GPNMB confers risk for Parkinson's disease through interaction with α-synuclein.
GPNMB confers risk for Parkinson's disease through interaction with α-synuclein.
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DOI：
10.1126/science.abk0637
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发表时间：
2022-08-19
期刊：
影响因子：
56.9
通讯作者：
Chen-Plotkin, Alice S.
中科院分区：
文献类型：
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作者：
Diaz-Ortiz, Maria E.;Seo, Yunji;Posavi, Marijan;Cordon, Marc Carceles;Clark, Elisia;Jain, Nimansha;Charan, Rakshita;Gallagher, Michael D.;Unger, Travis L.;Amari, Noor;Skrinak, R. Tyler;Davila-Rivera, Roseanne;Brody, Eliza M.;Han, Noah;Zack, Rebecca;Van Deerlin, Vivianna M.;Tropea, Thomas F.;Luk, Kelvin C.;Lee, Edward B.;Weintraub, Daniel;Chen-Plotkin, Alice S.
全基因组关联研究 (GWAS) 已经确定了帕金森病 (PD) 的许多风险位点，但目标基因和机制仍然很大程度上未知。我们通过表达数量性状基因座 (eQTL) 和 PD 风险信号的共定位分析，将源自 GWAS 的 7 号染色体基因座（前哨 SNP rs199347）与 GPNMB 连接起来，并通过人脑等位基因特异性表达研究证实。在细胞中，糖蛋白非转移性黑色素瘤蛋白 B 蛋白 (GPNMB) 与 α-突触核蛋白 (aSyn) 共免疫沉淀并共定位。在诱导多能干细胞衍生的神经元中，GPNMB 的缺失导致内化 aSyn 原纤维和发展 aSyn 病理学的能力丧失。在 731 个 PD 和 59 个对照生物样本中，PD 血浆中的 GPNMB 升高，与疾病严重程度相关。因此，GPNMB 代表了一种 PD 风险基因，具有生物标志物开发和治疗靶向的潜力。计算、细胞生物学和人体组织研究将 GPNMB 确定为 PD 的风险基因和治疗靶点。
Many risk loci for Parkinson’s disease (PD) have been identified by genome-wide association studies (GWAS), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel SNP rs199347) to GPNMB, through colocalization analyses of expression quantitative trait locus (eQTL) and PD risk signals, confirmed by allele-specific expression studies in human brain. In cells, Glycoprotein Nonmetastatic Melanoma Protein B protein (GPNMB) co-immunoprecipitated and co-localized with alpha-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene, with potential for biomarker development and therapeutic targeting. Computational, cell biological, and human tissue-based studies establish GPNMB as a risk gene and therapeutic target for PD.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
DOI：
10.1007/978-1-4939-3572-7_13
发表时间：
2016-01-01
期刊：
DATA MINING TECHNIQUES FOR THE LIFE SCIENCES
影响因子：
--
作者：
Dobin, Alexander;Gingeras, Thomas R.
通讯作者：
Gingeras, Thomas R.
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：
3.5
作者：
Chen-Plotkin, Alice S.;Geser, Felix;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
影响因子：
30.8
作者：
Chang D;Nalls MA;Hallgrímsdóttir IB;Hunkapiller J;van der Brug M;Cai F;International Parkinson's Disease Genomics Consortium;23andMe Research Team;Kerchner GA;Ayalon G;Bingol B;Sheng M;Hinds D;Behrens TW;Singleton AB;Bhangale TR;Graham RR
通讯作者：
Graham RR