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O2–02–02: The H1c risk haplotype of the MAPT gene is over–expressed in human temporal cortex relative to the other common alleles of MAPT
Author(s) -
Myers Amanda J.,
Pittman Alan M.,
Rohrer Kristen,
Zhao Alice,
Leung Doris,
Bryden Leslie,
Kaleem Mona,
Marlowe Lauren,
Chung Fung Hon,
Lees Andrew,
Morris Chris M.,
Silva Rohan,
Hardy John A.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.112
Subject(s) - haplotype , genetics , biology , rna splicing , allele , linkage disequilibrium , tau protein , exon , alternative splicing , gene , alzheimer's disease , disease , rna , medicine
(AD) has highlighted the amyloid hypothesis as a working model for AD causation. The common late-onset form of AD has complex inheritance and thus far the only robust genetic association remains that with APOE. Objectives: As the genes causing early onset AD, APP, PSEN1 and PSEN2, encode proteins that are in pathways modulating the metabolism of APP and beta amyloid, we sought to explore their interrelationships using gene-gene linkage interaction and analysis of the correlation of their expression in brain. In addition, we examined other genes encoding proteins known to be involved in the synthesis or degradation of beta amyloid. Methods: Linkage analyses were carried out on 451 sibling pairs affected with late onset AD. Gene-gene interactions were tested by including the ibd sharing at the second locus as a covariate. Expression correlations were calculated on Affymetrix microarray data generated from around 70 cortical, cerebellum and striatal samples in our own laboratory (GEO accession GSE3790) and available AD hippocampal data (GEO accession GSE1297). Results: The strongest correlation in expression was between PSEN1 and BACE1 which were significantly positively correlated in the cortical (r 0.836, p 10-7) and hippocampal AD datasets (r 0.914, p 10-7) and also significantly correlated in many other samples. We also detected significant positive correlations between BACE1 and APP, APH1A and APP, ECE1 and APP, ECE2 and APP and ECE1 and ECE2. Significant linkage interactions were observed between the following pairs of loci: BACE1/PSEN1 (p 0.002), BACE1/APP (p 0.02), ECE2/APP (p 0.005), ECE2/IDE (p 0.012) and APH1B/PSEN2 (p 0.016). Conclusions: These strong correlations could arise simply through expression of genes in the same cell type. However, the results may indicate that increased levels of APP are correlated with increased levels of components of the major gamma and beta secretase enzymes and that APP itself might be responsible for inducing their expression. The fact that several pairs of genes show correlations both in expression and linkage indicate that interactions between them may play an important role in the susceptibility to AD, thereby informing the direction of future genetic studies.