PDF(Pubmed)
Abstract：
The LRRK2 G2019S variant is the most common cause of monogenic Parkinson\'s disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.
摘要：
LRRK2G2019S变异体是单基因帕金森病(PD)的最常见原因;然而,关于外显率的问题仍然存在，临床表型和携带者的自然史。我们在大量1286名基因分型的LRRK2G2019S携带者和109154名对照者中进行了3.5年的前瞻性纵向在线研究，有和没有PD,从23andMe研究队列招募。我们每6个月收集自我报告的运动和非运动症状，以及人口统计，家族史和环境危险因素。在随访中发现了PD（表型转化者）的事件病例。我们使用加速故障时间模型确定了PD的终生风险，并探讨了多基因风险对外显率的影响。我们还计算了23andMe数据库中所有LRRK2G2019S携带者的遗传祖先，并确定了世界上携带者频率最高的地区。我们观察到，尽管疾病持续时间长1年(P=0.016)，患有PD的LRRK2G2019S携带者具有相似的运动症状负担，但包括认知障碍在内的非运动症状明显减少，REM睡眠行为障碍（RBD）和睡眠障碍（所有P值≤0.0002）。到80岁时，G2019S携带者中PD的累积发生率为49％。与非携带者相比，G2019S携带者患PD的风险是10倍。这在G2019S携带者中上升到27倍的风险，PD多基因风险评分在前25%，而非携带者在后25%。除了确定北非和阿什肯纳齐人血统的古代建国事件外，我们的遗传祖先分析推断G2019S变体后来被引入美洲的西班牙殖民地.我们的结果表明，LRRK2G2019SPD似乎是一种缓慢进展的主要运动亚型PD，其患病率较低，RBD和认知障碍。这表明当前的前驱标准，基于特发性PD，可能缺乏检测G2019S载波中LRRK2PD早期阶段的敏感性。我们表明，多基因负担可能有助于LRRK2G2019S携带者群体中PD的发展。总的来说，这些结果应有助于支持即将进行的LRRK2抑制剂早期疾病试验的筛查计划和候选富集策略.
