[Show abstract][Hide abstract] ABSTRACT: We previously reported strong genetic linkage on chromosome 14q to Alzheimer's disease (AD) using the presence of co-morbid hallucinations as a covariate. Those results suggested the presence of a gene increasing the risk for a genetically homogeneous form of AD characterized by the absence of comorbid hallucinations. Here we report our follow up of that study through the analysis of single nucleotide polymorphisms (SNPs) in five functional candidate genes. This work provides significant evidence of association for the gene coding for neuroglobin (NGB), a nervous system globin known to protect cells against amyloid toxicity and to attenuate the AD phenotype of transgenic mice. On further experiments we found that NGB expression is reduced with increasing age and lower in women consistent with their increased risk. NGB expression is up-regulated in the temporal lobe of AD patients consistent with a response to the disease process, as reported for NGB and hypoxia. We speculate that a compromised response due to DNA variation might increase the risk for AD. Our and others' data strongly support the involvement of NGB in AD.
Neurobiology of aging 12/2008; 31(11):1835-42. DOI:10.1016/j.neurobiolaging.2008.10.003 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor II) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele. We found previously that LOI of IGF2 occurs in approximately half of all Wilms tumors (i.e., those arising from lineage-committed nephrogenic progenitor cells). We investigated whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. We stratified 59 Wilms tumor samples by IGF2 LOI status by use of hot-stop reverse transcription-polymerase chain reaction and/or methylation analysis of the differentially methylated region of the H19 gene and identified 31 samples with and 28 without LOI. We used quantitative allele-specific expression analysis to determine whether six other imprinted genes (i.e., H19, KCNQ1, LIT1, TSSC5, GRB10, and MEG3) had subtle LOI. No statistically significant difference in allele-specific expression between Wilms tumor with or without LOI was found for LIT1, TSSC5, GRB10, and MEG3. For the KCNQ1 gene there was a slight difference between the groups with (37.0%, 95% confidence interval [CI] = 31.8% to 42.2%) and without (27.7%, 95% CI = 21.8% to 33.5%) LOI (P = .02 for F test of group differences in a mixed-effects model). For H19, we also found a slight difference between the groups with (7.5%, 95% CI = 2.4% to 12.7%) and without (2.2%, 95% CI = -3.2% to 7.6%) LOI of IGF2 (P = .15 for F test). In 27 tumor samples, we also used a microarray technique to analyze methylation of 378 genes, 38 of which were suspected or confirmed imprinted genes. We found that statistically significant alterations in only the differentially methylated region of the H19 gene were associated with LOI of IGF2. Thus, epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2.
Journal of the National Cancer Institute 09/2007; 99(16):1270-3. DOI:10.1093/jnci/djm069 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical signs and symptoms in a sample of 1,043 individuals with schizophrenia or schizoaffective disorder were subjected to latent class factor analysis. Positive, negative, disorganized, and affective factors were similar in content to factors described in a number of other studies, while a fifth factor representing early onset/developmental signs provided a new area for investigation. The five sets of factor scores were logistically regressed on psychiatric illness indicators in first and second degree relatives. Relatives of probands with higher positive or negative symptom factor scores had a lower risk of depressive illness. Higher affective factor scores in probands predicted more mania and depression in relatives. Both the disorganized and the early onset/developmental factors were related to increased risk of psychiatric hospitalization in relatives, as well as increased risk of psychosis (marginally so for the disorganization factor). Increased early onset/developmental signs in the proband were also associated with increased risk for depression in relatives. These findings suggest a possible endophenotypic role for the factor scores in future studies.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.
Human Molecular Genetics 01/2003; 12(1):23-32. DOI:10.1093/hmg/12.1.23 · 6.39 Impact Factor