与阿尔茨海默病恢复力相关的遗传变异和功能途径。

PubMed ID
发表日期 2020年Aug月

原始出处 脑:神经学杂志
Brain : a journal of neurology
作者 Dumitrescu  Logan  Mahoney  Emily R  Mukherjee  Shubhabrata  Lee  Michael L  Bush  William S  Engelman  Corinne D  Lu  Qiongshi  Fardo  David W  Trittschuh  Emily H  Mez  Jesse  Kaczorowski  Catherine  Hernandez Saucedo  Hector  Widaman  Keith F  Buckley  Rachel  Properzi  Michael  Mormino  Elizabeth  Yang  Hyun-Sik  Harrison  Tessa  Hedden  Trey  Nho  Kwangsik  Andrews  Shea J  Tommet  Doug  Hadad  Niran  Sanders  R Elizabeth  Ruderfer  Douglas M  Gifford  Katherine A  Moore  Annah M  Cambronero  Francis  Zhong  Xiaoyuan  Raghavan  Neha S  Vardarajan  Badri  Pericak-Vance  Margaret A  Farrer  Lindsay A  Wang  Li-San  Cruchaga  Carlos  Schellenberg  Gerard  Cox  Nancy J  Haines  Jonathan L  Dirk Keene  C  Saykin  Andrew J  Larson  Eric B  Sperling  Reisa A  Mayeux  Richard  Bennett  David A  Schneider  Julie A  Crane  Paul K  Jefferson  Angela L  Hohman  Timothy J 

文献标题 与阿尔茨海默病恢复力相关的遗传变异和功能途径。
Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

文献摘要

大约30%的老年人表现出阿尔茨海默病的神经病理学特征,没有认知障碍的迹象。然而,对于基因因素知之甚少,使得这些具有潜在韧性的个体在面对实质性的神经病理学时仍能保持清醒的认知能力。我们进行了一项大规模的全基因组关联研究(GWAS),对两个先前验证过的认知弹性指标进行了量化,使用潜在变量建模方法进行量化,并在给定的神经病理学水平上表现出比预期更好的认知表现。研究人员对5108名阿尔茨海默病临床试验和三项认知老化纵向队列研究的数据进行了统一。所有的分析都是在所有参与者身上进行的,并且重复地将样本限制在认知能力不好的个体身上,以便在疾病的早期阶段识别变异。正如预期的那样,所有的恢复力指标都与认知能力和受教育程度特征(P值<2.5×10-20)存在遗传相关性,而且我们观察到与神经精神状态的新相关性(P值<7.9×10-4)。值得注意的是,恢复力指标与临床阿尔茨海默病(P值>0.42)和载脂蛋白e(P值>0.13)均无遗传相关性。在单变异分析中,我们观察到ATP8B1上游18号染色体认知功能不受影响的受试者中存在一个全基因组显著的位点(单核苷酸多态性指数rs2571244,次要等位基因频率=0.08,P = 2.3 × 10-8)。该位点的顶端变异(rs2571244)与多个CpG位点的前额叶皮质组织甲基化显著相关,包括ATPB81上游的一个位点(cg19596477;P = 2 × 10-13)。总的来说,这一综合的弹性基因分析暗示了血管风险、新陈代谢和心理健康在保护患者免受神经病理学的认知后果方面的作用,同时也为胆汁酸代谢途径中的一个新的弹性基因提供了证据。此外,恢复力的基因结构似乎与临床阿尔茨海默病不同,这表明将注意力转移到恢复力的分子因素上可能会为治疗目标找到新的途径。


Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.


获取全文 10.1093/brain/awaa209