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. 2024 Feb;39(2):339-349.
doi: 10.1002/mds.29676. Epub 2023 Nov 28.

The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India

Shan V Andrews  1 , Prashanth L Kukkle  2   3 , Ramesh Menon  4 , Thenral S Geetha  4 , Vinay Goyal  5   6   7 , Rukmini Mridula Kandadai  8   9 , Hrishikesh Kumar  10 , Rupam Borgohain  8   9 , Adreesh Mukherjee  11 , Pettarusp M Wadia  12 , Ravi Yadav  13 , Soaham Desai  14 , Niraj Kumar  15   16 , Deepika Joshi  17 , Sakthivel Murugan  4 , Atanu Biswas  11 , Pramod K Pal  13 , Merina Oliver  4 , Sandhya Nair  4 , Anbu Kayalvizhi  4 , Praveena L Samson  4 , Manjari Deshmukh  4 , Akshi Bassi  4 , Charugulla Sandeep  4 , Nitin Mandloi  4 , Oliver B Davis  1 , Melissa A Roberts  1 , Dara E Leto  1 , Anastasia G Henry  1 , Gilbert Di Paolo  1 , Uday Muthane  18 , Shymal K Das  11 , Andrew S Peterson  4 , Thomas Sandmann  1 , Ravi Gupta  4 , Vedam L Ramprasad  4 ; Parkinson Research Alliance of India (PRAI)
Affiliations

The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India

Shan V Andrews et al. Mov Disord. 2024 Feb.

Abstract

Background: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome-wide association study (GWAS) 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.

Objective: The aim was to identify genetic risk factors for PD in a South Asian population.

Methods: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and AoO.

Results: A genome-wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region 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. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease.

Conclusions: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; SNCA; South Asian; early onset.

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