Association of genetic variation at the GJA5/ACP6 locus with motor progression in Parkinson's

Abstract

ImportanceThere is a pressing need to understand the biology of Parkinsons disease (PD) progression and to identify biological pathways as possible therapeutic targets. ObjectiveTo identify genomic variation associated with PD motor presentation and early stage progression. DesignGWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments. SettingMulticentre Participants3572 unrelated European ancestry individuals diagnosed with PD from 6 studies. Main Outcomes and MeasuresLinear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model. ResultsWe identified an association between the PD axial rate of progression and variation at the GJA5 locus at 1q12 (Beta = -0.25, SE = 0.04, P = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: < 10-8 in eQTLGen and 10-7 in PsychEncode). In addition, we found a nominal association between axial motor presentation and the MAD1L1 gene at 7q21.11 (Beta = 0.54, SE = 0.11, P = 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNA LINC00511 at 17q21.31 (Beta = -0.62, SE = 0.11, P = 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation of MAD1L1 expression. Variants at LINC00511 may cause a disruption of a distal epigenetic regulation of SOX9 through an anchored chromatin loop. Conclusions and RelevanceOur large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.