Summary

The authors looked at genotypes and methylation levels in 8000 samples from five Dutch biobanks. The authors identified methylation QTLs for 34% of all CpGs that they tested (n = 139k). The max number of meQTLs for a single CpG was 16. The authors generated RNAseq data for 2,101 of 3,841 individuals. eQTMs are CpGs whose methylation correlated with expression of genes in cis. 69% of eQTMs showed negative correlation with transcription, 30% showed positive correlations. Trans meQTL CpGs showed enrichment around TSS and were depleted in heterochromatin. Interchromosomal contacts might produce associations between SNPs and CpGs in trans. The authors infer the mechanism of the eQTMS as an increase in gene expression of transcription factors in cis results in the decrease in the methylation of the CpG sites targeted by this transcription factor.

Discussion

The authors find that one third of disease associated SNPs that they looked at in thisstudy had effects on methylation in trans in multiple regions of the genome. This is alarge fraction of the associated SNPs. Some of the discussion in the journal club revolvedaround inferring the direction of effect of these trans-eQTLs. The authors observe thata specific allele of the QTL is associated with increased(decreased) gene expression of some transcription factors in cis and a decrease(increase) in methylation of multiple targets of that transcription factor in trans. The authors interpret the increased expression of the transcription factor as causal for the decreased methylation of the CpG’s. This inference of indirect causality was a topic of discussion. Looking at a couple of articles after the journal club, it appears that this mechanism has been studied in the literature before.