Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans A Genome-Wide Association Study
Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans A Genome-Wide Association Study
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DOI：
10.1001/jamaneurol.2020.0428
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发表时间：
2020-06-01
期刊：
影响因子：
29
通讯作者：
Tan, Eng-King
中科院分区：
文献类型：
--
作者：
Foo, Jia Nee;Chew, Elaine Guo Yan;Tan, Eng-King
在欧洲人群中进行的大规模全基因组关联研究已经确定了90种与帕金森病（PD）相关的风险变异;然而，在世界上最大的人群中进行的研究有限，为了鉴定亚洲个体中PD的新的全基因组显著基因座，并比较亚洲和欧洲队列之间的遗传风险。作为一项正在进行的研究的一部分，从2016年1月1日至2018年12月31日收集了亚洲人群（即新加坡/马来西亚、中国香港、中国台湾、中国大陆和韩国）PD病例和对照的全基因组关联数据。将结果与逆方差荟萃分析相结合，并在欧洲和日本样本中复制顶级基因座。使用了31575名通过质量控制的35994名招募人员的发现样本，参与率超过90%。分析了1926361例欧洲血统和3509例日本血统样本的重复队列。帕金森病的诊断采用英国帕金森病协会脑库标准。主要结果和指标常见变异的基因型、与疾病状态的相关性和多基因风险评分。在探索研究中，分析了24 851例（平均[SD]年龄，64. 3 [10]岁;发病年龄，58. 8 [10. 6]岁; 3472例[53. 2%]男性）和24 851例对照组（年龄，59. 4 [11. 4]岁; 11 030例[45. 0%]男性）。11个全基因组显着的位点被确定，其中2个位点是新的（SV 2C和WBSCR 17）和9个以前在欧洲人中发现。欧洲血统和日本样本中的复制显示与SV 2C具有稳健的相关性（发现和复制样本的荟萃分析中;比值比，1.16; 95% CI，1.11-1.21; P = 1.17 x 10（-10）），但在WBSCR 17时显示潜在的遗传异质性（; I-2=67.1%;异质性P = 3.40 x 10（-3））。包括这11个基因座变异的多基因风险评分模型与仅基于78个欧洲基因座的模型的曲线下面积显著改善相关（63.1%对60.2%; P = 6.81x10（-12））结论和相关性本研究鉴定了2个明显新的基因位点，并发现9个先前鉴定的欧洲基因位点与本研究中的PD相关。在全球亚洲人群中进行的一项大型、全元基因组关联研究，报告了亚洲和欧洲个体在PD风险方面遗传风险因素的相似性和差异。这些发现可能会导致改善分层的亚洲患者和控制的基础上多基因风险评分。我们的研究结果对亚洲的风险分层和精准医学具有潜在的学术和临床意义。
IMPORTANCE Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).OBJECTIVES To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.DESIGN SETTING, AND PARTICIPANTS Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria.MAIN OUTCOMES AND MEASURES Genotypes of common variants, association with disease status, and polygenic risk scores.RESULTS Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 x 10(-10)in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (; I-2=67.1%; P = 3.40 x 10(-3)for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 x 10(-12)).CONCLUSIONS AND RELEVANCE This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.