Objective: This study aimed to determine single-nucleotide polymorphisms (SNPs) associated with AAO in Korean PD patients.

Background: Age at onset (AAO) of Parkinson’s disease (PD) is heterogenous among individuals and predict the various phenotypes, progression, and prognosis of PD. While most studies were mainly genome-wide association studies (GWAS) on risk loci susceptible to PD occurrence, genetic factors associated with AAO of PD have been studied less frequently, especially in East Asian population. Investigation of the predictive genetic factors for AAO is important for the evaluation of a disease-modifying treatment.

Method: A total of 1,048 PD patients who were ethnically Korean were finally recruited in the GWAS on AAO of PD. Genotyping was performed using a customized microarray chip optimized for Korean population, followed by imputation with reference panel 1000 genome phase 3 and principal component analyses. A linear regression model was used with adjustment for sex.

Results: We found two locus reaching genome-wide significant level, rs2134545 and rs2062782 (β = −2.459, SE = 0.851, and P = 1.898 × 10−8, respectively), intergenic SNPs around ALCAM gene. The leading SNP rs2134545 resulted in an average reduction of 3.47 years in AAO (P < 0.001). Another locus rs4366309 reached a suggestive significant level (β = 2.949, SE = 1.072, and P = 8.68 × 10−8) as a leading SNP which has linkage disequilibrium with other suggestive-significant SNPs. This variant in intron of LYST gene and downstream of MIR1537 gene resulted in an average delay of 3.05 years in AAO (P < 0.001).

Conclusion: We propose possible association of loci in ALCAM and LYST genes with AAO of PD, suggesting the possible role of genetics on midbrain dopaminergic neuronal growth in the determining the onset age of PD. These risk genes and loci were distinct from previously known risk loci susceptible to PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-association-study-revealing-novel-risk-loci-associated-with-age-at-onset-of-parkinsons-disease/