Genome-wide Analysis of Motor Progression in Parkinson Disease

Abstract

<jats:sec><jats:title>Background and Objectives</jats:title><jats:p>The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the<jats:italic>GJA5</jats:italic>locus at 1q12 (β = −0.25, SE = 0.04,<jats:italic>p</jats:italic>= 3.4e<jats:sup>−10</jats:sup>). Exploration of the regulation of gene expression in the region (<jats:italic>cis</jats:italic>-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of<jats:italic>ACP6</jats:italic>, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL<jats:italic>p</jats:italic>-values in blood and brain RNA expression data sets: &lt;10<jats:sup>−14</jats:sup>in eQTLGen and 10<jats:sup>−7</jats:sup>in PsychEncode).</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.</jats:p></jats:sec>