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Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study

Jian-Liang Li123, Michael R Hayden4, Simon C Warby4, Alexandra Durr5, Patrick J Morrison67, Martha Nance8, Christopher A Ross10119, Russell L Margolis109, Adam Rosenblatt9, Ferdinando Squitieri12, Luigi Frati13, Estrella Gómez-Tortosa14, Carmen Ayuso García14, Oksana Suchowersky15, Mary Lou Klimek15, Ronald JA Trent16, Elizabeth McCusker17, Andrea Novelletto18, Marina Frontali19, Jane S Paulsen20, Randi Jones21, Tetsuo Ashizawa22, Alice Lazzarini2324, Vanessa C Wheeler25, Ranjana Prakash1, Gang Xu12, Luc Djoussé26, Jayalakshmi Srinidhi Mysore25, Tammy Gillis25, Michael Hakky25, L Adrienne Cupples27, Marie H Saint-Hilaire1, Jang-Ho J Cha28, Steven M Hersch28, John B Penney28, Madaline B Harrison29, Susan L Perlman30, Andrea Zanko31, Ruth K Abramson32, Anthony J Lechich33, Ayana Duckett33, Karen Marder33, P Michael Conneally34, James F Gusella2535, Marcy E MacDonald25 and Richard H Myers12*

Author Affiliations

1 Department of Neurology, Boston University School of Medicine, Boston, MA, USA

2 Bioinformatics Program, Boston University, Boston, MA, USA

3 Department of Biological Technologies, Wyeth Research, Cambridge, MA, USA

4 Centre for Molecular Medicine & Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

5 INSERM U679, Hôpital de la Salpêtrière, Paris, France

6 Department of Medical Genetics, Belfast City Hospital, Belfast, UK

7 School of Biomedical Science, University of Ulster, Coleraine, UK

8 Department of Neurology, Hennepin County Medical Center, Minneapolis, Minnesota, USA

9 Departments of Psychiatry and Neurology, John Hopkins University, Baltimore, Maryland, USA

10 Program in Cellular and Molecular Medicine, John Hopkins University, Baltimore, Maryland, USA

11 Department of Neuroscience, John Hopkins University, Baltimore, Maryland, USA

12 Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Italy

13 Dept of Experimental Medicine and Pathology, University "La Sapienza" of Rome, Rome, Italy

14 Servicio de Neurología y Genética, Fundación Jiménez Díaz, Madrid, Spain

15 Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canada

16 Department of Medicine, University of Sydney, Sydney, Australia

17 Neurology Department, Westmead Hospital, Sydney, Australia

18 Department of Biology, University "Tor Vergata", 00133 Rome, Italy

19 Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy

20 Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA

21 Neurology Department, Emory University, Atlanta, Georgia, USA

22 Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA

23 Department of Neurology, Robert Wood Johnson school of Medicine and Dentistry of New Jersey, USA

24 Novartis Pharmaceuticals, New Brunswick, NJ, USA

25 Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

26 Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

27 Department of Biostatistics, School of Public Health, Boston University, Boston MA, USA

28 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

29 Health Sciences Center, University of Virginia, Charlottesville, Virginia, USA

30 Department of Neurology, University of California at Los Angeles, California, USA

31 Division of Medical Genetics, UCSF, San Francisco, California, USA

32 WMS Hall Psychiatric Institute, Columbia, South Carolina, USA

33 Department of Neurology, Columbia College of Physicians, New York, NY, USA

34 Department of Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

35 Department of Genetics, Harvard Medical School, Boston, MA, USA

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BMC Medical Genetics 2006, 7:71  doi:10.1186/1471-2350-7-71

Published: 17 August 2006



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.


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.


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.


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.