Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.

中文翻译：

---

帕金森氏病基因座基因的靶向测序突出了SYT11，FGF20和其他关联

全基因组关联研究（GWAS）已经确定了许多与帕金森氏病相关的基因座。在这些基因座的绝大多数中驱动关联的特定基因和变体是未知的。我们旨在对所选基因进行全面分析，以确定这些基因座中稀有和常见遗传变异的潜在作用。我们对来自先前与帕金森氏病相关的25个基因座的32个基因进行了完整测序，分别来自3个队列的2657名患者和3647个对照。使用靶向目标基因的外显子，外显子-内含子边界和非翻译区（UTR）的分子倒置探针进行捕获，然后进行测序。执行质量控制仅包括高质量的变体。我们检查了稀有变异（次要等位基因频率<0。01）使用优化的序列内核关联测试（SKAT-O）。通用变体的相关性是根据每个队列中要求的年龄，性别和种族调整后的回归模型估算的，然后进行荟萃分析。经过Bonferroni校正后，我们确定了SYT11，FGF20和GCH1与帕金森氏病有关。在另外21个基因中鉴定出名义关联。先前的报告表明，SYT11 GWAS关联是由附近GBA基因的变异驱动的。但是，SYT11的关联主要由罕见的3'UTR变异体（rs945006601）驱动，并且独立于GBA变异体（排除所有GBA变异体载体后p = 5.23E-05 ）。FGF20的缔合是由位于启动子区域的罕见5'UTR变体（rs1034608171）驱动的。先前报道的GCH1关联帕金森氏病的病因是由罕见的非同义变体驱动的，其中一些已知会引起多巴胺反应性肌张力障碍。我们还分别在十个和八个对照中鉴定了两个LRRK2变体p.Arg793Met和p.Gln1353Lys，但在患者中没有。我们在MAPT，TMEM175，BST1，SNCA和GPNMB中鉴定了与帕金森氏病相关的常见变体，它们均在各自的基因座中与已知的GWAS命中点处于强连锁不平衡（LD）中。常见的编码PM20D1变体p.Ile149Val与降低帕金森氏病的风险相关（OR 0.73，95％CI 0.60-0.89，p= 1.161E-03）。该变体不在LDAS中，在该基因座内具有最高的GWAS命中率，可能代表了一种新颖的关联。这些结果进一步证明了精细绘制GWAS基因座的重要性，并建议应考虑将SYT11，FGF20以及潜在的PM20D1，BST1和GPNMB作为帕金森氏病相关基因进行未来研究。