Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
-
Published:2006-08-17
Issue:1
Volume:7
Page:
-
ISSN:1471-2350
-
Container-title:BMC Medical Genetics
-
language:en
-
Short-container-title:BMC Med Genet
Author:
Li Jian-Liang,Hayden Michael R,Warby Simon C,Durr Alexandra,Morrison Patrick J,Nance Martha,Ross Christopher A,Margolis Russell L,Rosenblatt Adam,Squitieri Ferdinando,Frati Luigi,Gómez-Tortosa Estrella,García Carmen Ayuso,Suchowersky Oksana,Klimek Mary Lou,Trent Ronald JA,McCusker Elizabeth,Novelletto Andrea,Frontali Marina,Paulsen Jane S,Jones Randi,Ashizawa Tetsuo,Lazzarini Alice,Wheeler Vanessa C,Prakash Ranjana,Xu Gang,Djoussé Luc,Mysore Jayalakshmi Srinidhi,Gillis Tammy,Hakky Michael,Cupples L Adrienne,Saint-Hilaire Marie H,Cha Jang-Ho J,Hersch Steven M,Penney John B,Harrison Madaline B,Perlman Susan L,Zanko Andrea,Abramson Ruth K,Lechich Anthony J,Duckett Ayana,Marder Karen,Conneally P Michael,Gusella James F,MacDonald Marcy E,Myers Richard H
Abstract
Abstract
Background
Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.
Methods
In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.
Results
Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.
Conclusion
In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
Reference26 articles.
1. Bates G, Harper P, Jones L: Huntington's Disease. 2002, Oxford, Oxford Univ. Press, 3rd 2. Myers RH, Marans K, Macdonald ME: Huntington's disease. Genetic Instabilities and Hereditary Neurological Diseases . Edited by: Warren St, Wells RT. 1998, Academic Press, 301-323. 3. Hayden MR: Huntington's Chorea. 1981, New York, Springer-Verlag 4. The Huntington's Disease Collaboratide Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993, 72: 971-983. 10.1016/0092-8674(93)90585-E. 5. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayan J, Brocklebank D, Cherny SS, Cardon LR, Gray J, Dlouhy SR, Wiktorski S, Hodes ME, Conneally PM, Penney JB, Gusella J, Cha JH, Irizarry M, Rosas D, Hersch S, Hollingsworth Z, MacDonald M, Young AB, Andresen JM, Housman DE, De Young MM, Bonilla E, Stillings T, Negrette A, Snodgrass SR, Martinez-Jaurrieta MD, Ramos-Arroyo MA, Bickham J, Ramos JS, Marshall F, Shoulson I, Rey GJ, Feigin A, Arnheim N, Acevedo-Cruz A, Acosta L, Alvir J, Fischbeck K, Thompson LM, Young A, Dure L, O'Brien CJ, Paulsen J, Brickman A, Krch D, Peery S, Hogarth P, Higgins DSJ, Landwehrmeyer B: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A. 2004, 101: 3498-3503. 10.1073/pnas.0308679101.
Cited by
71 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|