Project 2 Genetic Studies of Huntington's Disease Since the discovery of the Huntington's disease (HD) gene in February of 1993, much of the research focus into the cause and treatment has relied on transgenic mouse models, containing either full length or shorter first exon bearing expanded trinucleotide repeats. These studies have been remarkable in their capacity to lend insight into the processes leading to huntingtin (htt) aggregation, now recognized as a critical hallmark of the disease. Further, the use of transgenic mice has yielded promising leads for therapeutic intervention as different treatments are found to delay onset and slow progression in these mice. Presently, much HD research focuses on mouse and other transgenics (e.g. fly, zebrafish, etc.). Yet, the genetic mechanisms regulating the human disease may differ markedly from those seen in animal models, and there is critical need to maintain human research component in the multi-pronged attack on the disease. We propose a coordinated effort among Projects 1, 2, and 3 of the HD Center to identify the genetic modifiers regulating HD onset age in a cohort of 352 pedigrees containing 754 sibling pairs. A unique set of 282 HD cases with unusually young or old onset ages, given their repeat sizes, will be used to validate finding of association in the families. The highlight of our proposal is the pursuit of a genetic modifier at 6q23- 24, identified by linkage analysis in two independent samples, HD MAPS I [LOD=3.8] and HD MAPS II [LOD=2.8] with a combined LOD score of 5.1.This compelling finding will be investigated through genotyping 1536 SNPs, in 1200 persons, in collaboration with the Broad Institute. Further, we will investigate four other regions with varying support for linkage 4p16 [LOD=1.92], 18q22 [LOD=1.83], 6p22.3 [LOD=1.41], and 2q33 [LOD=1.54]. We will explore carefully selected candidate genes and huntingtin interacting proteins under these peaks and in other regions of the genome. In a newly crafted AIM 2, we will explore gene-gene interaction models as well as two-locus linkage analysis. We present new preliminary data for a revised AIM 3, showing the first ever studies of heritability for other important HD clinical features, including motor impairment and psychiatric features. We will conduct linkage analysis and candidate gene studies for these traits. The identification of genetic modifiers in HD holds promise for the recognition of substances which may be invoked for pharmacologic intervention in this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS016367-29
Application #
7883255
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
29
Fiscal Year
2009
Total Cost
$267,989
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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HD iPSC Consortium (2017) Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice. Nat Neurosci 20:648-660
Chao, Michael J; Gillis, Tammy; Atwal, Ranjit S et al. (2017) Haplotype-based stratification of Huntington's disease. Eur J Hum Genet 25:1202-1209
Shin, Aram; Shin, Baehyun; Shin, Jun Wan et al. (2017) Novel allele-specific quantification methods reveal no effects of adult onset CAG repeats on HTT mRNA and protein levels. Hum Mol Genet 26:1258-1267
Keum, Jae Whan; Shin, Aram; Gillis, Tammy et al. (2016) The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease. Am J Hum Genet 98:287-98
Correia, Kevin; Harold, Denise; Kim, Kyung-Hee et al. (2015) The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease. J Huntingtons Dis 4:279-84
Lee, Jong-Min; Kim, Kyung-Hee; Shin, Aram et al. (2015) Sequence-Level Analysis of the Major European Huntington Disease Haplotype. Am J Hum Genet 97:435-44
Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S et al. (2015) Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease. Am J Med Genet B Neuropsychiatr Genet 168B:135-43
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium (2015) Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell 162:516-26
Biagioli, Marta; Ferrari, Francesco; Mendenhall, Eric M et al. (2015) Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation. Hum Mol Genet 24:2442-57

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