Mona Kaleem

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.

Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

Background: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Objective: To investigate the pathogenic basis of this association. Methods: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. Results: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case–control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least ∼56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. Conclusions: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson’s disease and other tauopathies, including Alzheimer’s 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.

Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease

Several studies have reported evidence for linkage of late‐onset Alzheimers disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ‐8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD. Ann Neurol 2005

Identification of a Novel Valosin-Containing Protein Polymorphism in Late-Onset Alzheimer’s Disease

Background/Aims: Recently, mutations in the valosin-containing protein gene (VCP) were found to be causative for a rare form of dementia [Watts GDJ, et al.: Nat Genet 2004;36:377–381]. This gene lies within a region on the genome that has been linked to late onset Alzheimer’s disease (LOAD) [Myers A, et al.: Am J Med Genet 2002;114:233–242]. In this study, we investigated whether variation within VCP could account for the LOAD linkage peak on chromosome 9. Methods: We sequenced 188 individuals from the set of sibling pairs we had used to obtain the linkage results for chromosome 9 to look for novel polymorphisms that could explain the linkage signal. Any variant that was found was then typed in 2 additional sets of neuropathologically confirmed samples to look for associations with Alzheimer’s disease. Results: We found 2 variants when we sequenced VCP. One was a novel rare variant (R92H) and the other is already reported within the publicly available databases (rs10972300). Neither explained the chromosome 9 linkage signal for LOAD. Conclusions: We have found a novel rare variant within the VCP gene, but we did not find a variant that could explain the linkage signal for LOAD on chromosome 9.

Visual characteristics of elderly night drivers in the Salisbury Eye Evaluation Driving Study.

PURPOSE To characterize visual factors among those who continue to drive and those who restrict night driving in the elderly population. METHODS The Salisbury Eye Evaluation Driving Study (SEEDS) is a study of vision, cognition, and driving behaviors of older drivers living in the greater Salisbury, Maryland, metropolitan area. Patients were recruited from listings in the Department of Motor Vehicle Administration. Data are reported from two visits conducted 2 years apart. Night driving was assessed using a real-time driving assessment tool, the Driving Monitor System. Night driving was defined by the presence of at least one episode of driving at night during a 5-day time period (seasonally adjusted). Participants also underwent a battery of cognitive and visual function testing including distance acuity, contrast sensitivity, and visual fields. Logistic regression was used to model factors associated with night driving. RESULTS Complete data were available for 990 of the 1080 participants (92%) attending both visits; 41% of participants were driving at night in each visit. Those who were younger (P < 0.001), male (P < 0.001), and had better measures of cognitive (P = 0.007) and visual function were observed driving at night, whereas those who were older, female, and had poorer measures of cognitive and visual function restricted their night driving behavior. An association was observed between depressive symptoms and less night driving in females (P = 0.003). In multivariate analysis, better contrast sensitivity (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.02-1.36, P = 0.02) and visual field detection (OR 1.21, 95% CI 1.00-1.47, P = 0.05) were associated with driving at night. Visual acuity was not found to be significantly related to night driving (OR 1.08, 95% CI 0.95-1.18, P = 0.12). CONCLUSIONS Restricting driving at night is a multifactorial behavior that has a vision component, notably poor contrast sensitivity, and some loss of visual fields.

Identification of the epitope of a monoclonal antibody to DJ-1.

Mutations in DJ-1 can cause early onset parkinsonism. Various antibodies have been generated to detect this protein, one of which is a commonly used monoclonal antibody (clone 3E8). Since results of in situ examinations of DJ-1 expression with this antibody have differed from analyses with species-specific antibodies (e.g. rat), it would be useful to know the epitope for this antibody. Using GFP-tagged deletion constructs of human DJ-1, we have localized the epitope region for this antibody to within residues 56-78 of human DJ-1. Mapping this region to the published three-dimensional structure of DJ-1 indicates that this is a solvent-accessible surface epitope. Immunonegativity of E64D mutant DJ-1 with the monoclonal antibody suggests that glutamate 64 of human DJ-1 contributes to the epitope recognized by this antibody. Moreover, the loss of immunoreactivity due to such a small substitution demonstrates the remarkable sensitivity of the monoclonal antibody 3E8 to DJ-1.

Referral to Low Vision Services for Glaucoma Patients: Referral Patterns and Characteristics of Those Who Refer

Purpose: To identify characteristics of ophthalmologists and practices who refer glaucoma patients to low vision services (LVS). Materials and Methods: An online survey was distributed to members of the American Glaucoma Society. The survey queried demographics of responders and their clinical practices, criteria and barriers to referral to LVS. Survey responders were categorized as high referrers if they reported referring >5 patients to LVS and low referrers if they referred ⩽5. &khgr;2 and Fischer exact tests were used to compare characteristics between high and low referrers. Logistic regression analyses were used to calculate odds ratios and 95% confidence intervals and determine factors associated with referrer status. Results: High referrers to LVS tended to have >10 patients per month who had already seen a low vision provider (53% vs. 10%, P<0.001), reported following the American Academy of Ophthalmology’s Preferred Practice Pattern (PPP) recommendations for LVS referrals (38% vs. 18%, P=0.011), and expressed satisfaction with their current referral practices (86% vs. 70%, P=0.049). In the fully adjusted model those who followed PPP were 2.5 times more likely to report being a high referrer as compared with a low referrer (95% confidence interval, 1.1-5.3). However, only 22% of ophthalmologists reported following these guidelines in their practice. The number of years in practice, practice location or type, volume of patients seen each week, and distance to a low vision clinic were not associated with referral. Conclusions: Familiarity with PPP guidelines may positively influence LVS referral practices.