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.

Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

“…In addition, we also found suggestive associations of all 3 SNPs with cognitive function as measured by MMSE score. Originally, Mubumbila et al [12] reported a significant association of the exon 5 SNP in 122 LOAD cases and 112 controls in a French-German population, but it was not confirmed in subsequent studies [3,5,15]. Recently, Kim et al [8] reported a significant association of this SNP among APOE*4 carriers in a Korean sample.…”

“…In a pilot study of 119 AD cases and 116 controls, Harold et al [5] reported significantly lower frequency of the A allele of the intron 9 SNP in AD cases than controls (15% vs. 23 %; p=0.034). In two replication samples, Harold et al [5] found similar but non-significant trend in one sample but not in the other sample.…”

“…Previously, some groups have examined the role of CHAT genetic variation with AD risk or AAO, but the results have been equivocal [5,8,12,15]. With the exception of one study that examined multiple SNPs in the CHAT gene [5], other studies examined only one SNP in exon 5, A120T [8,12,15], and most of these studies used relatively small number of cases and controls and thus fall short of providing conclusive results.…”

“…With the exception of one study that examined multiple SNPs in the CHAT gene [5], other studies examined only one SNP in exon 5, A120T [8,12,15], and most of these studies used relatively small number of cases and controls and thus fall short of providing conclusive results. The objective of this study was to use a well-powered and large case-control cohort to examine the role of three CHAT SNPs that previously showed suggestive associations with AD risk and quantitative trait of AD.…”

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia

“…The Cardiff group identified polymorphisms within KIAA0319 through dbSNP or by denaturing highperformance liquid chromatography as previously described, 28 while the Oxford group selected new markers that were located within multi-species conserved sequences (MCSs). 29 SNPs with a minor allele frequency < 5% were included if they were of putative functional significance (e.g.…”