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Abstract：
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).
To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.
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.
Genotypes of common variants, association with disease status, and polygenic risk scores.
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 (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 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 × 10-12).
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.
To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.
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.
Genotypes of common variants, association with disease status, and polygenic risk scores.
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 (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 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 × 10-12).
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.
摘要：
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，在全球最大的人口中进行的研究有限(即，亚洲人）。
确定亚洲个体中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。
从亚洲人群的PD病例和对照产生的全基因组关联数据（即，新加坡/马来西亚,香港,台湾,中国大陆,和韩国）从2016年1月1日至2018年12月31日收集，作为正在进行的研究的一部分。结果与逆方差荟萃分析相结合，并在欧洲和日本样品中进行了顶级基因座的复制。使用了通过35994名招募的质量控制的31575名个体的发现样本，参与率超过90%。分析了1926361个欧洲血统和3509个日本样本的复制队列。使用英国帕金森病学会脑库标准诊断帕金森病。
常见变异的基因型，与疾病状态有关，和多基因风险评分。
在鉴定的31575个样本中，6724例PD(平均[SD]年龄，64.3[10]岁；发病年龄，58.8[10.6]岁；男性3472[53.2%]）和24851名对照（年龄，59.4[11.4]年；11030[45.0%]男性）在发现研究中进行了分析。鉴定出11个全基因组重要基因座；这些基因座中有2个是新颖的（SV2C和WBSCR17），而先前在欧洲人中发现了9个。欧洲血统和日本样本的复制显示出SV2C的强关联(rs246814；优势比，1.16；95％CI，1.11-1.21；在发现和复制样本的荟萃分析中，P=1.17×10-10），但在WBSCR17显示出潜在的遗传异质性（rs9638616；I2=67.1％；亲缘性P=3.40×10-3）。与仅基于78个欧洲基因座的模型相比，包括这11个基因座的变异的多基因风险评分模型与曲线下面积的显着改善相关（63.1％vs60.2％；P=6.81×10-12）。
这项研究确定了2个明显新颖的基因位点，并发现了9个先前鉴定的欧洲位点与PD相关，在全球亚洲人群中进行的全基因组关联研究，并报告了亚洲和欧洲个体在PD风险方面的遗传风险因素的相似性和差异性。这些发现可能导致基于多基因风险评分的亚洲患者和对照组的分层改善。我们的发现对亚洲的风险分层和精准医学具有潜在的学术和临床重要性。
确定亚洲个体中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。
从亚洲人群的PD病例和对照产生的全基因组关联数据（即，新加坡/马来西亚,香港,台湾,中国大陆,和韩国）从2016年1月1日至2018年12月31日收集，作为正在进行的研究的一部分。结果与逆方差荟萃分析相结合，并在欧洲和日本样品中进行了顶级基因座的复制。使用了通过35994名招募的质量控制的31575名个体的发现样本，参与率超过90%。分析了1926361个欧洲血统和3509个日本样本的复制队列。使用英国帕金森病学会脑库标准诊断帕金森病。
常见变异的基因型，与疾病状态有关，和多基因风险评分。
在鉴定的31575个样本中，6724例PD(平均[SD]年龄，64.3[10]岁；发病年龄，58.8[10.6]岁；男性3472[53.2%]）和24851名对照（年龄，59.4[11.4]年；11030[45.0%]男性）在发现研究中进行了分析。鉴定出11个全基因组重要基因座；这些基因座中有2个是新颖的（SV2C和WBSCR17），而先前在欧洲人中发现了9个。欧洲血统和日本样本的复制显示出SV2C的强关联(rs246814；优势比，1.16；95％CI，1.11-1.21；在发现和复制样本的荟萃分析中，P=1.17×10-10），但在WBSCR17显示出潜在的遗传异质性（rs9638616；I2=67.1％；亲缘性P=3.40×10-3）。与仅基于78个欧洲基因座的模型相比，包括这11个基因座的变异的多基因风险评分模型与曲线下面积的显着改善相关（63.1％vs60.2％；P=6.81×10-12）。
这项研究确定了2个明显新颖的基因位点，并发现了9个先前鉴定的欧洲位点与PD相关，在全球亚洲人群中进行的全基因组关联研究，并报告了亚洲和欧洲个体在PD风险方面的遗传风险因素的相似性和差异性。这些发现可能导致基于多基因风险评分的亚洲患者和对照组的分层改善。我们的发现对亚洲的风险分层和精准医学具有潜在的学术和临床重要性。
