Davis Albert A, Andruska Kristin M, Benitez Bruno A, Racette Brad A, Perlmutter Joel S, Cruchaga Carlos
Department of Neurology, Washington University, St. Louis, MO, USA.
Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA.
Neurobiol Aging. 2016 Jan;37:209.e1-209.e7. doi: 10.1016/j.neurobiolaging.2015.09.014. Epub 2015 Sep 30.
Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.
多种基因变异与帕金森病（PD）风险相关，但已知的突变并不能解释大部分的PD病例总数。同样，全基因组关联研究（GWAS）已将多个基因座与PD风险关联起来。遗传因素对表型多样性的影响仍不清楚。很少有研究确定GWAS基因座是否也与发病年龄（AAO）或运动进展相关。我们使用了2个PD病例对照数据集（华盛顿大学和帕金森病进展标志物倡议组织）来确定位于GWAS最显著位点（GBA、ACMSD/TMEM163、STK39、MCCC1/LAMP3、GAK/TMEM175、SNCA和MAPT）的多态性是否与AAO或运动进展相关。我们发现GBA和MAPT基因座的单核苷酸多态性与PD的AAO和进展之间存在关联。这些发现强化了PD复杂的遗传基础，并表明不同的基因和变异解释了PD风险、发病和进展的遗传结构。
