Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain.
Neurology Service, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain.
Mov Disord. 2019 Sep;34(9):1333-1344. doi: 10.1002/mds.27770. Epub 2019 Jun 24.
Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored.
The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO.
Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium.
In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort.
These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.
α-突触核蛋白（SNCA）基因中的单核苷酸多态性（SNPs）与特发性和富亮氨酸重复激酶 2（LRRK2）相关帕金森病（PD）的风险和发病年龄（AAO）差异相关。然而，几个调节 PD 风险或 AAO 的多态性 SNP 之间的潜在组合或协同作用在很大程度上仍未得到充分探索。
雷帕霉素（mTOR）信号通路的机械靶标在 PD 中功能受损。在这里，我们探讨了 mTOR 通路中的 SNP 是否可以单独或通过与已知易感性因素的上位性相互作用来调节 PD 风险和 AAO。
基于功能相关性，我们总共选择了 64 个 SNP，这些 SNP 映射到 mTOR 通路中的 57 个基因，对包含 898 名 PD 患者和 921 名对照的发现系列队列进行了基因分型。作为复制系列，我们筛选了国际帕金森病基因组学联合会（International Parkinson's Disease Genomics Consortium）提供的 4170 名 PD 患者和 3014 名对照。
在发现系列队列中，我们发现了一个涉及 STK11 rs8111699、FCHSD1 rs456998、GSK3B rs1732170 和 SNCA rs356219 的 4 个位点相互作用，该相互作用与 PD 风险增加相关（比值比=2.59，P<.001）。此外，我们还发现了 RPTOR rs11868112 和 RPS6KA2 rs6456121 与 SNCA rs356219 的 3 个上位性组合，这与 AAO 的差异相关（比值比=2.89；P<.0001）。后者在国际帕金森病基因组学联合会队列中得到了进一步验证（比值比=1.56；P=.046-0.047）。
这些发现表明，mTOR 通路中的遗传变异以非线性上位性方式影响 SNCA 的作用，从而调节 PD 中 AAO 的差异，揭示了该级联在疾病发病机制中的贡献。© 2019 年国际帕金森病和运动障碍协会。
