The Future is The Past: Methylation QTLs in Schizophrenia - PubMed (original) (raw)

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The Future is The Past: Methylation QTLs in Schizophrenia

Anke Hoffmann et al. Genes (Basel). 2016.

Abstract

Genome-wide association studies (GWAS) have remarkably advanced insight into the genetic basis of schizophrenia (SCZ). Still, most of the functional variance in disease risk remains unexplained. Hence, there is a growing need to map genetic variability-to-genes-to-functions for understanding the pathophysiology of SCZ and the development of better treatments. Genetic variation can regulate various cellular functions including DNA methylation, an epigenetic mark with important roles in transcription and the mediation of environmental influences. Methylation quantitative trait loci (meQTLs) are derived by mapping levels of DNA methylation in genetically different, genotyped individuals and define loci at which DNA methylation is influenced by genetic variation. Recent evidence points to an abundance of meQTLs in brain tissues whose functional contributions to development and mental diseases are still poorly understood. Interestingly, fetal meQTLs reside in regulatory domains affecting methylome reconfiguration during early brain development and are enriched in loci identified by GWAS for SCZ. Moreover, fetal meQTLs are preserved in the adult brain and could trace early epigenomic deregulation during vulnerable periods. Overall, these findings highlight the role of fetal meQTLs in the genetic risk for and in the possible neurodevelopmental origin of SCZ.

Keywords: DNA memory; fetal brain; genome-wide association studies; induced pluripotent stem cells; methylation quantitative trait loci; non-coding variants; schizophrenia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Role of methylation quantitative trait loci (meQTLs) for gene expression. Genetic variation influences levels of DNA methylation at regulatory regions and can modulate gene expression leading to decreased or increased gene transcription. Importantly, the effects of genetically induced changes in DNA methylation critically depend on developmental stage, and possibly, environmental context. SNP: single nucleotide polymorphism.

Figure 2

Figure 2

Model for local meQTLs: (A) A local _cis_-acting variant (A-allele symbolized by a red star) resides in a regulatory element, for example a transcription factor (TF) binding site. Sequence variation (G-allele symbolized by a blue star) can result in reduced binding of the TF, diminished transcription of gene A, and encroachment of DNA methylation (left). As depicted by the chart, _cis_-meQTLs show differences in the amount of CpG-methylation (Me) between the two copies of an allele. Homozygous carriers of the transcriptionally active A-allele show less DNA methylation when compared to homozygous carriers of the transcriptionally less active G-allele or heterozygous carriers (right); (B) _Trans_-meQTLs result from differences in the expression, structure, or function of a diffusible factor that is equally available to both alleles at target sites. Accordingly, target sites (genes K and S) do not show differences in allele-specific methylation rates. _Trans_-meQTLs can involve variation in the sequence of TF binding sites (red star) driving expression of the diffusible factor or variation in the coding sequence of the diffusible factor leading to altered structure or function (left). Functionally, _trans_-meQTLs can affect transcription levels of multiple genes. Such trans associations can be shown on a circle plot (chromosomes (chr) labeled 1–22 with arrows pointing to location of a gene on a given chromosome) (right).

Figure 3

Figure 3

Findings on CpG methylation and on meQTLs in fetal and adult brains from control and SCZ individuals. Results from Jaffe el al. [52] (left) and from Hannon et al. [51] (right) are schematically summarized. In adult brain 62 of 104 Psychiatric Genomics Consortium (PGC) loci harbor a meQTL independent of case control status and fetal meQTLs are four-fold enriched in PGC risk loci. CTCF: CCCTC-binding factor; DBS: DNA binding site.

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