Data-Driven Genome-Wide Association Study of Pain Trajectories in Persons with Parkinson’s Disease (P7-11.012)

Abstract

<h3>Objective:</h3> To conduct the first genome-wide association study (GWAS) of pain in persons with Parkinson’s disease (PWP). <h3>Background:</h3> Pain is a common and complex non-motor symptom experienced by ~60% of PWP. Little is known about the genetic and non-genetic determinants of pain in PWP. <h3>Design/Methods:</h3> Using data spanning ~4.5 years from 8,612 PWP who are early in their disease course (&lt;3 years), and available through the Fox Insight Data Exploration Network, we empirically discerned 5 subgroups of PWP with similar longitudinal patterns of pain using latent class growth analysis. 4,411 PWP were also genotyped across two customized Illumina platforms that had significant overlap. Quality control criteria (minor allele frequency &lt;1%, Hardy Weinberg Equilibrium p&lt;5×10⁻⁵) were imposed prior imputation using the TOPMed reference panel. After post-imputation quality control (same as above + imputation R²&gt;70%), there were 7.7×10⁶ genetic variants. We retained 4,159 PWP who self-identified as White and who genetically clustered with other European samples. For this analysis, we focused on a GWAS of the most severe pain subgroup (N=97) to the least impaired subgroup (N=934). Gene-based and pathway enrichment analyses were also conducted. <h3>Results:</h3> For the GWAS of extreme pain phenotypes, top genic SNP association were <i>MAPK8</i>-rs72794357 (OR=4.6; p=1×10⁻⁶) and <i>VLDLR-</i>rs4741753 (OR=2.2; p=1.5×10⁻⁶) and top gene-based results included <i>CTNNB1</i> (p=3.5×10⁻⁵) and <i>KLK7</i> (p=7.7×10⁻⁵). These results are intriguing since <i>MAPK8</i> is involved in opioid receptor pathways, <i>VLDLR</i> is a ApoE receptor involved in brain development through Reelin signaling, <i>CTNNB1</i> promotes neurogenesis and de novo mutations have been associated with polyneuropathy in lower limbs, and <i>KLK7</i> is an astrocyte-derived amyloid-β degrading enzyme. Overall there was an enrichment of genes associated with oxytocin signaling (p=0.14), opioid signaling (p=0.045), and Wnt signaling pathway (p=0.021). <h3>Conclusions:</h3> The findings are consistent with known neuropathic mechanisms, thus therapeutic targets for these mechanisms may be relevant for PWP. <b>Disclosure:</b> The institution of Miss Liu has received research support from NIH/NIGMS. The institution of Miss Liu has received research support from Diana Jacobs Kalman/AFAR Scholarships for Research in the Biology of Aging The Program. The institution of Miss Liu has received research support from Michael J. Fox Foundation. Doug Gunzler has nothing to disclose. Dr. Gunzler has received research support from NIH/NINDS. The institution of Dr. Gunzler has received research support from Biogen. The institution of Dr. Gunzler has received research support from Amneal. Dr. Gunzler has received research support from Michael J Fox Foundation. Dr. Crawford has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Genetics. The institution of Dr. Crawford has received research support from NIH/NIDDK. The institution of Dr. Crawford has received research support from NIH/NCATS. The institution of Dr. Crawford has received research support from VA. The institution of Dr. Crawford has received research support from NIH/NIGMS. The institution of Dr. Crawford has received research support from NHGRI. The institution of Dr. Crawford has received research support from NIH/NIA. Dr. Crawford has received personal compensation in the range of $500-$4,999 for serving as a Member with NIH Study Section. The institution of Prof. Briggs has received research support from NIH. The institution of Prof. Briggs has received research support from Michael J. Fox Foundation.