Family-Based Association between Alzheimer's Disease and Variants in UBQLN1
Lars Bertram, M.D., Mikko Hiltunen, Ph.D., Michele Parkinson, B.S., Martin Ingelsson, M.D., Christoph Lange, Ph.D., Karunya Ramasamy, B.S., Kristina Mullin, B.S., Rashmi Menon, B.S., Andrew J. Sampson, B.A., Monica Y. Hsiao, B.S., Kathryn J. Elliott, M.S., Gonül Velicelebi, Ph.D., Thomas Moscarillo, B.A., Bradley T. Hyman, M.D., Steven L. Wagner, Ph.D., K. David Becker, Ph.D., Deborah Blacker, M.D., Sc.D., and Rudolph E. Tanzi, Ph.D.
Background Recent analyses suggest that the known Alzheimer'sdisease genes account for less than half the genetic variancein this disease. The gene encoding ubiquilin 1 (UBQLN1) is oneof several candidate genes for Alzheimer's disease located neara well-established linkage peak on chromosome 9q22.
Methods We evaluated 19 single-nucleotide polymorphisms in threegenes within the chromosome 9q linkage region in 437 multiplexfamilies with Alzheimer's disease from the National Instituteof Mental Health (NIMH) sample (1439 subjects). We then testedthe single-nucleotide polymorphisms showing a positive resultin an independently identified set of 217 sibships discordantfor Alzheimer's disease (Consortium on Alzheimer's Genetics[CAG] sample; 489 subjects) and assessed the functional effectof an implicated single-nucleotide polymorphism in brain tissuefrom 25 patients with Alzheimer's disease and 17 controls.
Results In the NIMH sample, we observed a significant associationbetween Alzheimer's disease and various single-nucleotide polymorphismsin UBQLN1. We confirmed these associations in the CAG sample.The risk-conferring haplotype in both samples was defined bya single intronic single-nucleotide polymorphism located downstreamof exon 8. The risk allele was associated with a dose-dependentincrease in an alternatively spliced UBQLN1 (lacking exon 8)transcript in RNA extracted from brain samples of patients withAlzheimer's disease.
Conclusions Our findings suggest that genetic variants in UBQLN1on chromosome 9q22 substantially increase the risk of Alzheimer'sdisease, possibly by influencing alternative splicing of thisgene in the brain.
Source Information
From the Genetics and Aging Research Unit (L.B., M.H., M.P., K.M., R.M., A.J.S., M.Y.H., R.E.T.) and the Alzheimer Disease Research Unit (M.I., K.R.. B.T.H.), MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, and the Gerontology Research Unit, Department of Psychiatry (T.M., D.B.), Massachusetts General Hospital, Charlestown; the Departments of Biostatistics (C.L.) and Epidemiology (D.B.), Harvard School of Public Health, Boston; and Neurogenetics, La Jolla, Calif. (K.J.E., G.V., S.L.W., K.D.B.). Drs. Bertram and Hiltunen contributed equally to the article.
Address reprint requests to Dr. Tanzi at the Genetics and Aging Research Unit, MIND, MGH-East, 114 16th St., Charlestown, MA 02129, or at tanzi{at}helix.mgh.harvard.edu.
Kim, M., Suh, J., Romano, D., Truong, M. H., Mullin, K., Hooli, B., Norton, D., Tesco, G., Elliott, K., Wagner, S. L., Moir, R. D., Becker, K. D., Tanzi, R. E.
(2009). Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum Mol Genet
18: 3987-3996
[Abstract][Full Text]
Tomaszewski, M., Charchar, F. J., Barnes, T., Gawron-Kiszka, M., Sedkowska, A., Podolecka, E., Kowalczyk, J., Rathbone, W., Kalarus, Z., Grzeszczak, W., Goodall, A. H., Samani, N. J., Zukowska-Szczechowska, E.
(2009). A Common Variant in Low-Density Lipoprotein Receptor-Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol. Arterioscler. Thromb. Vasc. Bio.
29: 1316-1321
[Abstract][Full Text]
Kim, S. H., Shi, Y., Hanson, K. A., Williams, L. M., Sakasai, R., Bowler, M. J., Tibbetts, R. S.
(2009). Potentiation of Amyotrophic Lateral Sclerosis (ALS)-associated TDP-43 Aggregation by the Proteasome-targeting Factor, Ubiquilin 1. J. Biol. Chem.
284: 8083-8092
[Abstract][Full Text]
Schjeide, B.-M. M., Hooli, B., Parkinson, M., Hogan, M. F., DiVito, J., Mullin, K., Blacker, D., Tanzi, R. E., Bertram, L.
(2009). GAB2 as an Alzheimer Disease Susceptibility Gene: Follow-up of Genomewide Association Results. Arch Neurol
66: 250-254
[Abstract][Full Text]
Oddo, S., Caccamo, A., Tseng, B., Cheng, D., Vasilevko, V., Cribbs, D. H., LaFerla, F. M.
(2008). Blocking A{beta}42 Accumulation Delays the Onset and Progression of Tau Pathology via the C Terminus of Heat Shock Protein70-Interacting Protein: A Mechanistic Link between A{beta} and Tau Pathology. J. Neurosci.
28: 12163-12175
[Abstract][Full Text]
Lee, J. H., Cheng, R., Graff-Radford, N., Foroud, T., Mayeux, R., for the National Institute on Aging Late-Onset Alz,
(2008). Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: Implication of Additional Loci. Arch Neurol
65: 1518-1526
[Abstract][Full Text]
Schaffer, B. A. J., Bertram, L., Miller, B. L., Mullin, K., Weintraub, S., Johnson, N., Bigio, E. H., Mesulam, M., Wiedau-Pazos, M., Jackson, G. R., Cummings, J. L., Cantor, R. M., Levey, A. I., Tanzi, R. E., Geschwind, D. H.
(2008). Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia. Arch Neurol
65: 1368-1374
[Abstract][Full Text]
Waring, S. C., Rosenberg, R. N.
(2008). Genome-Wide Association Studies in Alzheimer Disease. Arch Neurol
65: 329-334
[Abstract][Full Text]
Jayadev, S., Steinbart, E. J., Chi, Y.-Y., Kukull, W. A., Schellenberg, G. D., Bird, T. D.
(2008). Conjugal Alzheimer Disease: Risk in Children When Both Parents Have Alzheimer Disease. Arch Neurol
65: 373-378
[Abstract][Full Text]
Ganguly, A., Feldman, R.M. R., Guo, M.
(2008). ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila. Hum Mol Genet
17: 293-302
[Abstract][Full Text]
Li, A., Xie, Z., Dong, Y., McKay, K. M., McKee, M. L., Tanzi, R. E.
(2007). Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes. Hum Mol Genet
16: 2626-2639
[Abstract][Full Text]
Huttunen, H. J., Guenette, S. Y., Peach, C., Greco, C., Xia, W., Kim, D. Y., Barren, C., Tanzi, R. E., Kovacs, D. M.
(2007). HtrA2 Regulates beta-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation. J. Biol. Chem.
282: 28285-28295
[Abstract][Full Text]
Boddaert, J., Kinugawa, K., Lambert, J.-C., Boukhtouche, F., Zoll, J., Merval, R., Blanc-Brude, O., Mann, D., Berr, C., Vilar, J., Garabedian, B., Journiac, N., Charue, D., Silvestre, J.-S., Duyckaerts, C., Amouyel, P., Mariani, J., Tedgui, A., Mallat, Z.
(2007). Evidence of a Role for Lactadherin in Alzheimer's Disease. Am. J. Pathol.
170: 921-929
[Abstract][Full Text]
Chisa, J. L., Burke, D. T.
(2007). Mammalian mRNA Splice-Isoform Selection Is Tightly Controlled. Genetics
175: 1079-1087
[Abstract][Full Text]
Thomas, P., Fenech, M.
(2007). A review of genome mutation and Alzheimer's disease. Mutagenesis
22: 15-33
[Abstract][Full Text]
Bertram, L., Mullin, K., Parkinson, M., Hsiao, M., Moscarillo, T. J, Wagner, S. L, Becker, K D., Velicelebi, G., Blacker, D., Tanzi, R. E
(2007). Is {alpha}-T catenin (VR22) an Alzheimer's disease risk gene?. J. Med. Genet.
44: e63-e63
[Abstract][Full Text]
Hiltunen, M., Lu, A., Thomas, A. V., Romano, D. M., Kim, M., Jones, P. B., Xie, Z., Kounnas, M. Z., Wagner, S. L., Berezovska, O., Hyman, B. T., Tesco, G., Bertram, L., Tanzi, R. E.
(2006). Ubiquilin 1 Modulates Amyloid Precursor Protein Trafficking and Abeta Secretion. J. Biol. Chem.
281: 32240-32253
[Abstract][Full Text]
Thomas, A. V., Herl, L., Spoelgen, R., Hiltunen, M., Jones, P. B., Tanzi, R. E., Hyman, B. T., Berezovska, O.
(2006). Interaction between Presenilin 1 and Ubiquilin 1 as Detected by Fluorescence Lifetime Imaging Microscopy and a High-throughput Fluorescent Plate Reader. J. Biol. Chem.
281: 26400-26407
[Abstract][Full Text]
Li, Y., Grupe, A., Rowland, C., Nowotny, P., Kauwe, J. S.K., Smemo, S., Hinrichs, A., Tacey, K., Toombs, T. A., Kwok, S., Catanese, J., White, T. J., Maxwell, T. J., Hollingworth, P., Abraham, R., Rubinsztein, D. C., Brayne, C., Wavrant-De Vrieze, F., Hardy, J., O'Donovan, M., Lovestone, S., Morris, J. C., Thal, L. J., Owen, M., Williams, J., Goate, A.
(2006). DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Hum Mol Genet
15: 2560-2568
[Abstract][Full Text]
Brickell, K. L., Steinbart, E. J., Rumbaugh, M., Payami, H., Schellenberg, G. D., Van Deerlin, V., Yuan, W., Bird, T. D.
(2006). Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease.. Arch Neurol
63: 1307-1311
[Abstract][Full Text]
Law, A. J., Lipska, B. K., Weickert, C. S., Hyde, T. M., Straub, R. E., Hashimoto, R., Harrison, P. J., Kleinman, J. E., Weinberger, D. R.
(2006). Neuregulin 1 Transcripts Are Differentially Expressed in Schizophrenia and Regulated by 5' SNPs Associated With the Disease. Focus
4: 350-
[Abstract][Full Text]
Johnson, S. C., Schmitz, T. W., Trivedi, M. A., Ries, M. L., Torgerson, B. M., Carlsson, C. M., Asthana, S., Hermann, B. P., Sager, M. A.
(2006). The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation.. J. Neurosci.
26: 6069-6076
[Abstract][Full Text]
Law, A. J., Lipska, B. K., Weickert, C. S., Hyde, T. M., Straub, R. E., Hashimoto, R., Harrison, P. J., Kleinman, J. E., Weinberger, D. R.
(2006). Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proc. Natl. Acad. Sci. USA
103: 6747-6752
[Abstract][Full Text]
Almeida, C. G., Takahashi, R. H., Gouras, G. K.
(2006). Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system.. J. Neurosci.
26: 4277-4288
[Abstract][Full Text]
Morita, M., Al-Chalabi, A., Andersen, P. M., Hosler, B., Sapp, P., Englund, E., Mitchell, J. E., Habgood, J. J., de Belleroche, J., Xi, J., Jongjaroenprasert, W., Horvitz, H. R., Gunnarsson, L. -G., Brown, R. H. Jr
(2006). A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology
66: 839-844
[Abstract][Full Text]
Wang, H., Lim, P. J., Yin, C., Rieckher, M., Vogel, B. E., Monteiro, M. J.
(2006). Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet
15: 1025-1041
[Abstract][Full Text]
Ficklin, M. B., Zhao, S., Feng, G.
(2005). Ubiquilin-1 Regulates Nicotine-induced Up-regulation of Neuronal Nicotinic Acetylcholine Receptors. J. Biol. Chem.
280: 34088-34095
[Abstract][Full Text]
Slifer, M. A., Martin, E. R., Haines, J. L., Pericak-Vance, M. A., Bertram, L., Tanzi, R. E.
(2005). The Ubiquilin 1 Gene and Alzheimer's Disease. NEJM
352: 2752-2753
[Full Text]
Previous
