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    • Our study like that of Zill et al

    2024-03-27

    Our study, like that of Zill et al. (2012) included European Caucasians, although their population was much smaller (n=162) and more heterogeneous (19–72years). Further, potential confounding or effect modification by other health, lifestyle or genetic factors was not considered. These differences may account for the divergent findings. Methylation levels change with age (the “epigenetic clock”), with reports of global hypomethylation (Johnson et al., 2012) and gene-specific hypermethylation with increasing age (Jung and Pfeifer, 2015), hence decreases in ACE methylation may be specifically associated with late-life depression. Furthermore, increased dysfunction of the HPA axis has been observed in older individuals (Otte et al., 2005), which may be differentially influenced by ACE. Zill et al. (2012) also focused on patients diagnosed with MDD, which represents only 4.3% (n=16) of our study population. The majority of our study participants had severe depressive symptoms (as assessed with the CES-D), which may differ to clinically diagnosed MDD in its causation and associated physiological processes (Fiske et al., 2009, Fournier et al., 2010). To our knowledge, this is the first study to show that ACE promoter methylation was significantly negatively correlated with basal cortisol levels. Although in only a small sub-sample of participants, it is interesting to note that the direction of these associations supports the main findings of our study: decreased methylation was observed in depressed individuals (with specific genotypes) and was associated with heightened basal cortisol levels. An over-activation of cortisol signalling is frequently reported as a feature of depression (Lloyd and Nemeroff, 2011). Cortisol secretion has also previously been shown to be modulated by ACE polymorphisms (Baghai et al., 2006, Ancelin et al., 2013, Baghai et al., 2002). Our findings are in line with previous research demonstrating potential functional consequences of methylation at this region, with promoter methylation inversely correlated with ACE expression and serum concentration in a dose-dependent manner (Riviere et al., 2011, Zill et al., 2012). Peripheral methylation levels have also been observed to be comparable to levels in post-mortem CH5138303 australia and hippocampal tissues, which are part of a network that is regulated by the HPA axis and dysregulated in depressive disorders (Zill et al., 2012). Therefore, peripheral ACE methylation could be correlated with HPA axis activity, as measured by cortisol secretion. This suggests that ACE methylation may be more suited as a biomarker for cortisol levels and/or HPA axis activity than for depression. However, no definitive conclusions can be drawn from this result, with further research needed, particularly considering the potential role of cortisol in depression (Herbert, 2013). Also unique to our study is the inclusion of six ACE polymorphisms shown to be independently associated with methylation levels at several CpGs within the ACE promoter. Such genetic variants that influence DNA methylation at specific sites are referred to as methylation quantitative trait loci or mQTLs. This fits with emerging literature highlighting the importance of the genome in regulating the epigenome (Gaunt et al., 2016). The effects of mQTLs tend to be more pronounced at CpG sites in close proximity (cis effect) with a distance of less than 1 Megabase (MB), although some act more distally (trans effect) (Zhang et al., 2010). The studied polymorphisms may be acting in cis on specific CpGs, as our promoter (rs1800764, rs4291) and intronic SNPs (rs4295, rs4311, rs4333, rs4343, rs4351) are within a distance of 13kb from the promoter. Further studies are now needed to investigate the functionality of this putative layer of regulation. An interesting finding from our study was that all seven polymorphisms investigated significantly modified the association between methylation and depression at several CpG units. This suggests that an effective biomarker would need to be a combination of ACE methylation and genetic variants. For example, lower methylation levels at CpG 28.29.30 were associated with depression for four variants, but only in individuals homozygous for the T allele of rs1800764, the A allele of rs4351, or the C allele of rs4295 or rs4311. On the other hand, ACE methylation levels at CpG 4.5.6.7, 14, and 17 were higher in depressed individuals, but only for those homozygous for T allele of rs4291, the C allele of rs4333, or the A allele of rs4343 genotypes. In modulating susceptibility to diseases, genetic variants may modify the probability of DNA methylation and in turn regulate gene expression (Rakyan et al., 2011) and/or combine to modify depression risk (Zhi et al., 2013). While these findings add to the growing body of research in this field, further investigation is needed to clarify these complex genotype and site-specific methylation interactions of studied polymorphisms and their functional consequences.