Whole-genome sequencing of 197 cases with Parkinson’s Disease reveals novel pathogenic variants in the Indian population

Research overview

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Background Most genetic studies of Parkinson’s disease (PD) have been performed in European cohorts, and large-scale studies in Indian populations are lacking. Consequently, many variants common in Europeans are rare or absent in Indian patients, emphasizing the need for population-specific genomic studies. Objectives To identify novel genetic variants contributing to PD in Indian populations, and quantify the polygenic burden of the disease in cases versus controls. Methods We performed WGS of 197 cases (106 early-onset PD (EOPD) and 91 late-onset PD (LOPD)) and 32 controls from India. We prioritized pathogenic variants in 67 PD-associated genes using ACMG guidelines. We quantified polygenic risk scores (PRS) for PD in our cohort using summary statistics from European GWAS, and tested PRS differences between cases and controls. Results We identified likely pathogenic variants in 31 cases across eight PD-associated genes ( GBA1, PRKN, PINK1, PARK7, SYNJ1, SNCA, and PLA2G6 ), giving a diagnostic yield of 27.63% in EOPD and 2.19% in LOPD. Of 29 identified variants, seven were novel. GBA1 was the most frequently mutated gene, followed by PRKN . Genes with pathogenic variants were enriched in lysosomal pathways. Cases had significantly higher PRS than controls, confirming a polygenic contribution to PD risk. Conclusions This study represents one of the first WGS-based genetic investigations of PD in India with both EOPD and LOPD cases. Novel variants in PRKN, GBA1, LRRK2, ATXN2 and SNCA point to the presence of population-specific variants, and reinforce the importance of genetic studies in diverse populations.

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