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Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study
Author(s) -
Cook Lynnette J.,
Ho Luk W.,
Wang Lin,
Terrenoire Edith,
Brayne Carol,
Evans John Grimley,
Xuereb John,
Cairns Nigel J.,
Turic Dragana,
Hollingworth Paul,
Moore Pamela J.,
Jehu Luke,
Archer Nicola,
Walter Sarah,
Foy Catherine,
Edmondson Amanda,
Powell John,
Lovestone Simon,
Williams Julie,
Rubinsztein David C.
Publication year - 2004
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30068
Subject(s) - choline acetyltransferase , acetylcholinesterase , butyrylcholinesterase , allele , genotype , cholinergic , biology , nicotinic acetylcholine receptor , single nucleotide polymorphism , genetics , candidate gene , gene , alzheimer's disease , polymorphism (computer science) , genetic association , acetylcholine receptor , medicine , disease , endocrinology , aché , receptor , enzyme , biochemistry
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 χ 1 2 = 12.84, P = 0.0003; genotype χ 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 χ 1 2 = 1.02, P =0.32; genotype χ 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 χ 1 2 = 12.37, P = 0.0004; genotype χ 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. © 2004 Wiley‐Liss, Inc.