Common X-Chromosome Variants Are Associated with Parkinson Disease Risk.
Common X-Chromosome Variants Are Associated with Parkinson Disease Risk.
复制标题
DOI：
10.1002/ana.26051
复制
发表时间：
2021-07
影响因子：
11.2
通讯作者：
Greicius MD
中科院分区：
文献类型：
--
作者：
Le Guen Y;Napolioni V;Belloy ME;Yu E;Krohn L;Ruskey JA;Gan-Or Z;Kennedy G;Eger SJ;Greicius MD
本研究的目的是确定与帕金森病（PD）风险相关的x染色体遗传变异。我们通过性别分层分析的meta分析结果进行了一项PD风险的全x染色体关联研究（XWAS）。为了避免虚假的关联，我们设计了x染色体的特定协调管道，并专注于欧洲血统样本。我们纳入了11,142例，280,164例对照，5379例代理病例，基于父母的PD病史。此外，我们测试了显著变异与(1)PD风险的关联，在一个独立的复制中，有1,561例和2,465例对照，(2)来自UK Biobank的33,360个人的壳核体积。在发现荟萃分析中，我们发现rs7066890（优势比[OR] = 1.10, 95%置信区间[CI] = 1.06-1.14, p = 2.2 × 10−9）、GPM6B内含子和rs28602900（优势比[OR] = 1.10, 95% CI = 1.07-1.14, p = 1.6 × 10−8）位于RPL10、ATP6A1、FAM50A和PLXNA3等高基因密度区域。在基因型-组织表达项目中，rs28602900与PD的关联被复制（OR = 1.16, 95% CI = 1.03-1.30, p = 0.016），并显示与一个调控RPL10表达的显著表达定量位点（eQTL）共定位在壳核和其他脑组织中。此外，rs28602900位点被发现与脑壳核体积减少有关。在性别分层分析中，没有结果达到全基因组意义。我们报道了PD的第一个XWAS，并鉴定了2个全基因组显著位点。rs28602900的关联在一个独立的PD数据集中得到了复制，并显示出其与壳核体积的关联一致。重要的是，rs26802900是RPL10的重要eQTL。这些结果支持核糖体蛋白在帕金森病发病机制中的作用，并表明x染色体有助于帕金森病的遗传风险。
The objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk. 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 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with (1) PD risk in an independent replication with 1,561 cases and 2,465 controls and (2) putamen volume in 33,360 individuals from the UK Biobank. In the discovery meta-analysis, we identified rs7066890 (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.06–1.14, p = 2.2 × 10−9), intron of GPM6B, and rs28602900 (OR = 1.10, 95% CI = 1.07–1.14, p = 1.6 × 10−8) in a high gene density region including RPL10, ATP6A1, FAM50A, and PLXNA3. The rs28602900 association with PD was replicated (OR = 1.16, 95% CI = 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 the Genotype-Tissue Expression Project. 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. We report the first XWAS of PD and identify 2 genome-wide significant loci. The rs28602900 association was 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.
登录
查看更多内容
DOI：
10.1212/nxg.0000000000000009
发表时间：
2015-06
期刊：
Neurology. Genetics
影响因子：
--
作者：
Lesage S;Bras J;Cormier-Dequaire F;Condroyer C;Nicolas A;Darwent L;Guerreiro R;Majounie E;Federoff M;Heutink P;Wood NW;Gasser T;Hardy J;Tison F;Singleton A;Brice A;French Parkinson's Disease Genetics Study Group (PDG) and the International Parkinson's Disease Genomics Consortium (IPDGC)
通讯作者：
French Parkinson's Disease Genetics Study Group (PDG) and the International Parkinson's Disease Genomics Consortium (IPDGC)
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
64.5
作者：
Martin I;Kim JW;Lee BD;Kang HC;Xu JC;Jia H;Stankowski J;Kim MS;Zhong J;Kumar M;Andrabi SA;Xiong Y;Dickson DW;Wszolek ZK;Pandey A;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
15.1
作者：
Mata IF;Jang Y;Kim CH;Hanna DS;Dorschner MO;Samii A;Agarwal P;Roberts JW;Klepitskaya O;Shprecher DR;Chung KA;Factor SA;Espay AJ;Revilla FJ;Higgins DS;Litvan I;Leverenz JB;Yearout D;Inca-Martinez M;Martinez E;Thompson TR;Cholerton BA;Hu SC;Edwards KL;Kim KS;Zabetian CP
通讯作者：
Zabetian CP