Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Nat Genet. 2009 Dec;41(12):1308-12. doi: 10.1038/ng.487. Epub 2009 Nov 15.
We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
我们在 1713 名欧洲血统的帕金森病（PD）患者和 3978 名对照者中进行了全基因组关联研究（GWAS）。在对 3361 例病例和 4573 例对照进行复制后，我们观察到两个强烈的关联信号，一个位于编码α-突触核蛋白（SNCA）的基因中（rs2736990，OR=1.23，P=2.24×10(-16)），另一个位于 MAPT 基因座（rs393152，OR=0.77，P=1.95×10(-16)）。我们与正在进行日本 PD 病例 GWAS 的同事交换了数据。在日本 GWAS 中对 SNCA 的 PD 关联得到了复制，证实了这是人群中主要的风险基因座。我们复制了在日本队列中检测到的新基因座（PARK16，rs823128，OR=0.66，P=7.29×10(-8)）的效果，并提供了支持性证据，表明 LRRK2 周围的常见变异调节 PD 的风险（rs1491923，OR=1.14，P=1.55×10(-5)）。这些数据表明常见遗传变异在典型 PD 的发病机制中具有明确的作用，并表明该疾病在人群中存在特定的遗传异质性。
