title: Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK
authors.forename: Lynnette J
authors.initials: LJ
authors.lastname: Cook
authors.forename: Luk W
authors.initials: LW
authors.lastname: Ho
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Edith
authors.initials: E
authors.lastname: Terrenoire
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: John Grimley
authors.initials: JG
authors.lastname: Evans
authors.forename: John
authors.initials: J
authors.lastname: Xuereb
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Dragana
authors.initials: D
authors.lastname: Turic
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Moore
authors.forename: Luke
authors.initials: L
authors.lastname: Jehu
authors.forename: Nicola
authors.initials: N
authors.lastname: Archer
authors.forename: Sarah
authors.initials: S
authors.lastname: Walter
authors.forename: Catherine
authors.initials: C
authors.lastname: Foy
authors.forename: Amanda
authors.initials: A
authors.lastname: Edmondson
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: 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
chemical_list: D002795:Choline O-Acetyltransferase