Abstract

The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z < 0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE ε4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.

Links

Publisher Full Text

Authors

Hamilton G, Harris SE, Davies G, Liewald DC, Tenesa A, Payton A, Horan MA, Ollier WE, Pendleton N, Genetic and Environmental Risk for Alzheimer's Disease (GERAD1) Consortium, Starr JM, Porteous D, Deary IJ

Institution

Medical Genetics, Molecular Medicine Centre, University of Edinburgh, Edinburgh, UK. g.hamilton@ed.ac.uk

Source

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 159B:6 2012 Sep pg 696-709

MeSH

Aged
Aging
Alzheimer Disease
Amyloid beta-Peptides
Aspartic Acid Endopeptidases
Cognition
Cohort Studies
Female
Genetic Predisposition to Disease
Humans
Male
Meta-Analysis as Topic
Metalloendopeptidases
Middle Aged
Neuropsychological Tests
Phenotype
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Proteolysis
Risk Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22693153