Abstract
Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson’s correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP–CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.
Highlights
Genome-wide association studies have shown that the level of DNA methylation, probably the best-studied epigenetic mark, is partly associated with nearby single-nucleotide polymorphisms (SNPs).[1,2,3] An increasing number of SNPs have been associated with the pathogenesis of psychiatric disorders.[4]
The differences in methylation levels at cg01089319 are 3% between carriers and non-carriers of rs2058725 and rs2241165, respectively. These findings were not confirmed in the validation set, which has a more homogeneous composition (Supplementary Table 1B). To our knowledge, this is the first study that investigates the association between SNPs known to be related to different psychiatric diseases and the genome-wide methylation pattern
By further investigating the association of SNP-related CpG sites with gene expression and phenotypic psychiatric disease measures, this paper elucidates novel mechanistic insights on how the detected CpG sites in focus may influence the expression of genes
Summary
Genome-wide association studies have shown that the level of DNA methylation, probably the best-studied epigenetic mark, is partly associated with nearby single-nucleotide polymorphisms (SNPs).[1,2,3] An increasing number of SNPs have been associated with the pathogenesis of psychiatric disorders.[4]. Brain maturation occurs during adolescence through processes such as synaptic pruning.[9] Normal brain development and function are highly dependent on DNA methylation as stable chemical modification of cytosines in CpG dinucleotides. The importance of these reactions was demonstrated for several cognitive processes, such as learning and memory[10] and neuronal activity.[11] This includes a previous study that showed a relationship between differential DNA methylation and genes involved in γ-aminobutyric acid (GABA)-ergic pathways.[11] In 2013, Domschke et al.[12] revealed that, compared with healthy controls, GAD1 methylation levels were lower in adults with panic disorder
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