Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science
ABSTRACT Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Abeta, the principal component of beta-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the IDE gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the IDE gene.
Full-textDOI: · Available from: Rudy Tanzi, Aug 25, 2015
- SourceAvailable from: Joseph H Lee
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- "One of the functionally plausible candidate genes lying within the genetic region showing evidence for association or linkage reported by these studies is IDE occurring in a ~250kb haplotype block with KIFF11 and HHEX. Following the initial report on linkage and association of markers around IDE with LOAD (Bertram et al., 2000), some studies that used LOAD as the phenotype did not find an association (Cousin et al., 2009; Reiman et al., 2007) but other independent studies identified haplotypes spanning the IDE-KIFF-HHEX complex that show association with LOAD risk or intermediate LOAD phenotypes (Ertekin- Taner et al., 2004; Prince et al., 2003), including CSF tau levels, MMSE scores, senile plaque and neurofibrillary tangle density, and age-at-onset (Prince et al., 2003). The same haplotypes were associated with plasma Aβ levels in 24 extended Caucasian LOAD families, and with LOAD status in two independent case control series (Ertekin-Taner et al., 2004). "
ABSTRACT: Genetic linkage and association studies in late-onset Alzheimer's disease (LOAD) or its endophenotypes have pointed to several regions on chromosome 10q, among these the ∼ 250 kb linkage disequilibrium (LD) block harboring the genes IDE, KIF1, and HHEX. We explored the association between variants in the genomic region harboring the IDE-KIF11-HHEX complex with plasma Aβ40 and Aβ42 levels in a case-control cohort of Caribbean Hispanics. First, we performed single marker linear regression analysis relating the individual single nucleotide polymorphisms (SNPs) with plasma Aβ40 and Aβ42 levels. Then we performed 3-SNP sliding window haplotype analyses, correcting all analyses for multiple testing. Out of 32 SNPs in this region, 3 SNPs in IDE (rs2421943, rs12264682, rs11187060) were associated with plasma Aβ40 or Aβ42 levels in single marker and haplotype analyses after correction for multiple testing. All these SNPs lie within the same LD block, and are in LD with the previously reported haplotypes. Our findings provide support for an association in the IDE region on chromosome 10q with Aβ40 and 42 levels.Neurobiology of aging 01/2012; 33(1):199.e13-7. DOI:10.1016/j.neurobiolaging.2010.07.005 · 4.85 Impact Factor
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- "Linkage studies have identified several promising chromosomal regions to harbor additional AD genes, including chromosomes 12, 10, 9 and 6 (Kamboh, 2004). A broad linkage peak encompassing a >60 cM region between chromosome 10q21 and 10q25 that influences both AD risk and age at onset has been suggested (Bertram et al., 2000; Ertekin- Taner et al., 2000; Li et al., 2002; Myers et al., 2002). There are more than 300 genes in this broad genomic region of chromosome 10 and thus the task of identifying the candidate gene is daunting. "
ABSTRACT: Linkage studies point to the long arm of chromosome 10 being a susceptibility region for Alzheimer's disease (AD). Additionally, the gene choline O-acetyltransferase (CHAT) located on chromosome 10 was discussed for conveying risk towards AD, but the results are ambiguous. We examined a possible association of nineteen single-nucleotide polymorphisms (SNPs) in the CHAT gene in a longitudinal cohort study, the Vienna Tansdanube Aging (VITA)-study, in which all subjects were 75 years old at baseline. For replication, we used a more heterogeneous case-control sample from Milano with early and late AD. Nominal allelic and genotypic associations with AD risk in the cross-sectional VITA sample were found for rs3810950 (p = 0.038 for genotype, OR = 1.66 95% CI 1.03-2.68, p = 0.052 allele-wise). When combining both VITA- and Milano study rs3810950 was significantly associated with AD (p(combined) = 0.01634; power = 82%). This association was highly significant for APOEε4 carriers (p = 0.009 for genotype, OR = 3.21 95% CI 1.43-7.19 p = 0.007 allele-wise). Furthermore, an association of rs1880676 with AD was specific to carriers of the APOEε4 risk allele (p = 0.008, genotype; OR = 3.47 95% CI 1.50-8.01 p = 0.005 allele-wise). For depressive symptoms, we found a nominally significant association of rs3810950 with minor and major depression (p = 0.023, genotype; p = 0.008, allele). Applying Benjamini and Hochberg correction these associations could not be confirmed and also not be replicated in the more heterogeneous Milano sample. While our data therefore do not seem to support a major role for CHAT genetic variation in geriatric depression and AD, there might be a minor contribution in geriatric patients with depression and late onset AD, in particular those carrying the APOEε4 genotype.Journal of Psychiatric Research 04/2011; 45(9):1250-6. DOI:10.1016/j.jpsychires.2011.03.017 · 4.09 Impact Factor
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- "In particular, TFAM is located in the long arm of chromosome 10, which is the most frequently tested region for association in the field of AD (Bertram et al., 2007). Numerous studies have reported linkage between AD and chromosome 10q (Bertram et al., 2000; Myers et al., 2000; Blacker et al., 2003; Johansson et al., 2005). Thus, further experimental research is necessary to define the direct association between TFAM polymorphisms and the occurrence of AD. "
ABSTRACT: Chronic mitochondria DNA (mtDNA) damage and mitochondrial dysfunction induced by increased reactive oxygen species (ROS) have been proved to contribute to the development of Alzheimer's disease (AD). Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mtDNA integrity. Recently, some studies suggested two single nucleotide polymorphisms (SNPs) (rs1937 and rs2306604) in the TFAM gene are associated with sporadic late-onset AD (LOAD) in Caucasians. To explore the correlation between TFAM gene and LOAD, we performed a case-control study in a large Chinese cohort consisting of 394 patients and 390 healthy controls. The results showed that there were significant differences in genotype (P=0.03) and allele (P=0.04) frequencies of the SNP rs1937 between LOAD patients and controls. The minor C allele of rs1937 acted as a moderate protective factor of LOAD (P=0.04, odds ratios/OR=0.76). The logistic regression analysis also suggested an association of LOAD with SNP rs1937 (dominant model: P=0.03, OR=0.71; recessive model: P=0.02, OR=0.25; additive model: P=0.01, OR=0.68). No significant association was observed between rs2306604 and LOAD. Haplotype analysis identified the haplotype CC as a protective factor of LOAD (P=0.038, OR=0.76). This study provides the evidence that variations in TFAM are involved in the pathogenesis of sporadic LOAD in the Han Chinese population.Brain research 10/2010; 1368:355-60. DOI:10.1016/j.brainres.2010.10.074 · 2.83 Impact Factor