ABSTRACT
Two recent case-control studies have suggested a strong association of a missense polymorphism in exon 2 of the cathepsin D gene (CTSD) and Alzheimer disease (AD). However, these findings were not confirmed in another independent study. We analyzed this polymorphism in two large and independent AD study populations and did not detect an association between CTSD and AD. The first sample was family-based and included 436 subjects from 134 sibships discordant for AD that were analyzed using the sibship disequilibrium test (SDT, p = 0.68) and the sib transmission/disequilibrium test (Sib-TDT, p = 0.81). The second sample of 200 AD cases and 182 cognitively normal controls also failed to show significant differences in the allele or genotype distribution in cases versus controls (chi2, p = 0.91 and p = 0.88, respectively). In addition, two-point linkage analyses in an enlarged family sample (n = 670) did not show evidence for linkage of the chromosomal region around CTSD. Thus, our analyses on more than 800 subjects suggest that if an association between the CTSD exon 2 polymorphism and AD exists, it is likely to be smaller than previously reported.
Subject(s)
Alzheimer Disease/genetics , Cathepsin D/genetics , Genetic Linkage/genetics , Polymorphism, Genetic/genetics , Aged , Case-Control Studies , Exons/genetics , Genotype , HumansABSTRACT
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.
Subject(s)
Alzheimer Disease/genetics , Chromosomes, Human, Pair 10/genetics , Genetic Linkage , Insulysin/genetics , Age of Onset , Aged , Aged, 80 and over , Alleles , Apolipoproteins E/genetics , Chromosome Mapping , Genetic Markers , Humans , Linkage Disequilibrium , Middle AgedABSTRACT
Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date, a large number of candidate genes have been associated with the disease, however none of these findings has been consistently replicated in independent datasets. In this study we report the results of family-based analyses for polymorphisms of five such candidates on chromosomes 2 (interleukin-1beta, IL-1B), 3 (butyrylcholinesterase, BCHE), 11 (cathepsin D, CTSD; Fe65, APBB1) and 12 (lipoprotein receptor-related protein-1, LRP1) that were all suggested to be associated with AD in recent case-control studies. To minimize the possibility of spurious findings due to population admixture, we used a family-based design applying the sibship disequilibrium test (SDT) as well as two-point parametric linkage analyses on families from the National Institute of Mental Health (NIMH) Genetics Initiative. Contrary to the initial reports, none of the polymorphisms that were analyzed showed evidence for association or linkage with AD in our families. Our results suggest that the previously reported associations from case-control studies are either (a) false positive results, e.g. due to type I error or population admixture, (b) smaller than initially proposed, or (c) due to linkage disequilibrium with an as yet unidentified polymorphism nearby.
