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

<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

Genes Associated with <i>GAK25</i> Expression in PD brain are Significantly Enriched in GO Terms Related to Synaptic and Mitochondrial Structure.

<p>Genes Associated with <i>GAK25</i> Expression in PD brain are Significantly Enriched in GO Terms Related to Synaptic and Mitochondrial Structure.</p

<i>GAK</i> exons significantly associated to case status primarily encode for the clathrin-binding and J domains of <i>GAK</i> protein.

<p><i>GAK</i> exon 25 (<i>GAK25)</i>, which was found to be associated to both case status and the risk SNP, is highlighted in magenta (under Gene), while <i>GAK</i> exons associated with case status only are highlighted in blue. All Gencode transcripts are shown below the gene structure, with transcript functionality listed below each contig. <i>GAK25</i> represents the 5’UTR of Gencode transcript 009 (Boxed in red). The <i>GAK</i> protein domains (under Protein) are denoted by color: J domain (green), clathrin-binding domain (yellow), phosphatase/tensin domain (blue), and kinase domain (red). Transcript data from <a href="http://www.ensembl.org/" target="_blank">http://www.ensembl.org</a>.</p

<i>GAK</i> Gencode exons in the 3’ region are differentially expressed in PD.

<p>(A) The mean normalized expression for PD cases and controls is plotted for each of the 71 <i>GAK</i> exon feature bins (x-axis). Exon 1 corresponds to the 3’ end of the gene, while Exon 71 corresponds to the 5’ end. Brackets indicate groups of exons significantly increased in PD relative to control (* = <i>q</i>-value < 0.05). (B) The mean normalized expression of <i>GAK</i> exon 25 (<i>GAK25</i>) is plotted for each stratified group. The samples are stratified by case status (Control and PD) and by genotype in an additive fashion (CC = Major allele homozygote, CT = Heterozygote, TT = Risk allele homozygote). (C and D) -ΔΔCT (log2 fold change) of <i>GAK</i> normalized to <i>PPIA</i> is plotted for all control and PD samples for (<b>c</b>) <i>GAK</i> 3’ exons and (<b>d</b>) <i>GAK</i> 5’ exons.</p