TY - JOUR
T1 - Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease
AU - Harold, Denise
AU - Peirce, Timothy
AU - Moskvina, Valentina
AU - Myers, Amanda
AU - Jones, Susan
AU - Hollingworth, Paul
AU - Moore, Pamela
AU - Lovestone, Simon
AU - Powell, John
AU - Foy, Catherine
AU - Archer, Nicola
AU - Walter, Sarah
AU - Edmondson, Amanda
AU - McIlroy, Stephen
AU - Craig, David
AU - Passmore, Peter A
AU - Goate, Alison
AU - Hardy, John
AU - O'Donovan, Michael
AU - Williams, Julie
AU - Liddell, Malcolm
AU - Owen, Michael J
AU - Jones, Lesley
PY - 2003/8
Y1 - 2003/8
N2 - 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.
AB - 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.
KW - Aged
KW - Alleles
KW - Alzheimer Disease
KW - Carrier Proteins
KW - Case-Control Studies
KW - Choline O-Acetyltransferase
KW - European Continental Ancestry Group
KW - Female
KW - Genetic Predisposition to Disease
KW - Humans
KW - Linkage Disequilibrium
KW - Male
KW - Membrane Transport Proteins
KW - Polymerase Chain Reaction
KW - Polymorphism, Restriction Fragment Length
KW - Polymorphism, Single Nucleotide
KW - United Kingdom
KW - Vesicular Acetylcholine Transport Proteins
KW - Vesicular Transport Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
KW - Research Support, U.S. Gov't, P.H.S.
U2 - 10.1007/s00439-003-0960-2
DO - 10.1007/s00439-003-0960-2
M3 - Article
C2 - 12759818
VL - 113
SP - 258
EP - 267
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 3
ER -