Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease

Denise Harold, Timothy Peirce, Valentina Moskvina, Amanda Myers, Susan Jones, Paul Hollingworth, Pamela Moore, Simon Lovestone, John Powell, Catherine Foy, Nicola Archer, Sarah Walter, Amanda Edmondson, Stephen McIlroy, David Craig, Peter A Passmore, Alison Goate, John Hardy, Michael O'Donovan, Julie Williams & 3 others Malcolm Liddell, Michael J Owen, Lesley Jones

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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.

LanguageEnglish
Pages258-267
Number of pages10
JournalHuman Genetics
Volume113
Issue number3
Early online date21 May 2003
DOIs
Publication statusPublished - Aug 2003

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Alzheimer Disease
Exons
Chromosomes, Human, Pair 10
Linkage Disequilibrium
Genes
Single Nucleotide Polymorphism
Untranslated Regions
Minisatellite Repeats
Choline O-Acetyltransferase
Genetic Promoter Regions
Introns
Cholinergic Agents
DNA

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Harold, D., Peirce, T., Moskvina, V., Myers, A., Jones, S., Hollingworth, P., ... Jones, L. (2003). Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease. Human Genetics, 113(3), 258-267. https://doi.org/10.1007/s00439-003-0960-2
Harold, Denise ; Peirce, Timothy ; Moskvina, Valentina ; Myers, Amanda ; Jones, Susan ; Hollingworth, Paul ; Moore, Pamela ; Lovestone, Simon ; Powell, John ; Foy, Catherine ; Archer, Nicola ; Walter, Sarah ; Edmondson, Amanda ; McIlroy, Stephen ; Craig, David ; Passmore, Peter A ; Goate, Alison ; Hardy, John ; O'Donovan, Michael ; Williams, Julie ; Liddell, Malcolm ; Owen, Michael J ; Jones, Lesley. / Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease. In: Human Genetics. 2003 ; Vol. 113, No. 3. pp. 258-267.
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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.",
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Harold, D, Peirce, T, Moskvina, V, Myers, A, Jones, S, Hollingworth, P, Moore, P, Lovestone, S, Powell, J, Foy, C, Archer, N, Walter, S, Edmondson, A, McIlroy, S, Craig, D, Passmore, PA, Goate, A, Hardy, J, O'Donovan, M, Williams, J, Liddell, M, Owen, MJ & Jones, L 2003, 'Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease', Human Genetics, vol. 113, no. 3, pp. 258-267. https://doi.org/10.1007/s00439-003-0960-2

Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease. / Harold, Denise; Peirce, Timothy; Moskvina, Valentina; Myers, Amanda; Jones, Susan; Hollingworth, Paul; Moore, Pamela; Lovestone, Simon; Powell, John; Foy, Catherine; Archer, Nicola; Walter, Sarah; Edmondson, Amanda; McIlroy, Stephen; Craig, David; Passmore, Peter A; Goate, Alison; Hardy, John; O'Donovan, Michael; Williams, Julie; Liddell, Malcolm; Owen, Michael J; Jones, Lesley.

In: Human Genetics, Vol. 113, No. 3, 08.2003, p. 258-267.

Research output: Contribution to journalArticle

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

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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.

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KW - Alleles

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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

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SP - 258

EP - 267

JO - Human Genetics

T2 - Human Genetics

JF - Human Genetics

SN - 0340-6717

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Harold D, Peirce T, Moskvina V, Myers A, Jones S, Hollingworth P et al. Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease. Human Genetics. 2003 Aug;113(3):258-267. https://doi.org/10.1007/s00439-003-0960-2