To provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated GBA variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically matched controls.

The p.E326K, p.T369M, p.N370S, and p.L444P variants were screened using an allele-specific multiplexed PCR approach. All statistical procedures were performed using R or Plink v1.07.

Among the 4 analyzed variants, the p.L444P confirmed to be the most strongly associated with disease risk for PD, PD dementia (PDD), and dementia with Lewy bodies (DLB) (odds ratio [OR] for PD 15.63, 95% confidence interval [CI] = 8.04–30.37, p = 4.97*10^–16; OR for PDD 29.57, 95% CI = 14.07–62.13, p = 3.86*10^–19; OR for DLB 102.7, 95% CI = 31.38–336.1, p = 1.91*10^–14). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.80, 95% CI = 2.87–8.02, p = 2.12*10^–9; OR for DLB 12.24, 95% CI = 4.95–30.24, p = 5.71*10^–8), which, on the basis of the impact on glucocerebrosidase activity, would be expected to be mild. The 1.5–2:1 male sex bias described in sporadic PD was lost in p.T369M carriers. We also showed that PD penetrance for p.L444P could reach the 15% at age 75 years.

We report a large monocentric study on GBA-PD assessing mutation-specific data on the sex distribution, penetrance, incidence, and association with dementia of the 4 most frequent deleterious variants in GBA.

为了提供 4 种最常见的帕金森病 (PD) 相关GBA变体的发病率、外显率、性别分布和与痴呆的关联的变体特异性估计，我们分析了 4,923 名意大利无关的原发性退行性帕金森病患者（包括3,832 PD）在一个单一的三级护理中心和 7,757 名种族匹配的对照。

使用等位基因特异性多重 PCR 方法筛选 p.E326K、p.T369M、p.N370S 和 p.L444P 变体。所有统计程序均使用 R 或 Plink v1.07 进行。

在 4 个分析的变体中，p.L444P 被证实与 PD、PD 痴呆 (PDD) 和路易体痴呆 (DLB) 的疾病风险最密切相关（PD 的优势比 [OR] 为 15.63，95% 置信度区间 [CI] = 8.04–30.37，p = 4.97*10 ^–16；或 PDD 29.57，95% CI = 14.07–62.13，p = 3.86*10 ^–19；或 DLB 102.7，95% CI = 31.38–336.1 , p = 1.91*10 ^–14 )。然而，p.E326K 导致痴呆的风险出乎意料地高（PDD 4.80，95% CI = 2.87-8.02，p = 2.12* ^10-9；DLB 12.24，95% CI = 4.95-30.24，p = 5.71*10 ^–8)，根据对葡糖脑苷脂酶活性的影响，预计其是温和的。散发性 PD 中描述的 1.5–2:1 男性性别偏见在 p.T369M 携带者中消失了。我们还表明 p.L444P 的 PD 外显率在 75 岁时可以达到 15%。

我们报告了一项关于GBA -PD的大型单中心研究，该研究评估了GBA中 4 种最常见有害变异的性别分布、外显率、发病率以及与痴呆症相关的突变特异性数据。