This repository contains the scripts (R Markdown files) that were used for the analyses accompanying the manuscript "Identification of SENP7 and UTF1/VENTX as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study".
In this manuscript, we performed a systematic genome-wide analysis to identify loci affecting cPCDH methylation to shed light on the mechanisms involved. The key points of our analysis are:
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We use a dataset of 3777 blood samples to evaluate the association of >7 million genetic variants with DNA methylation at 607 cPCDH CpGs and validated findings in prefrontal cortex samples obtained from 523 brain donors.
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We show that cPCDH methylation patterns were highly concordant between blood and prefrontal cortex.
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We report the role of the SMCHD1 locus in cPCDH methylation and highlight its broad impact on methylation of all three PCDH subclusters in both blood and prefrontal cortex.
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We identified two novel loci (SENP7 and UTF1/VENTX) to have widespread, subcluster-specific effects on cPCDH methylation in blood which we validated in prefrontal cortex.
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SENP7 can indirectly affect DNA methylation through the deSUMOylation of the chromatin repressor KAP1/TRIM28 while it is currently unclear how UTF1 and VENTX genes could influence epigenetic regulation.
Our findings add new understanding into the generation of neuronal cell surface barcodes and can guide studies into the role of cPCDH in human health and disease. More generally, it provides an exciting showcase of a discovery analysis in a peripheral tissue (blood) that can be translated to new insights in epigenetic regulation in the functionally important tissue (brain).