Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.
Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.
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全基因组生存研究确定了帕金森病认知进展的新突触位点和多基因评分
DOI：
10.1038/s41588-021-00847-6
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发表时间：
2021-06
期刊：
影响因子：
30.8
通讯作者：
Scherzer CR
中科院分区：
文献类型：
--
作者：
Liu G;Peng J;Liao Z;Locascio JJ;Corvol JC;Zhu F;Dong X;Maple-Grødem J;Campbell MC;Elbaz A;Lesage S;Brice A;Mangone G;Growdon JH;Hung AY;Schwarzschild MA;Hayes MT;Wills AM;Herrington TM;Ravina B;Shoulson I;Taba P;Kõks S;Beach TG;Cormier-Dequaire F;Alves G;Tysnes OB;Perlmutter JS;Heutink P;Amr SS;van Hilten JJ;Kasten M;Mollenhauer B;Trenkwalder C;Klein C;Barker RA;Williams-Gray CH;Marinus J;International Genetics of Parkinson Disease Progression (IGPP) Consortium;Scherzer CR
帕金森病（PD）患者健康和临床试验的一个关键驱动因素是疾病随时间推移的过程（进展和预后）。为了评估遗传变异如何影响PD随着时间的推移进展为痴呆（PDD），这是生活质量的主要决定因素，我们在3，821名PD患者中进行了一项全基因组生存研究（GWSS），其中包括1120万个变异，超过31，053次纵向访视。我们发现并复制RIMS 2作为一个进展位点，（P = 2.78 × 10−11;风险比（HR）= 4.77），确定TMEM的提示性证据108（HR = 2.86，P = 2.09 × 10−8）和WWOX（HR = 2.12，P = 2.37 × 10−8），并证实了GBA（HR = 1.93，P = 0.0002）和APOE（HR = 1.48，P = 0.001）的相关性。多基因进展评分显示出与痴呆风险的实质性总体相关性，而多基因易感性评分不具有预测性。这项研究确定了一种新的突触位点和多基因评分的认知疾病进展的PD，并提出了不同的遗传结构的进展和易感性。
A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia (PDD), a major determinant for quality of life, we performed a genome-wide survival study (GWSS) of 11.2 million variants in 3,821 PD patients over 31,053 longitudinal visits. We discover and replicate RIMS2 as a progression locus (P = 2.78 × 10−11; hazard ratio (HR) = 4.77), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8), and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
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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：
48
作者：
Irwin, David;Grossman, Murray;Weintraub, Daniel;Hurtig, Howard I.;Duda, John E.;Xie, Sharon X.;Lee, Edward B.;Van Deerlin, Vivianna M.;Lopez, Oscar L.;Kofler, Julia K.;Nelson, Peter T.;Jicha, Gregory A.;Woltjer, Randy;Quinn, Joseph F.;Kaye, Jeffery;Leverenz, James B.;Tsuang, Debby;Longfellow, Katelan;Yearout, Dora;Kukull, Walter;Keene, C. Dirk;Montine, Thomas J.;Zabetian, Cyrus P.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
3.7
作者：
Bien SA;Wojcik GL;Zubair N;Gignoux CR;Martin AR;Kocarnik JM;Martin LW;Buyske S;Haessler J;Walker RW;Cheng I;Graff M;Xia L;Franceschini N;Matise T;James R;Hindorff L;Le Marchand L;North KE;Haiman CA;Peters U;Loos RJ;Kooperberg CL;Bustamante CD;Kenny EE;Carlson CS;PAGE Study
通讯作者：
PAGE Study