National Neuroscience Institute, Singapore.
Duke-NUS Medical School, Singapore.
J Parkinsons Dis. 2024;14(4):713-724. doi: 10.3233/JPD-230455.
A genome-wide association study (GWAS) variant associated with Parkinson's disease (PD) risk in Asians, rs9638616, was recently reported, and maps to WBSCR17/GALNT17, which is involved in synaptic transmission and neurite development.
To test the association of the rs9638616 T allele with imaging-derived measures of brain microstructure and function.
We analyzed 3-Tesla MRI and genotyping data from 116 early PD patients (aged 66.8±9.0 years; 39% female; disease duration 1.25±0.71 years) and 57 controls (aged 68.7±7.4 years; 54% female), of Chinese ethnicity. We performed voxelwise analyses for imaging-genetic association of rs9638616 T allele with white matter tract fractional anisotropy (FA), grey matter volume and resting-state network functional connectivity.
The rs9638616 T allele was associated with widespread lower white matter FA (t = -1.75, p = 0.042) and lower functional connectivity of the supplementary motor area (SMA) (t = -5.05, p = 0.001), in both PD and control groups. Interaction analysis comparing the association of rs9638616 and FA between PD and controls was non-significant. These imaging-derived phenotypes mediated the association of rs9638616 to digit span (indirect effect: β= -0.21 [-0.42,-0.05], p = 0.031) and motor severity (indirect effect: β= 0.15 [0.04,0.26], p = 0.045).
We have shown that a novel GWAS variant which is biologically linked to synaptic transmission is associated with white matter tract and functional connectivity dysfunction in the SMA, supported by changes in clinical motor scores. This provides pathophysiologic clues linking rs9638616 to PD risk and might contribute to future risk stratification models.
最近有一项全基因组关联研究（GWAS）发现了一个与亚洲人帕金森病（PD）风险相关的变异，rs9638616，该变异位于 WBSCR17/GALNT17 基因上，该基因与突触传递和神经突发育有关。
检测 rs9638616 T 等位基因与脑结构和功能的影像学指标之间的关联。
我们分析了 116 名早期 PD 患者（年龄 66.8±9.0 岁；39%为女性；病程 1.25±0.71 年）和 57 名对照组（年龄 68.7±7.4 岁；54%为女性）的 3T MRI 和基因分型数据，这些患者均为中国人。我们对 rs9638616 T 等位基因与白质束各向异性分数（FA）、灰质体积和静息状态网络功能连接的影像学遗传关联进行了体素分析。
rs9638616 T 等位基因与 PD 患者和对照组的广泛白质 FA 降低有关（t=-1.75，p=0.042），也与 SMA 的功能连接降低有关（t=-5.05，p=0.001）。比较 PD 患者和对照组中 rs9638616 与 FA 的关联的交互分析没有统计学意义。这些影像学衍生表型介导了 rs9638616 与数字跨度（间接效应：β=-0.21[-0.42，-0.05]，p=0.031）和运动严重程度（间接效应：β=0.15[0.04，0.26]，p=0.045）之间的关联。
我们发现，一个与突触传递有关的新型 GWAS 变异与 SMA 中的白质束和功能连接功能障碍有关，这一发现得到了运动评分变化的支持。这为 rs9638616 与 PD 风险的关联提供了病理生理学线索，并可能为未来的风险分层模型做出贡献。
