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.
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