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Am J Hum Genet DOI:10.1016/j.ajhg.2012.01.005

Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region.

Publication TypeJournal Article
Year of Publication2012
AuthorsLee, J-M, Gillis, T, Mysore, JSrinidhi, Ramos, EMarisa, Myers, RH, Hayden, MR, Morrison, PJ, Nance, M, Ross, CA, Margolis, RL, Squitieri, F, Griguoli, A, Di Donato, S, Gomez-Tortosa, E, Ayuso, C, Suchowersky, O, Trent, RJ, McCusker, E, Novelletto, A, Frontali, M, Jones, R, Ashizawa, T, Frank, S, Saint-Hilaire, M-H, Hersch, SM, Rosas, HD, Lucente, D, Harrison, MB, Zanko, A, Abramson, RK, Marder, K, Sequeiros, J, MacDonald, ME, Gusella, JF
JournalAm J Hum Genet
Date Published2012 Mar 09
KeywordsAge of Onset, Alleles, Case-Control Studies, Chromosomes, Human, Pair 4, Founder Effect, Genome-Wide Association Study, Haplotypes, Humans, Huntington Disease, Mutation, Polymorphism, Single Nucleotide, Trinucleotide Repeats

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID22387017
PubMed Central IDPMC3309179
Grant ListUL1 TR000064 / TR / NCATS NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
P50 NS016367 / NS / NINDS NIH HHS / United States
NS16367 / NS / NINDS NIH HHS / United States
R01 NS032765 / NS / NINDS NIH HHS / United States
NS32765 / NS / NINDS NIH HHS / United States
U54 RR020278 / RR / NCRR NIH HHS / United States