TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease

• Authors: Ji-Hyun Lee, Yonsei University; Jong-Min Lee, Massachusetts General Hospital; Eliana M Ramos, Massachusetts General Hospital; Tammy Gillis, Massachusetts General Hospital; Jayalakshmi S Mysore, Massachusetts General Hospital; Shotaro Kishikawa, Massachusetts General Hospital; Tiffany Hadzi, Boston University; Audrey E Hendricks, Boston University; Michael R Hayden, University of British Columbia; Patrick J Morrison, Belfast HSC Trust; Martha Nance, Hennepin County Medical Center; Christopher A Ross, Johns Hopkins University; Russell L Margolis, Johns Hopkins University; Ferdinando Squitieri, IRCCS Neuromed; Cinzia Gellera, Istituto Nazionale Neurologico C. Besta; Estrella Gomez-Tortosa, Fundación Jiménez Diaz; Carmen Ayuso, Fundación Jiménez Diaz; Oksana Suchowersky, Fundación Jiménez Diaz; Ronald J Trent, University of Sydney; Elizabeth McCusker, Westmead Hospital,; Andrea Novelletto, University Tor Vergata, 00133 Rome; Marina Frontali, Institute of Neurobiology and Molecular Medicine, 00133 Rome; Randi Jones, Emory University; Tetsuo Ashizawa, University of Florida; Samuel Frank, Boston University; Marie-Helene Saint-Hilaire, Boston University; Steven M Hersch, Massachusetts General Hospital; Herminia D Rosas, Massachusetts General Hospital; Diane Lucente, Massachusetts General Hospital; Madaline B Harrison, University of Virginia; Andrea Zanko, University of California San Francisco; Ruth K Abramson, University of South Carolina; Karen Marder, Columbia University; Jorge Sequeiros, Universidade do Porto; Bernhard G Landwehrmeyer, Ulm University; Ira Shoulson, Georgetown University; Richard H Myers, Boston University; Marcy E MacDonald, Massachusetts General Hospital; James F Gusella, Massachusetts General Hospital
• Journal Title: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• Volume: Volume 424, Number 3
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE | 2012-08-03, Pages 404-408
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.bbrc.2012.06.120
• Subjects: Biology, Biostatistics; Health Sciences, Mental Health
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Biophysics; Huntington's disease (HD); Age at onset; GRIK2; Genetic modifier; TRINUCLEOTIDE REPEAT; OF-ONSET; AT-ONSET; MODIFIER; POLYMORPHISM; ASSOCIATION; LENGTH

Abstract

Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3' untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the GRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease. © 2012 Elsevier Inc.