Identification of SENP7 and UTF1 / VENTX as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study

The epigenetic regulation of clustered protocadherin (c PCDH ) genes is tightly linked to their function as specific cell surface barcodes for neural self-nonself discrimination. Differential c PCDH DNA methylation in both blood and brain has been implicated in diverse human traits and diseases ranging from BMI, aging, cancer and brain disorders. However, the unique regulation of c PCDH methylation remains poorly understood. Therefore, we performed a genome-wide association study to evaluate the association of >7 million genetic variants with DNA methylation at 607 c PCDH CpGs measured in whole blood of 3777 individuals and validated findings in prefrontal cortex samples obtained from 523 brain donors. We observed concordant c PCDH methylation patterns in blood and prefrontal cortex, which switched between hypo-, intermediate and hypermethylation over short distances with the former overlapping with the promoter regions of each c PCDH member. Through methylation quantitative trait locus (meQTL) analysis in trans , we first confirmed the broad effect of the candidate gene SMCHD1 on c PCDH methylation in blood which validated in prefrontal cortex. Through a genome-wide analysis, we next identified the SENP7 and UTF1 / VENTX loci to have widespread, subcluster-specific effects on c PCDH methylation in blood which was validated in prefrontal cortex. While SENP7 can indirectly affect DNA methylation through the deSUMOylation of the chromatin repressor KAP1 , UTF1 and VENTX are two genes involved in embryonic development not previously implicated in epigenetic regulation. Our findings shed new light on the processes involved in c PCDH methylation that may underlie associations with disease.