The 4p16.3 Parkinson Disease Risk Locus Is Associated with <i>GAK</i> Expression and Genes Involved with the Synaptic Vesicle Membrane

Abstract

<div><p>Genome-wide association studies (GWAS) have identified the <i>GAK</i>/<i>DGKQ</i>/<i>IDUA</i> region on 4p16.3 among the top three risk loci for Parkinson’s disease (PD), but the specific gene and risk mechanism are unclear. Here, we report transcripts containing the 3’ clathrin-binding domain of <i>GAK</i> identified by RNA deep-sequencing in post-mortem human brain tissue as having increased expression in PD. Furthermore, carriers of 4p16.3 PD GWAS risk SNPs show decreased expression of one of these transcripts, <i>GAK25</i> (Gencode Transcript 009), which correlates with the expression of genes functioning in the synaptic vesicle membrane. Together, these findings provide strong evidence for <i>GAK</i> clathrin-binding- and J-domain transcripts’ influence on PD pathogenicity, and for a role for <i>GAK</i> in regulating synaptic function in PD.</p></div