title: Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease.
abstract: There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.
authors.affiliation: Department of Psychological Medicine, University of Wales College of Medicine, CF14 4XN, Cardiff, UK.
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.forename: Timothy
authors.initials: T
authors.lastname: Peirce
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Amanda
authors.initials: A
authors.lastname: Myers
authors.forename: Susan
authors.initials: S
authors.lastname: Jones
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Pamela
authors.initials: P
authors.lastname: Moore
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Catherine
authors.initials: C
authors.lastname: Foy
authors.forename: Nicola
authors.initials: N
authors.lastname: Archer
authors.forename: Sarah
authors.initials: S
authors.lastname: Walter
authors.forename: Amanda
authors.initials: A
authors.lastname: Edmonson
authors.forename: Stephen
authors.initials: S
authors.lastname: McIlroy
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.forename: Peter A
authors.initials: PA
authors.lastname: Passmore
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Malcolm
authors.initials: M
authors.lastname: Liddell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002795:Choline O-Acetyltransferase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D026901:Membrane Transport Proteins; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D044465:White People / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D002795:Choline O-Acetyltransferase