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A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study |
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| Authors: | Li Jian-Liang Hayden Michael R Almqvist Elisabeth W Brinkman Ryan R Durr Alexandra Dodé Catherine Morrison Patrick J Suchowersky Oksana Ross Christopher A Margolis Russell L Rosenblatt Adam Gómez-Tortosa Estrella Cabrero David Mayo Novelletto Andrea Frontali Marina Nance Martha Trent Ronald J A McCusker Elizabeth Jones Randi Paulsen Jane S Harrison Madeline Zanko Andrea Abramson Ruth K Russ Ana L Knowlton Beth Djoussé Luc Mysore Jayalakshmi S Tariot Suzanne Gusella Michael F Wheeler Vanessa C Atwood Larry D Cupples L Adrienne Saint-Hilaire Marie Cha Jang-Ho J Hersch Steven M |
| Institution: | 1 Department of Neurology, Harvard Medical School, Boston 2 Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Harvard Medical School, Boston 3 Bioinformatics Program Harvard Medical School, Boston 4 Department of Biostatistics, School of Public Health, Boston University, Harvard Medical School, Boston 5 Molecular Neurogenetics Unit, Harvard Medical School, Boston 6 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston 7 Department of Genetics, Harvard Medical School, Boston 8 Department of Genomics, Wyeth Research, Cambridge, MA 9 Centre for Molecular Medicine &; Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver 10 INSERM U289, Hôpital de la Salpêtrière, Moléculaire, Hôpital Cochin, Paris 11 Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, Paris 12 Department of Medical Genetics, Belfast City Hospital, Belfast 13 School of Biomedical Science, University of Ulster, Coleraine, United Kingdom 14 Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary 15 Department of Psychiatry John Hopkins University, Baltimore 16 Department of Neuroscience, John Hopkins University, Baltimore 17 Program in Cellular and Molecular Medicine, John Hopkins University, Baltimore 18 Servicio de Neurología y Genética, Fundación Jiménez Díaz, Madrid 19 Department of Cell Biology, University of Calabria, Rende, Italy 20 Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Rome 21 Department of Neurology, Hennepin County Medical Center, Minneapolis 22 Department of Medicine, University of Sydney, Sydney 23 Neurology Department, Westmead Hospital, Sydney 24 Neurology Department, Emory University, Atlanta 25 Department of Psychiatry, University of Iowa, Iowa City 26 Health Sciences Center, University of Virginia, Charlottesville 27 Division of Medical Genetics, University of California San Francisco, San Francisco 28 William S. Hall Psychiatric Institute, Columbia, SC |
| Abstract: | Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21–23 (LOD=2.29), and 6q24–26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD. |
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