ABSTRACT
Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples.
Subject(s)
Alzheimer Disease/genetics , Chromosomes, Human, Pair 10 , Polymorphism, Single Nucleotide , Age of Onset , Aged , Aged, 80 and over , Alzheimer Disease/epidemiology , Ankyrins/genetics , Case-Control Studies , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Female , Genetic Linkage , Genetic Predisposition to Disease , Genotype , Humans , Intercellular Signaling Peptides and Proteins/genetics , Male , Middle Aged , Mixed Function Oxygenases , Proto-Oncogene Proteins/genetics , alpha Catenin/geneticsABSTRACT
The neuropathology of Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles and the extracellular deposition of beta-amyloid (Abeta) in senile plaques. Abeta has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, although the pathological mechanism of Abeta remains largely unknown. Recent evidence suggests that the FISH adapter protein binds to, and potentially regulates, ADAM12 (a disintegrin and metalloprotease 12) to mediate a neurotoxic effect of Abeta. The ADAM12 gene lies on chromosome 10q26.3, and the gene encoding FISH, SH3MD1, lies within a region of linkage to late-onset AD (LOAD) on 10q25.1. This study investigates whether there is a relationship between variation in ADAM12 and SH3MD1 and susceptibility to LOAD in a sample of 1,051 AD cases and 1,269 matched controls. We observe significant interactions between variants in the two genes that may influence susceptibility to LOAD. The most significant statistical interaction is between rs3740473, a synonymous single nucleotide polymorphism (SNP) in SH3MD1 and rs11244787, an intronic SNP in ADAM12 (effect size = 2.1 for interaction term, P = 0.006).
Subject(s)
ADAM Proteins/genetics , Adaptor Proteins, Vesicular Transport/genetics , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Genetic Predisposition to Disease , Membrane Proteins/genetics , ADAM12 Protein , Age of Onset , Aged , Alleles , Case-Control Studies , Female , Heterozygote , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , United Kingdom/epidemiologyABSTRACT
Late-onset Alzheimer's disease (LOAD) is a common neurodegenerative disorder, with a complex etiology. APOE is the only confirmed susceptibility gene for LOAD. Others remain yet to be found. Evidence from linkage studies suggests that a gene (or genes) conferring susceptibility for LOAD resides on chromosome 10. We studied 23 positional/functional candidate genes from our linkage region on chromosome 10 (APBB1IP, ALOX5, AD037, SLC18A3, DKK1, ZWINT, ANK3, UBE2D1, CDC2, SIRT1, JDP1, NET7, SUPV3L1, NEN3, SAR1, SGPL1, SEC24C, CAMK2G, PP3CB, SNCG, CH25H, PLCE1, ANXV111) in the MRC genetic resource for LOAD. These candidates were screened for sequence polymorphisms in a sample of 14 LOAD subjects and detected polymorphisms tested for association with LOAD in a three-stage design involving two stages of genotyping pooled DNA samples followed by a third stage in which markers showing evidence for association in the first stages were subjected to individual genotyping. One hundred and twenty polymorphisms were identified and tested in stage 1 (4 case + 4 control pools totaling 366 case and 366 control individuals). Single nucleotide polymorphisms (SNPs) showing evidence of association with LOAD were then studied in stage 2 (8 case + 4 control pools totaling 1,001 case and 1,001 control individuals). Five SNPs, in four genes, showed evidence for association (P < 0.1) at stage 2 and were individually genotyped in the complete dataset, comprising 1,160 LOAD cases and 1,389 normal controls. Two SNPs in SGPL1 demonstrated marginal evidence of association, with uncorrected P values of 0.042 and 0.056, suggesting that variation in SGPL1 may confer susceptibility to LOAD.
