Chang Diana, Nalls Mike A, Hallgrímsdóttir Ingileif B, Hunkapiller Julie, van der Brug Marcel, Cai Fang, Kerchner Geoffrey A, Ayalon Gai, Bingol Baris, Sheng Morgan, Hinds David, Behrens Timothy W, Singleton Andrew B, Bhangale Tushar R, Graham Robert R
Genentech, Inc., South San Francisco, California, USA.
Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Nat Genet. 2017 Oct;49(10):1511-1516. doi: 10.1038/ng.3955. Epub 2017 Sep 11.
Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinson's disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 × 10) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 × 10) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis-expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.
迄今为止，常见变异全基因组关联研究（GWAS）已确定了超过24个帕金森病（PD）风险位点。为了发现更多位点，我们开展了一项GWAS，将6476例PD患者与302042例对照进行比较，随后与一项近期针对9830个重叠变异的、纳入了超过13000例PD患者和95000例对照的研究进行荟萃分析。然后，我们在一个包含5851例患者和5866例对照的复制队列中对35个位点（P < 1×10）进行了检验。在对26035例患者和403190例对照的联合分析中，我们鉴定出了17个新的风险位点（P < 5×10）。我们采用以神经为中心的策略为这些位点分配候选风险基因。我们在41个PD位点中的29个位点上鉴定出了与索引变异处于连锁不平衡状态的蛋白质改变或顺式表达数量性状位点（cis-eQTL）变异。这些结果表明自噬和溶酶体生物学在PD风险中起关键作用，并提示了PD潜在的新药物靶点。
