The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal
The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal
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DOI：
10.1016/j.neulet.2017.08.040
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发表时间：
2017-09-29
影响因子：
2.5
通讯作者：
Toft, Mathias
中科院分区：
文献类型：
--
作者：
Berge-Seidl, Victoria;Pihlstrom, Lasse;Toft, Mathias
目的：GBA 基因的编码变异已被确定为帕金森病 (PD) 中最重要的遗传风险因素。此外，全基因组关联研究 (GWAS) 已确定染色体 1q22 上 SYT11-GBA 区域与 PD 的关联，但与 GBA 编码变体的关系仍不清楚。本研究的目的是对临床队列中的完整 GBA 基因进行测序，并研究 GBA 基因内的编码变异是否可能驱动报告的关联信号。 方法：我们分析了 366 名 PD 患者的 GBA 所有编码外显子的高通量测序数据。已确定的低频编码变异在三个斯堪的纳维亚病例对照系列（786 名患者和 713 名对照）中进行了基因分型。先前报道的 1 号染色体 SYT11-GBA 基因座内两个独立关联信号的风险变异也在同一样本中进行了基因分型。我们进行了关联分析并评估了变体之间的连锁不平衡 (LD)。结果：我们在 GBA 中发现了 6 个罕见突变 (1.6%) 和两个低频编码变体。与对照组相比，E326K (rs2230288) 在 PD 患者中出现的频率明显更高（OR 1.65，p = 0.03）。 T369M (rs75548401) 与疾病没有明确的关联（OR 1.43，p = 0.24）。对同一样本集中的两个 GWAS 命中 rs35749011 和 rs114138760 进行基因分型，我们复制了 rs35749011 与疾病状态之间的关联（OR 1.67，p = 0.03），而发现 rs114138760 在患者和对照中具有相似的等位基因频率。分析显示，E326K 和 rs35749011 的 LD 非常高 (r(2) 0.95)。结论：我们的结果证实 GBA 变体 E326K 是 PD 的易感等位基因。结果表明，E326K 可能完全解释了先前 PD GWAS 中在染色体 1q22 观察到的主要关联信号。
Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals.Methods: We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants.Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p = 0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p = 0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p = 0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r(2) 0.95).Conclusions: Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.