TY - JOUR
T1 - Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset
AU - Ramos, Eliana Marisa
AU - Latourelle, Jeanne C.
AU - Gillis, Tammy
AU - Mysore, Jayalakshmi S.
AU - Squitieri, Ferdinando
AU - Di Pardo, Alba
AU - Di Donato, Stefano
AU - Gellera, Cinzia
AU - Hayden, Michael R.
AU - Morrison, Patrick J.
AU - Nance, Martha
AU - Ross, Christopher A.
AU - Margolis, Russell L.
AU - Gomez-Tortosa, Estrella
AU - Ayuso, Carmen
AU - Suchowersky, Oksana
AU - Trent, Ronald J.
AU - McCusker, Elizabeth
AU - Novelletto, Andrea
AU - Frontali, Marina
AU - Jones, Randi
AU - Ashizawa, Tetsuo
AU - Frank, Samuel
AU - Saint-Hilaire, Marie Helene
AU - Hersch, Steven M.
AU - Rosas, Herminia D.
AU - Lucente, Diane
AU - Harrison, Madaline B.
AU - Zanko, Andrea
AU - Abramson, Ruth K.
AU - Marder, Karen
AU - Gusella, James F.
AU - Lee, Jong Min
AU - Alonso, Isabel
AU - Sequeiros, Jorge
AU - Myers, Richard H.
AU - MacDonald, Marcy E.
N1 - Funding Information:
The authors thank Drs. Ignacio Muñoz-Sanjuan, Seung Kwak, and Jamshid Arjomand from CHDI Foundation, Inc., as well as the HD families, whose participation in genetic studies made this work possible; the COHORT co-investigators and contributors (see “”); contributors to the HD-MAPS study, Drs. Alexandra Durr, Adam Rosenblatt, Luigi Frati, Susan Perlman, P. Michael Conneally, Mary Lou Klimek, Melissa Diggin, Tiffany Hadzi, and Ayana Duckett; the Harvard Brain Tissue Resource Center at McLean Hospital; and the National Neurological Research Specimen Bank at the VA West Los Angeles Healthcare Center. EMR is the recipient of a scholarship from the Fundação para a Ciência e a Tecnologia of Portugal (SFRH/BD/44335/2008). Study funding was supported by NIH grants from the NINDS NS16367 (The Massachusetts HD Center Without Walls) and NS32765, and the CHDI Foundation, Inc.
PY - 2013/11
Y1 - 2013/11
N2 - Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
AB - Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
KW - Dopamine pathway
KW - Genetic modifiers
KW - Glutamate receptors
KW - Huntington's disease
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U2 - 10.1007/s10048-013-0364-y
DO - 10.1007/s10048-013-0364-y
M3 - Article
C2 - 23644918
AN - SCOPUS:84888063832
SN - 1364-6745
VL - 14
SP - 173
EP - 179
JO - Neurogenetics
JF - Neurogenetics
IS - 3-4
ER -