Sulkava Sonja, Haukka Jari, Kaivola Karri, Doagu Fatma, Lahtinen Alexandra, Kantojärvi Katri, Pärn Kalle, Palta Priit, Myllykangas Liisa, Sulkava Raimo, Laatikainen Tiina, Tienari Pentti J, Paunio Tiina
Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
Department of Psychiatry and SleepWell Research Program, Faculty of Medicine, Helsinki University Central Hospital, University of Helsinki , Helsinki, Finland.
Sci Rep. 2024 Jun 13;14(1):13668. doi: 10.1038/s41598-024-62600-3.
Previous genome-wide association and replication study for job-related exhaustion indicated a risk variant, rs13219957 in the UST gene. Epidemiological studies suggest connection of stress-related conditions and dementia risk. Therefore, we first studied association of rs13219957 and register-based incident dementia using survival models in the Finnish National FINRISK study surveys (N = 26,693). The AA genotype of rs13219957 was significantly associated with 40% increased risk of all-cause dementia. Then we analysed the UST locus association with brain pathology in the Vantaa 85+ cohort and found association with tau pathology (Braak stage) but not with amyloid pathology. Finally, in the functional analyses, rs13219957 showed a highly significant association with two DNA methylation sites of UST, and UST expression. Thus, the results suggest a common risk variant for a stress-related condition and dementia. Mechanisms to mediate the connection may include differential DNA methylation and transcriptional regulation of UST.
先前针对工作相关倦怠的全基因组关联和重复研究表明，UST基因中的一个风险变异rs13219957。流行病学研究表明，与压力相关的状况与痴呆风险之间存在关联。因此，我们首先在芬兰全国FINRISK研究调查（N = 26,693）中，使用生存模型研究了rs13219957与基于登记的新发痴呆之间的关联。rs13219957的AA基因型与全因痴呆风险增加40%显著相关。然后，我们在万塔85岁及以上队列中分析了UST基因座与脑病理学的关联，发现与tau病理学（Braak分期）有关，但与淀粉样蛋白病理学无关。最后，在功能分析中，rs13219957与UST的两个DNA甲基化位点以及UST表达显示出高度显著的关联。因此，结果表明存在一种与压力相关状况和痴呆相关的常见风险变异。介导这种联系的机制可能包括UST的DNA甲基化差异和转录调控。
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