PDF(Pubmed)
Abstract：
Up to 80% of Parkinson\'s disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson\'s disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson\'s disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson\'s disease and dementia with Lewy bodies/Parkinson\'s disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson\'s, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson\'s Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.
摘要：
高达80%的帕金森病患者发展为痴呆,但是痴呆的时间与运动症状的发作有很大的不同。路易体痴呆的临床特征与帕金森病痴呆相似，但认知障碍先于或与运动发作同时发生。路易体痴呆和帕金森病痴呆是不同的病症还是代表疾病谱的一部分仍存在争议。疾病异质性的生物学机制，特别是痴呆症的发展，仍然知之甚少，但可能是了解疾病途径的关键，最终,治疗发展。先前关于帕金森病和痴呆与路易体/帕金森病痴呆的全基因组关联研究已经确定了将患者与对照组区分开的风险位点。我们整理了7804名欧洲血统的帕金森病患者的数据，牛津发现队列,和加速医学伙伴关系-帕金森病倡议。我们进行了一项离散表型全基因组关联研究，通过调查路易体病中痴呆的遗传驱动因素，比较有和没有痴呆的路易体病，以解码疾病异质性。我们发现风险等位基因rs429358标记APOEe4会增加患痴呆症的几率，MMRN1和SNCA-AS1基因附近的rs7668531和在12号染色体上标记LRRK2G2019S的内含子变体rs17442721对痴呆具有保护作用。这些结果应在未来的研究中在尸检证实的病例中得到验证。
