Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis.
Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis.
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DOI：
10.1002/ana.26032
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发表时间：
2021-05
影响因子：
11.2
通讯作者：
Pihlstrom, Lasse
中科院分区：
文献类型：
--
作者：
Andersen, Maren Stolp;Bandres-Ciga, Sara;Reynolds, Regina H.;Hardy, John;Ryten, Mina;Krohn, Lynne;Gan-Or, Ziv;Holtman, Inge R.;Pihlstrom, Lasse
了解免疫系统的不同部分如何促进帕金森病的发病机制是一个具有重要治疗意义的紧迫挑战。我们研究了帕金森病常见变异遗传度的富集，按免疫和脑细胞类型分层。我们使用了帕金森病全基因组关联研究的最新荟萃分析的汇总统计数据，并使用连锁不平衡评分回归对遗传性进行了分区，根据开放染色质区域定义的特定细胞类型进行分层。我们还使用多基因风险评分方法验证了富集结果，并使用表观遗传数据和表达定量基因座验证了疾病相关变体，以提名和探索推定的小胶质细胞基因座。我们发现在小胶质细胞和单核细胞的开放染色质区域中帕金森病风险遗传性显著富集。基因组注释在这2种细胞类型之间基本上重叠，并且仅小胶质细胞的富集信号在联合模型中保持显著。我们目前的证据表明，P2RY12，一个关键的小胶质细胞基因和抗血栓药物氯吡格雷的目标，作为一个显着的帕金森病相关信号的可能驱动程序的染色体3。我们的研究结果进一步支持免疫机制在帕金森病发病机制中的重要性，强调小胶质细胞失调是一个致病因素，并提名一个可靶向的小胶质细胞基因候选者作为致病因素。免疫过程可以通过治疗来调节，对帕金森病的未来治疗具有潜在的重要临床意义。
Understanding how different parts of the immune system contribute to pathogenesis in Parkinson’s disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson’s disease stratified by immune and brain cell types. We used summary statistics from the most recent meta-analysis of genomewide association studies in Parkinson’s disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types, as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus. We found significant enrichment of Parkinson’s disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these 2 cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the antithrombotic agent clopidogrel, as the likely driver of a significant Parkinson’s disease association signal on chromosome 3. Our results provide further support for the importance of immune mechanisms in Parkinson’s disease pathogenesis, highlight microglial dysregulation as a contributing etiological factor, and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson’s disease.
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影响因子：
25
作者：
Galatro, Thais F.;Holtman, Inge R.;Eggen, Bart J. L.
通讯作者：
Eggen, Bart J. L.
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
2.5
作者：
Berge-Seidl, Victoria;Pihlstrom, Lasse;Toft, Mathias
通讯作者：
Toft, Mathias