Investigation of the genetic aetiology of Lewy body diseases with and without dementia.
Investigation of the genetic aetiology of Lewy body diseases with and without dementia.
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伴有和不伴有痴呆的路易体疾病的遗传病因学调查。
DOI：
10.1101/2023.10.17.23297157
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Wu L
中科院分区：
文献类型：
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作者：
Wu L
高达 80% 的帕金森病患者会出现痴呆，但从运动症状出现到痴呆的时间差异很大。路易体痴呆的临床特征与帕金森病痴呆相似，但认知障碍先于运动发作或与运动发作同时发生。路易体痴呆和帕金森病痴呆是否是不同的病症或代表疾病谱的一部分仍然存在争议。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以及最终开发治疗方法的关键。先前对帕金森病和路易体痴呆/帕金森病痴呆的全基因组关联研究已经确定了区分患者与对照的风险位点。我们从追踪帕金森病、牛津发现队列和加速医学合作伙伴-帕金森病倡议中整理了 7804 名欧洲血统患者的数据。我们进行了一项离散表型全基因组关联研究，比较有和没有痴呆的路易体疾病，通过调查路易体疾病中痴呆的遗传驱动因素来解码疾病异质性。我们发现，标记APOEe4的风险等位基因rs429358会增加患痴呆症的几率，MMRN1和SNCA-AS1基因附近的rs7668531以及12号染色体上标记LRRK2G2019S的内含子变体rs17442721可以预防痴呆症。这些结果应该在未来的研究中在尸检确诊的病例中得到验证。
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 taggingAPOEe4increases the odds of developing dementia, and that rs7668531 near theMMRN1andSNCA-AS1genes and an intronic variant rs17442721 taggingLRRK2G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.