Genetic analysis of candidate genes modifying the age-at-onset in Huntington's disease.
The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.
Metzger
Silke
S
Department of Medical Genetics, University of Tübingen, Calwerstrasse 7, 72076, Tübingen, Germany.
Bauer
Peter
P
Tomiuk
Jürgen
J
Laccone
Franco
F
Didonato
Stefano
S
Gellera
Cinzia
C
Mariotti
Caterina
C
Lange
Herwig W
HW
Weirich-Schwaiger
Helga
H
Wenning
Gregor K
GK
Seppi
Klaus
K
Melegh
Bela
B
Havasi
Viktoria
V
Balikó
Laszlo
L
Wieczorek
Stefan
S
Zaremba
Jacek
J
Hoffman-Zacharska
Dorota
D
Sulek
Anna
A
Basak
A Nazli
AN
Soydan
Esra
E
Zidovska
Jana
J
Kebrdlova
Vera
V
Pandolfo
Massimo
M
Ribaï
Pascale
P
Kadasi
Ludovit
L
Kvasnicova
Marta
M
Weber
Bernhard H F
BH
Kreuz
Friedmar
F
Dose
Matthias
M
Stuhrmann
Manfred
M
Riess
Olaf
O
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011110:Polymorphism, Genetic; D018092:Kainic Acid Receptors / Q000235:genetics; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018092:Kainic Acid Receptors; D035181:TATA-Box Binding Protein; D000097806:GluK2 Kainate Receptor; C073368:HIP1 protein, human; C086055:HTT protein, human; C473038:ZDHHC17 protein, human