Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study.
Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003; genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele chi(1) (2) = 1.02, P = 0.32; genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004; genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.
Cook
Lynnette J
LJ
Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK
Ho
Luk W
LW
Wang
Lin
L
Terrenoire
Edith
E
Brayne
Carol
C
Evans
John Grimley
JG
Xuereb
John
J
Cairns
Nigel J
NJ
Turic
Dragana
D
Hollingworth
Paul
P
Moore
Pamela J
PJ
Jehu
Luke
L
Archer
Nicola
N
Walter
Sarah
S
Foy
Catherine
C
Edmondson
Amanda
A
Powell
John
J
Lovestone
Simon
S
Williams
Julie
J
Rubinsztein
David C
DC
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002795:Choline O-Acetyltransferase / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D016017:Odds Ratio; D011110:Polymorphism, Genetic
D002795:Choline O-Acetyltransferase