Family-based association between Alzheimer's disease and variants in UBQLN1
Family-based association between Alzheimer's disease and variants in UBQLN1
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DOI：
10.1056/nejmoa042765
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发表时间：
2005-03-03
影响因子：
158.5
通讯作者：
Tanzi, RE
中科院分区：
文献类型：
--
作者：
Bertram, L;Hiltunen, M;Tanzi, RE
背景
近期分析表明，已知的阿尔茨海默病基因在这种疾病的遗传变异中所占比例不到一半。编码泛素连接酶1（UBQLN1）的基因是位于9号染色体9q22一个已确定的连锁峰附近的几个阿尔茨海默病候选基因之一。
方法
我们对来自美国国家心理健康研究所（NIMH）样本（1439名受试者）的437个阿尔茨海默病多重家庭中9号染色体连锁区域内的三个基因的19个单核苷酸多态性进行了评估。然后，我们在一组独立确定的217个阿尔茨海默病不一致的同胞对（阿尔茨海默病遗传学联盟[CAG]样本；489名受试者）中对显示阳性结果的单核苷酸多态性进行了测试，并评估了一个相关单核苷酸多态性在25名阿尔茨海默病患者和17名对照者的脑组织中的功能效应。
结果
在NIMH样本中，我们观察到阿尔茨海默病与UBQLN1中的各种单核苷酸多态性之间存在显著关联。我们在CAG样本中证实了这些关联。两个样本中的致险单倍型由位于外显子8下游的一个单一内含子单核苷酸多态性所确定。在从阿尔茨海默病患者脑样本中提取的RNA中，致险等位基因与一种可变剪接的UBQLN1（缺失外显子8）转录本的剂量依赖性增加相关。
结论
我们的研究结果表明，9号染色体9q22上UBQLN1的基因变异显著增加了阿尔茨海默病的风险，可能是通过影响该基因在大脑中的可变剪接。
BACKGROUNDRecent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22.METHODSWe evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls.RESULTSIn the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease.CONCLUSIONSOur findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.