Leslie Bryden

GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimers disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimers neuropathology.

A survey of genetic human cortical gene expression

It is widely assumed that genetic differences in gene expression underpin much of the difference among individuals and many of the quantitative traits of interest to geneticists. Despite this, there has been little work on genetic variability in human gene expression and almost none in the human brain, because tools for assessing this genetic variability have not been available. Now, with whole-genome SNP genotyping arrays and whole-transcriptome expression arrays, such experiments have become feasible. We have carried out whole-genome genotyping and expression analysis on a series of 193 neuropathologically normal human brain samples using the Affymetrix GeneChip Human Mapping 500K Array Set and Illumina HumanRefseq-8 Expression BeadChip platforms. Here we present data showing that 58% of the transcriptome is cortically expressed in at least 5% of our samples and that of these cortically expressed transcripts, 21% have expression profiles that correlate with their genotype. These genetic-expression effects should be useful in determining the underlying biology of associations with common diseases of the human brain and in guiding the analysis of the genomic regions involved in the control of normal gene expression.

Genetic Control of Human Brain Transcript Expression in Alzheimer Disease

We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

Sorl1 as an Alzheimer’s Disease Predisposition Gene?

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) Ε4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval.

Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimers disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin‐degrading enzyme (IDE), a protease involved in the catabolism of Aβ. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three “tagging” SNPs identified in an earlier study. We used four case‐control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P‐value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over‐represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.

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

(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.