Jong-Min Lee^{1, 2}, Tammy Gillis¹, Jayalakshmi Srinidhi Mysore¹, Eliana Marisa Ramos^{1, 3}, Richard H. Myers⁴, Michael R. Hayden⁵, Patrick J. Morrison^{6, 7}, Martha Nance⁸, Christopher A. Ross⁹, Russell L. Margolis⁹, Ferdinando Squitieri¹⁰, Annamaria Griguoli¹⁰, Stefano Di Donato¹¹, Estrella Gomez-Tortosa¹², Carmen Ayuso¹³, Oksana Suchowersky¹⁴, Ronald J. Trent¹⁵, Elizabeth McCusker¹⁶, Andrea Novelletto¹⁷, Marina Frontali¹⁸, Randi Jones¹⁹, Tetsuo Ashizawa²⁰, Samuel Frank⁴, Marie-Helene Saint-Hilaire⁴, Steven M. Hersch²¹, Herminia D. Rosas²¹, Diane Lucente¹, Madaline B. Harrison²², Andrea Zanko²³, Ruth K. Abramson²⁴, Karen Marder²⁵, Jorge Sequeiros^{3, 26}, Marcy E. MacDonald^{1, 2} and James F. Gusella^{1, 2}

¹ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
² Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
³ UnIGENe, Institute for Molecular and Cell Biology, Universidade do Porto, 4150-180 Porto, Portugal
⁴ Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
⁵ University of British Columbia, Center for Molecular Medicine and Therapeutics, Vancouver, British Columbia V5Z 4H4, Canada
⁶ Regional Medical Genetics Centre, Belfast Health and Social Care Trust, Belfast BT9 7AB, UK
⁷ University of Ulster, Cromore Road, Coleraine BT52 15A, UK
⁸ Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA
⁹ Johns Hopkins University, Department of Psychiatry and Behavioral Sciences, Baltimore, MD 21287, USA
¹⁰ Neurogenetics Unit and Centre for Rare Diseases, Instituto di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli (IS), Italy
¹¹ Fondazione IRCCS, Istituto Nazionale Neurologico C. Besta, 20133 Milan, Italy
¹² Department of Neurology, Fundacion Jimenez Diaz, Madrid 28040, Spain
¹³ Department of Genetics, IIS-Fundacion Jimenez Diaz, CIBERER, Madrid 28040, Spain
¹⁴ Departments of Medicine (Neurology) and Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2B7, Canada
¹⁵ Sydney Medical School, University of Sydney, NSW 2006, Australia
¹⁶ Department of Neurology, Westmead Hospital, Westmead, Sydney NSW 2145, Australia
¹⁷ Department of Biology, University Tor Vergata, 00133 Rome, Italy
¹⁸ Istituto di Farmacologia Traslazionale del Consiglio Nazionale delle Ricerche, 00133 Rome, Italy
¹⁹ Department of Neurology, Emory University, Atlanta, GA 30329, USA
²⁰ Department of Neurology, University of Florida, Gainesville, FL 32610, USA
²¹ MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
²² Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
²³ Department of Pediatrics, University of California, San Francisco, CA 94143, USA
²⁴ Department of Neuropsychiatry and Behavioral Science, University of South Carolina School of Medicine, Columbia, SC 29209, USA
²⁵ Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
²⁶ Instituto de Ciencias Biomedicas Abel Salazar, Universidade do Porto, 4099-003 Porto, Portugal

Corresponding author : James F. Gusella

Abstract
Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of synthetic association with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for 50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for 83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.