title: Replication of twelve association studies for Huntington's disease residual age of onset in large Venezuelan kindreds.
abstract: BACKGROUND
  The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat. Significant variance remains, however, in residual age of onset even after repeat length is factored out. Many genetic polymorphisms have previously shown evidence of association with age of onset of Huntington's disease in several different populations.
  
  
  OBJECTIVE
  To replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela.
  
  
  METHODS
  Previously tested polymorphisms were analysed in the HD gene itself (HD), the GluR6 kainate glutamate receptor (GRIK2), apolipoprotein E (APOE), the transcriptional coactivator CA150 (TCERG1), the ubiquitin carboxy-terminal hydrolase L1 (UCHL1), p53 (TP53), caspase-activated DNase (DFFB), and the NR2A and NR2B glutamate receptor subunits (GRIN2A, GRIN2B).
  
  
  RESULTS
  The GRIN2A single-nucleotide polymorphism explains a small but considerable amount of additional variance in residual age of onset in our sample. The TCERG1 microsatellite shows a trend towards association but does not reach statistical significance, perhaps because of the uninformative nature of the polymorphism caused by extreme allele frequencies. We did not replicate the genetic association of any of the other genes.
  
  
  CONCLUSIONS
  GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease. The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease. The lack of association in the Venezuelan kindreds may be due to the extremely low frequency of the key (TAA)(16) allele in this population.
authors.affiliation: Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. jma@mit.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Andresen
authors.forename: J
authors.initials: J
authors.lastname: Gayán
authors.forename: S S
authors.initials: SS
authors.lastname: Cherny
authors.forename: D
authors.initials: D
authors.lastname: Brocklebank
authors.forename: G
authors.initials: G
authors.lastname: Alkorta-Aranburu
authors.forename: E A
authors.initials: EA
authors.lastname: Addis
authors.forename: L R
authors.initials: LR
authors.lastname: Cardon
authors.forename: D E
authors.initials: DE
authors.lastname: Housman
authors.forename: N S
authors.initials: NS
authors.lastname: Wexler
mesh_terms: D017668:Age of Onset; D001057:Apolipoproteins E / Q000235:genetics; D003851:Deoxyribonucleases / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000453:epidemiology* / Q000235:genetics*; D018895:Microsatellite Repeats; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D018092:Kainic Acid Receptors / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D035602:Transcriptional Elongation Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D014687:Venezuela; D000097806:GluK2 Kainate Receptor
chemical_list: D001057:Apolipoproteins E; D003851:Deoxyribonucleases; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D015534:Trans-Activators; D035602:Transcriptional Elongation Factors; D016159:Tumor Suppressor Protein p53; D043222:Ubiquitin Thiolesterase; D000097806:GluK2 Kainate Receptor; C086055:HTT protein, human; C121001:NR2B NMDA receptor; C108440:TCERG1 protein, human; C482860:UCHL1 protein, human; C113696:DFFB protein, human