The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

Abstract

ImportanceRecent studies have advanced our understanding of the genetic drivers of Parkinson’s Disease (PD). Rare variants in more than 20 genes are generally accepted to be causal for PD, and the latest PD GWAS study identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.ObjectiveTo identify genetic risk factors for PD in a South Asian population and therefore increase understanding of PD genetics more broadly.DesignThis study included common variant (minor allele frequency, MAF > 5%) genome-wide association studies (GWAS) for PD diagnosis (case-control analysis) and age of onset of motor symptoms (case-only analysis). In addition, rare variant (MAF < 1%) analyses delimiting the presence of pathogenic or likely pathogenic variants in previously known PD genes (case-only) and evaluating differential burden of predicted deleterious variants at the gene level (case-control) were performed. Finally, rare and common variants were combined to examine the distribution of a PD polygenic risk score within groups defined by presence of a PD gene mutation.Setting10 specialty movement disorder centers across India.Participants674 PD subjects predominantly with age of onset ≤ 50 years (encompassing juvenile, young, or early-onset PD) were recruited from the contributing centers over a 2-year period. 1,376 control subjects were selected from the reference population GenomeAsia, Phase 2.Main Outcomes & MeasuresDiagnosis of PD, age of onset of motor symptoms.ResultsCommon variant GWAS of PD diagnosis yielded a genome-wide significant signal (lead SNP p-value = 4.11E-11) in theSNCAregion, strongly colocalized (posterior probability = 1) withSNCAregion signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. The top-ranked gene from gene burden studies of rare predicted loss-of-function and deleterious variants wasBSN, which encodes Bassoon, a presynaptic protein previously associated with neurodegenerative disease.Conclusions & RelevanceThis study constitutes the largest genetic investigation of PD and first demonstration ofSNCAassociation with PD in an Indian population to date. Ongoing work seeks to expand this cohort, enabling improved statistical power to detect PD genes in this understudied group.