Identification of Novel Genetic Loci Affecting Age at Onset of Parkinson's Disease: A Genome‐wide Association Study

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Abstract Background The age at onset (AAO) of Parkinson's disease (PD) varies widely among individuals and significantly influences disease progression and prognosis. However, few genome‐wide association studies (GWASs) have investigated genetic variants determining AAO, particularly in East Asian populations. Objectives To identify single‐nucleotide polymorphisms (SNPs) affecting AAO of PD in Korean patients. Methods We conducted a GWAS on AAO of PD in 1048 Korean patients using sex‐adjusted linear regression models. Additionally, we conducted downstream analyses of our primary GWAS results. Results rs2134545 demonstrated genome‐wide significance (β = −2.459; standard error [SE] = 0.851; P = 1.898 × 10−8) and is an intergenic SNP near the ALCAM gene associated with an average AAO reduction of 3.47 years. Additionally, rs4366309 (LYST; MIR1537) demonstrated suggestive significance (β = 2.949; SE = 1.072; P = 8.68 × 10−8) and was associated with an average delay of 3.05 years. The polygenic risk score based on known PD risk loci also affected the AAO for European and Korean PD risk loci, respectively (β = −0.149; P < 0.001 and β = −0.096; P = 0.002). However, the proportion of variance was small (r2 = 0.022 and 0.009, respectively). Conclusion We identified a novel SNP associated with the AAO of PD near the ALCAM gene, distinct from previously reported PD risk loci. These findings need further functional validation; however, they suggest unique genetic pathways influencing the AAO of PD and highlight the need for further research in diverse populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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