Correspondence
The Ubiquilin 1 Gene and Alzheimer's Disease
N Engl J Med 2005; 352:2752-2753June 30, 2005
- Article
To the Editor:
Bertram et al. (March 3 issue)1 report that in two family-based cohorts, a genetic variant of the UBQ-8i single-nucleotide polymorphism on chromosome 9q22 putatively increased the risk of Alzheimer's disease in an additive disease model. We attempted replication in a similarly ascertained but independent family-based data set based on 288 families in which linkage to microsatellites at 9q22.1 and 9q34.2 was demonstrated in a genome scan.2 In addition, we analyzed a previously described independent data set based on patients with Alzheimer's disease and 1005 controls.3
We found no association between the risk of Alzheimer's disease and UBQ-8i, or any of six additional single-nucleotide polymorphisms within the UBQLN1 gene, in either of the independent data sets. However, using age at onset as the trait of interest, we found a significant association between the putative UBQ-8i risk allele and an older age at onset in a recessive-disease model only in our case–control data set (Table 1Table 1
UBQ-8i Allelic Associations.). We found an additional, significant effect related to age at onset only in our family-based data set with a different single-nucleotide polymorphism in UBQLN1. Thus, although we found no evidence of risk with any single-nucleotide polymorphism in UBQLN1, our results suggest that age at onset may be germane and that additional, detailed examination of UBQLN1, including a search for the functional variant (or variants), is warranted.5 ReferencesMichael A. Slifer, M.D.
Eden R. Martin, Ph.D.
Duke University Medical Center, Durham, NC 27710
slife001@mc.duke. edu Jonathan L. Haines, Ph.D.
Vanderbilt University Medical Center, Nashville, TN 37232Margaret A. Pericak-Vance, Ph.D.
Duke University Medical Center, Durham, NC 277101
Bertram L ,Hiltunen M ,Parkinson BS , et al. Family-based association between Alzheimer's disease and variants in UBQLN1. N Engl J Med 2005;352:884-894
Full Text | Web of Science | Medline2
Pericak-Vance MA ,Grubber J ,Bailey LR , et al. Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol 2000;35:1343-1352
CrossRef | Web of Science | Medline3
van der Walt JM ,Dementieva YA ,Martin ER , et al. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 2004;365:28-32
CrossRef | Web of Science | Medline4
Martin ER ,Bass MP ,Gilbert JR ,Pericak-Vance MA ,Hauser ER . Genotype-based association test for general pedigrees: the genotype-PDT. Genet Epidemiol 2003;25:203-213
CrossRef | Web of Science | Medline5
Abecasis GR ,Cardon LR ,Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000;66:279-292
CrossRef | Web of Science | Medline
Author/Editor Response
We are pleased by Slifer and colleagues' report of a significant genetic association between single-nucleotide polymorphisms in the UBQLN1 gene and the age at onset of Alzheimer's disease in two separate and independent samples, providing further support for our original finding that UBQLN1 variants may influence the pathogenesis of Alzheimer's disease.1 Given the significant age-at-onset effects in their samples, it is puzzling that they did not observe significant effects on the risk of disease, since these two traits are correlated. Possible explanations include allelic heterogeneity, lack of power in the risk analyses, and methodologic differences in sample ascertainment and statistical procedures.
It is also worth noting that the two original linkage signals (according to a binary phenotype definition) reported for the family-based sample analyzed by Slifer et al.2 were located more than 40 cM away (in either direction) from UBQLN1 and our linkage peak.3 Thus, their sample may not be optimal for detecting risk effects of the magnitude described in our initial report.3 Notwithstanding these differences, the fact that several UBQLN1 single-nucleotide polymorphisms now show an association with either the age at onset or the risk of Alzheimer's disease in a number of independent samples suggests the possibility of linkage disequilibrium with one or more additional pathogenic variants.
Along these lines, since our original report,1 we have now found additional evidence of an association between the risk of Alzheimer's disease and the T allele of a UBQLN1 promoter single-nucleotide polymorphism (rs12345514) in both the National Institutes of Mental Health family sample (P=0.02 by the Family-Based Association Test) and the Consortium on Alzheimer's Genetics family sample (P=0.04). The combined data sets yielded the strongest evidence of an association (P=0.002), which is consistent with our previous findings. Collectively, these data suggest that the pathogenesis of Alzheimer's disease may be influenced by changes not only in the splicing of UBQLN1,1 but also in its expression. Ultimately, meta-analysis of these and additional association studies4 should provide a more precise measure of the actual contribution of UBQLN1 variants to Alzheimer's disease.
4 ReferencesLars Bertram, M.D.
Rudolph E. Tanzi, Ph.D.
Massachusetts General Hospital, Charlestown, MA 02129-4404
tanzi@helix.mgh. harvard. edu 1
Bertram L ,Hiltunen M ,Parkinson BS , et al. Family-based association between Alzheimer's disease and variants in UBQLN1. N Engl J Med 2005;352:884-894
Full Text | Web of Science | Medline2
Pericak-Vance MA ,Grubber J ,Bailey LR , et al. Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol 2000;35:1343-1352
CrossRef | Web of Science | Medline3
Blacker D ,Bertram L ,Saunders AJ , et al. Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum Mol Genet 2003;12:23-32
CrossRef | Web of Science | Medline4
Alzheimer Research Forum. The AlzGene database. (Accessed June 9, 2005, at http://www.alzgene.org.)
- Citing Articles (8)
Citing Articles
1
Tauser Roxana-Georgiana, Antohe Dan-Stefan. 2011. Overview of CNS Neuropharmaceuticals. .
CrossRef2
Michael A. Slifer, Eden R. Martin, John R. Gilbert, Jonathan L. Haines, Margaret A. Pericak-Vance. (2009) Resolving the relationship between ApolipoproteinE and depression. Neuroscience Letters 455:2, 116-119
CrossRef3
A ARIASVASQUEZ, L DELAU, L PARDO, F LIU, B FENG, A BERTOLIAVELLA, A ISAACS, Y AULCHENKO, A HOFMAN, B OOSTRA. (2007) Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function. Neuroscience Letters 424:1, 1-5
CrossRef4
Dimitrios Avramopoulos. 2007. Alzheimer's Disease: A Complex Paradigm. , 1-34.
CrossRef5
Rodney T. Perry, Howard Wiener, Lindy E. Harrell, Deborah Blacker, Rudolph E. Tanzi, Lars Bertram, Susan S. Bassett, Rodney C.P. Go. (2007) Follow-up mapping supports the evidence for linkage in the candidate region at 9q22 in the NIMH Alzheimer's disease Genetics Initiative cohort. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 144B:2, 220-227
CrossRef6
Faiza Bensemain, Julien Chapuis, Jinzhou Tian, Jing Shi, Uma Thaker, Corinne Lendon, Takeshi Iwatsubo, Philippe Amouyel, David Mann, Jean-Charles Lambert. (2006) Association study of the Ubiquilin gene with Alzheimer's disease. Neurobiology of Disease 22:3, 691-693
CrossRef7
M.A. Slifer, E.R. Martin, P.G. Bronson, C. Browning-Large, P.M. Doraiswamy, K.A. Welsh-Bohmer, J.R. Gilbert, J.L. Haines, M.A. Pericak-Vance. (2006) Lack of association between UBQLN1 and Alzheimer disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 141B:3, 208-213
CrossRef8
M I Kamboh, R L Minster, E Feingold, S T DeKosky. (2006) Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Molecular Psychiatry 11:3, 273-279
CrossRef
