Genome-wide significant risk factors on chromosome 19 and the APOE locus (original) (raw)
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Neuroscience Letters, 1999
Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missence mutation (T → C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (Ͼ60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.
Neurobiology of Aging, 2003
The search for further variation at the APOE gene in a sample of patients with sporadic late-onset Alzheimer's disease (AD) and related controls revealed two different mutations in the exon 3 of the gene. One, the Leu28 → Pro, always found on an APOE e * 4 allele, was present in five of the 94 patients and in 1 of the 157 controls. The other, Thr42 → Ala, found on an e * 3 allele, was observed in only one AD patient, who also carried the Leu28 → Pro, but in none of the controls. In the AD patient group the allele e * 4 − , corresponding to Leu28 → Pro, showed a frequency of 0.027, compared with only 0.003 in the controls. Compared to E3/3 and E3/2 genotypes, the risk of developing AD associated with the genotypes carrying the e * 4 allele, the well-established risk allele for AD onset, was observed to be high (OR = 3.16; 95% CI = 1.62-6.20; P = 0.0009), but the risk associated with genotypes carrying the Leu28 → Pro mutation was higher still (OR = 10.95; 95% CI = 1.25-95.75; P = 0.015). The higher risk associated with this mutation was assessed by meta-analysis carried out using the data of three patient groups from a previously published study Kamboh et al. [4] and from our study. The results indicated that, compared with all the other APOE genotypes, those carrying the Leu28 → Pro mutation were at a substantially higher risk of developing AD (OR = 4.25; 95% CI = 1.21-14.97).
Oncotarget, 2018
The apolipoprotein E () gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer's disease (AD). Additional signals associated with AD have been located in chromosome 19, including (19p13.3) and 19q13.41). The gene has been replicated in most populations. However, the contribution to AD of other signals close to gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of and loci to AD risk and explore LRLD patterns across region. To evaluate AD risk conferred by rs4147929:G>A and rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12-1.19; = 1.60 x 10). rs3865444:C>A was not associated with AD in t...
Absence of association between Alzheimer disease and the −491 regulatory region polymorphism of APOE
Neuroscience Letters, 1998
A novel polymorphism (−491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the −491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE e2/e3/e4 polymorphism.
Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease
Neurogenetics, 2004
Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the -219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influence...
Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13?
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008
We have studied the impact of the apolipoprotein E gene (APOE) on the chromosome 19 linkage peak from an analysis of sib-pairs affected by Alzheimer's disease. We genotyped 417 affected sibpairs (ASPs) collected in Sweden and Norway (SWE), the UK and the USA for 10 microsatellite markers on chromosome 19. The highest Zlr (3.28, chromosome-wide P-value 0.036) from the multipoint linkage analysis was located approximately 1 Mb from APOE, at marker D19S178. The linkage to chromosome 19 was well explained by APOE in the whole sample as well as in the UK and USA subsamples, as identity by descent (IBD) increased with the number of ε4 alleles in ASPs. There was a suggestion from the SWE subsample that linkage was higher than would be expected from APOE alone, although the test for this did not reach formal statistical significance. There was also a significant age at onset (aao) effect on linkage to chromosome 19q13 in the whole sample, which manifested itself as increased IBD sharing in relative pairs with lower mean aao. This effect was partially, although not completely, explained by APOE. The aao effect varied considerably between the different subsamples, with most of the effect coming from the UK sample. The other samples showed smaller effects in the same direction, but these were not significant.
Neuroscience Letters, 1998
The −491 polymorphism in the promoter region of the apolipoprotein E gene (APOE) has been suggested to be associated with increased risk for Alzheimer's disease (AD) independent of APOE status. We studied the association between the −491 polymorphism and risk for early-onset Alzheimer's disease in 99 Dutch and 78 Spanish patients. In patients with early-onset AD, we found no consistent relationship with a single allele of the −491 polymorphism. Linkage disequilibrium between the polymorphism and the APOE gene was found which most likely might explain the inconsistent findings.
Analysis of Association at Single Nucleotide Polymorphisms in the APOE Region
Genomics, 2000
The discussion of the prospects of using a dense map of single nucleotide polymorphisms (SNPs) to identify disease genes with association analysis has been extensive. However, there is little empiric evidence to support this strategy. To begin to examine the practical issues surrounding this methodology, we identified 10 SNPs in the region immediately surrounding the apolipoprotein E locus (APOE), an established susceptibility gene for Alzheimer disease. Our goal was to examine patterns of allelic association to begin to investigate the question of whether APOE could have been identified using SNPs. Our strongest evidence of association was at the 2 SNPs immediately flanking APOE.
A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease
Human Molecular Genetics, 1998
The ε4 allele of the Apolipoprotein E gene (APOE), one of the main allele of APOE polymorphism, is a major risk factor for the development of Alzheimer's disease. However, several data suggest that genetic factors, within the APOE locus, may also modulate the risk associated with this polymorphism. We look for new mutations in the APOE promoter, susceptible to modify the risk associated with the APOE ε4 allele. We characterised a G→T mutation at -186 bp of the APOE gene TATA box, named Th1/E47cs. This new polymorphism is located in a consensus sequence of a potential transcriptional (Th1/E47) factor binding site. We studied the impact of this new polymorphism with those of other markers of the APOE locus in a large case-control study and observed that Th1/E47cs modulated the influence of the APOE ε4 allele on the risk of Alzheimer's disease.