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

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

  • 期刊论文

  • 发表日期：

    2025年10月2日

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  • Yunfeng Liu,
  • Maja Vukic,
  • Eilis Hannon,
  • Hailiang Mei,
  • Emma Walker,
  • Lucy Sinke,
  • Jonathan Mill,
  • Lucia Daxinger,
  • Bastiaan T. Heijmans

摘要

The epigenetic regulation of clustered protocadherin (cPCDH) genes is tightly linked to their function as specific cell surface barcodes for neural self-nonself discrimination. Differential cPCDH DNA methylation has been implicated in diverse neurological diseases as well as body weight, cancer and aging. However, the unique regulation of cPCDH 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 cPCDH CpGs measured in whole blood of 3777 individuals and validated findings in prefrontal cortex samples obtained from 523 brain donors. We observed concordant cPCDH 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 cPCDH member. Through methylation quantitative trait locus (meQTL) analysis in trans, we first confirmed the broad effect of the candidate gene SMCHD1 on cPCDH methylation in blood and then validated this effect in prefrontal cortex. Through a genome-wide analysis, we next identified the SENP7 and UTF1/VENTX loci to have widespread, subcluster-specific effects on cPCDH methylation in blood and brain. 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 cPCDH methylation that may underlie associations with neurological disease.