Bertram Lars, Hiltunen Mikko, Parkinson Michele, Ingelsson Martin, Lange Christoph, Ramasamy Karunya, Mullin Kristina, Menon Rashmi, Sampson Andrew J, Hsiao Monica Y, Elliott Kathryn J, Velicelebi Gonül, Moscarillo Thomas, Hyman Bradley T, Wagner Steven L, Becker K David, Blacker Deborah, Tanzi Rudolph E
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown 02129, USA.
N Engl J Med. 2005 Mar 3;352(9):884-94. doi: 10.1056/NEJMoa042765.
Recent 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.
We 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.
In 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.
Our 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.
近期分析表明，已知的阿尔茨海默病基因在该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q22区域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。
我们评估了来自美国国立精神卫生研究所（NIMH）样本（1439名受试者）的437个患阿尔茨海默病的多重家庭中9号染色体q连锁区域内三个基因的19个单核苷酸多态性。然后，我们在另一组独立鉴定的217个患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）中测试了显示阳性结果的单核苷酸多态性，并评估了一个相关单核苷酸多态性对25例阿尔茨海默病患者和17名对照者脑组织的功能影响。
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。两个样本中的风险单倍型由位于外显子8下游的一个内含子单核苷酸多态性定义。风险等位基因与从阿尔茨海默病患者脑样本中提取的RNA中一种选择性剪接的UBQLN1（缺少外显子8）转录本的剂量依赖性增加相关。
我们的研究结果表明，9号染色体q22上UBQLN1的基因变异可能通过影响该基因在大脑中的选择性剪接，大幅增加患阿尔茨海默病的风险。
