Pihlstrøm Lasse, Rengmark Aina, Bjørnarå Kari Anne, Dizdar Nil, Fardell Camilla, Forsgren Lars, Holmberg Björn, Larsen Jan Petter, Linder Jan, Nissbrandt Hans, Tysnes Ole-Bjørn, Dietrichs Espen, Toft Mathias
1] Department of Neurology, Oslo University Hospital, Oslo, Norway [2] University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
J Hum Genet. 2015 Jul;60(7):357-62. doi: 10.1038/jhg.2015.34. Epub 2015 Apr 9.
The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.
位于1号染色体上跨越五个基因的PARK16基因座，是最早在帕金森病（PD）中显示全基因组关联的遗传区域之一。后续研究发现，PARK16的顶级关联信号和关联模式在不同人群中存在差异，目前尚不清楚其中涉及的基因和机制。在本研究中，我们旨在探讨PARK16基因变异对斯堪的纳维亚人群患PD风险的影响。我们对来自挪威和瑞典的2570名个体的病例对照样本集中的17个单核苷酸多态性进行了基因分型，以精细定位该基因座。对387例患者样本子集的DNA池进行了SLC45A3、NUCKS1、RAB7L1、SLC41A1和PM20D1全编码区的靶向重测序。我们发现rs1775143以及位于RAB7L1 5'区域附近的一个单倍型与PD存在关联，这些变异与最近一项针对高加索人的大型荟萃分析中最强信号的连锁不平衡程度不高。我们还为RAB7L1和LRRK2之间的上位性提供了提示性支持，这是其他人之前所假设的。将我们的结果与之前的研究进行比较，PARK16处的等位基因异质性似乎很可能存在，有必要进行进一步研究以理清复杂的关联模式并确定功能相关的变异。
