The Genomic Research Laboratory for Neurodegeneration, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Laboratory for Early Markers of Neurodegeneration, Center for the study of Movement, Cognition and Mobility, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Israel.
Mol Genet Metab. 2019 Dec;128(4):470-475. doi: 10.1016/j.ymgme.2019.10.001. Epub 2019 Oct 13.
GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD.
1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes.
All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86-12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively).
Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.
GBA 变种是全球最常见的帕金森病（PD）遗传风险因素，在高达 20%的阿什肯纳兹 PD 患者中可以发现。E326K 变体，不被认为是导致戈谢病的突变，最近被证明会增加 PD 的风险。由于 E326K 是欧洲人常见的变体，芬兰人和阿什肯纳兹人（分别为 2.4%、8.6%和 1.2%的携带者率），我们旨在细化其在 PD 中的作用。
1200 名连续招募的完全阿什肯纳兹血统的 PD 患者被 10 种 GBA 变体、LRRK2-G2019S 和 SMPD1-L302P 进行基因分型。将等位基因频率与由 378 名老年健康个体和非神经 gnomAD 阿什肯纳兹数据库组成的对照组进行比较。还计算了所有基因型的优势比（OR）和发病年龄（AAO）。
所有测试的等位基因变异均具有显著的等位基因 OR，显示出广泛的范围（1.86-12.84）。E326K 的最低等位基因 OR 观察到（p=0.013）。与对照组的 2 例（0.53%）相比，1200 例中有 45 例（3.75%）至少有两种突变（12 种测试）（p=0.0013）。在携带 E326K 的患者中，37%（10/27）携带额外的突变，仅携带 E326K 变体的个体的基因型 OR 为 1.07。即使在模拟 E326K 在 100,000 名阿什肯纳兹对照中的预期携带者频率时，这也没有达到统计学意义（p=0.39）。此外，与仅携带这些基因之一的突变（模拟 OR 11.79 与 7.58 和 2.49 相比）相比，携带 LRRK2-G2019S 和轻度 GBA 突变（N370S 或 R496H）的突变携带者的风险表现出累加效应。还提出了携带 LRRK2/轻度 GBA 双重突变的携带者在 AAO 更早（比非携带者早 5.0 年，分别为 3.1 年和 2.2 年）方面的累加效应。
与以前的研究相比，我们在这里证明了携带两种突变的 PD 患者的频率更高。当 GBA-E326K 与另一种突变同时存在时，更有可能影响 PD 风险，并且对携带 LRRK2/轻度 GBA 双突变的携带者提出了风险和发病年龄更早的累加效应。总的来说，这些数据支持 PD 遗传学的多基因方法。
