylation levels were measured (by means of Illumina Infinium HumanMethylation450 Beadchip) in peripheral blood of thirty-four monozygotic twins informative for depressive psychopathology (lifetime DSM-IV diagnoses). This dataset was explored to identify outlying epigenetic signatures of depression, operationalized as extreme hyper- or hypo-methylation in affected co-twins from discordant pairs that is not observed across the rest of the study sample. After adjusting for blood cell count, there were thirteen CpG sites across which depressed co-twins from the discordant pairs exhibited outlying DNA methylation signatures. None of them exhibited a methylation outlier profile in the concordant and healthy pairs, and some of these loci spanned genes previously associated with neuropsychiatric phenotypes, such as GHSR and KCNQ1. This exploratory study provides preliminary proof-of-concept validation that epigenetic outlier profiles derived from genome-wide DNA methylation data may be related to depression risk.

Fig 1. Sixteen DNA methylation probes across the genome exhibit larger methylation variance in the depression-affected co-twins than in their healthy counterparts.

The statistical significance of these p-values is already adjusted for multiple comparisons using the FDR protocol proposed by Storey and Tibshirani (2003).

Fig 2. CpG probes with large and statistically significant DNA methylation variances in the diagnostic-discordant MZ twins.

The thirteen probes displayed here are those with genome-wide statistically significant methylation variance increases in affected co-twins from the discordant pairs. PairID: randomly assigned pair number.

Fig 3. Assessment of DNA methylation levels in diagnostic-concordant and healthy pairs at the 13 CpG probes with epigenetic outlier profiles in affected co-twins from discordant pairs.

The thirteen probes displayed here are those with genome-wide statistically significant methylation variance increases in affected co-twins from the discordant pairs (see Fig 2). PairID: randomly assigned pair number.