BackgroundThe 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.ObjectivesTo identify single‐nucleotide polymorphisms (SNPs) affecting AAO of PD in Korean patients.MethodsWe 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.Resultsrs2134545 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).ConclusionWe 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.

中文翻译：

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鉴定影响帕金森病发病年龄的新遗传位点：一项全基因组关联研究


背景帕金森病 （PD） 的发病年龄 （AAO） 因人而异，并显着影响疾病进展和预后。然而，很少有全基因组关联研究 （GWAS） 调查决定 AAO 的遗传变异，尤其是在东亚人群中。目的确定影响韩国患者 PD AAO 的单核苷酸多态性 （SNP）。方法我们使用性别调整线性回归模型对 1048 例韩国患者 PD 的 AAO 进行了 GWAS。此外，我们还对主要 GWAS 结果进行了下游分析。结果rs2134545 显示出全基因组显著性 （β = −2.459;标准误差 [SE] = 0.851;P = 1.898 × 10-8），并且是 ALCAM 基因附近的基因间 SNP，与平均 AAO 降低 3.47 年相关。此外，rs4366309 （LYST;MIR1537） 表现出提示意义 （β = 2.949;SE = 1.072;P = 8.68 × 10−8），并且与 3.05 年的平均延迟相关。基于已知 PD 风险位点的多基因风险评分也分别影响了欧洲和韩国 PD 风险位点的 AAO （β = −0.149;P < 0.001 和 β = −0.096;P = 0.002）。然而，方差的比例很小（分别为 r2 = 0.022 和 0.009）。结论我们在 ALCAM 基因附近鉴定了一个与 PD AAO 相关的新 SNP，与既往报道的 PD 风险位点不同。这些发现需要进一步的功能验证;然而，他们提出了影响 PD AAO 的独特遗传途径，并强调了在不同人群中进一步研究的必要性。© 2024 作者。由 Wiley Periodicals LLC 代表国际帕金森和运动障碍协会出版的《运动障碍》。