Objective: Identify genetic variants on the X-chromosome associated with Parkinson's disease (PD) risk. Methods: We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,324 cases, 280,060 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with: (i) PD risk in an independent replication with 1,564 cases and 2,467 controls, and (ii) putamen volume in 33,360 individuals from the UK Biobank. Results: In the discovery meta-analysis, we identified: rs7066890 (OR=1.10 [1.06-1.14]; P=2.2×10^-9) intron of GPM6B, and rs28602900 (OR=1.10 [1.07-1.14]; P=1.6×10^-8) in a high gene density region including RPL10, ATP6A1, FAM50A, PLXNA3. The rs28602900 association with PD was replicated (OR=1.16 [1.03-1.30]; P=0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in GTEx. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses. Interpretation: We report the first XWAS of PD and identify two genome-wide significant loci. The rs28602900 association replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10.These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk.

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常见的X染色体变异与帕金森氏病风险相关

目的：确定与帕金森氏病（PD）风险相关的X染色体上的遗传变异。方法：我们通过对按性别分层分析的结果进行荟萃分析，进行了PD风险的X染色体全关联研究（XWAS）。为避免虚假关联，我们为X染色体设计了特定的协调管道，并着重于欧洲血统样本。根据PD的父母病史，我们纳入了11,324例，280,060例对照和5,379例代理病例。此外，我们测试了显着变异与以下因素的关联：（i）具有1,564例病例和2,467例对照的独立复制中的PD风险，以及（ii）UK Biobank中33,360例个体的壳聚糖量。结果：在发现荟萃分析中，我们鉴定出：rs7066890（OR = 1.10 [1.06-1.14]; P = 2.2×10 ^-9）内含子GPM6B和rs28602900（OR = 1.10 [1.07-1.14]; P = 1.6×10 ^-8）在包括RPL10，ATP6A1，FAM50A，PLXNA3在内的高基因密度区域中。rs28602900与PD的关联被复制（OR = 1.16 [1.03-1.30]； P = 0.016），并显示与GTEx中壳聚糖和其他脑组织中RPL10表达的重要表达定量基因座（eQTL）共定位。此外，发现rs28602900基因座与大脑壳核体积减少有关。在按性别分层的分析中，没有结果达到全基因组意义。解释：我们报告了P​​D的第一个XWAS，并鉴定了两个全基因组的重要基因座。rs28602900关联在独立的PD数据集中复制，并在与壳聚糖体积关联中显示出一致的效果。重要的是，rs26802900是一个显著eQTL RPL10这些结果支持核糖体蛋白在PD发病机理中的作用，并表明X染色体有助于PD遗传风险。