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Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position -656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A(-656) allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations.

Typical, later-onset forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci, combinations of which contribute to the development of this disorder. We previously reported the results of a systematic survey of the human genome for the identification of highly informative DNA polymorphisms (SSTRPs) that target new AD risk genes. In addition to the APOE locus, our survey detected five new candidate susceptibility loci for AD, including D10S1423. An association of the D10S1423 234-bp allele with AD has been reported in three independent samples of AD cases and controls (Boston, Pittsburgh, Bonn). Data from our case-control studies suggest a strong synergistic interaction between the D10S1423 234-bp and APOE E4 risk alleles (234-bp carrier: OR = 2.5, 95% CI = 1.4--4.5; E4 carrier: OR = 8.3, 95% CI = 4.3--15.8; both alleles: OR = 23.1, 95% CI = 5.3--99.5). This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele, the APOE E4 allele, or both, after 11.5 years of systematic follow-up. A total of 18 incident cases of AD were detected during the first 3379 subject-years of this longitudinal study. The effects of carrying either or both of the D10S1423 234-bp and APOE E4 alleles on the age-specific risk of developing AD were determined using Kaplan-Meier survival analysis. The age-specific risk of developing AD was the greatest for individuals who carried both alleles (Mantel--Cox statistic = 20.12, df = 3, P = 0.0002; Breslow statistic = 13.36, df = 3, P = 0.004). Cox proportional hazards models were developed to estimate the risk ratios for each genotype, controlling for the potential effects of age at recruitment, sex, and years of education. In the resulting best fitting model, only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 16.2, P = 0.008, 95% CI = 2.1--128.3). After controlling for these genotypes, female gender was also significantly associated with increased risk of developing AD (risk ratio = 5.1, P = 0.02, 95% CI = 1.2--21.1). Neither age at recruitment nor years of education made significant contributions to the model.

Background: In a previous genome survey, we detected associations of alleles at six microsatellite loci with typical-onset AD, including the 234bp allele of the D10S1423 locus. The goal of the current study was to explore the clinical, neuropathological, and neurochemical correlates of the D10S1423 234bp allele in a group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacked other brain diseases., Methods: Clinical assessments were performed as part of a longitudinal study of AD and related disorders. Autopsies were performed using standardized methods and diagnoses were made according to established criteria. Genotyping, morphometry, and neurochemical analyses were performed using postmortem brain tissue., Results: Patients with AD who carried the D10S1423 234bp allele manifested substantial reductions in dopamine levels in all six cortical regions examined. In contrast, carriers tended to have higher concentrations of cortical norepinephrine and revealed a dosage effect of the D10S1423 234bp allele., Conclusions: These findings support the results of our genome survey and suggest that a novel susceptibility gene for AD resides near the D10S1423 locus. The characterization of biologically meaningful subtypes, including genotypic subtypes with particular neurobiological derangements, may be important for the advancement of experimental therapeutics in AD.

Species of Colletotrichum use diverse strategies for invading host tissue, ranging from intracellular hemibiotrophy to subcuticular intramural necrotrophy. In addition, these pathogens develop a series of specialized infection structures, including germ tubes, appressoria, intracellular hyphae, and secondary necrotrophic hyphae. Colletotrichum species provide excellent models for studying the molecular basis of infection structure differentiation and fungal-plant interactions. In this review we cover the various stages of the infection processes of Colletotrichum species, including spore adhesion and germination, germ tube and appressorium differentiation and functions, and biotrophic and necrotrophic development. The contribution of molecular, biochemical, and immunological approaches to the identification of genes and proteins relevant to each stage of fungal development will be considered. As well as reviewing results from several groups, we also describe our own work on the hemibiotrophic pathogen, C. lindemuthianum., (Copyright 1999 Academic Press.)

Objective: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease and its relationship to the APOE epsilon4 genotype., Method: This report describes the results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease., Results: Nine incident cases of Alzheimer's disease were detected during the first 2,220 subject-years of the follow-up period. Age, increased platelet membrane fluidity, and the APOE epsilon4 allele made significant independent contributions to the risk of developing Alzheimer's disease, while sex and years of education did not. Increased platelet membrane fluidity was associated with incident Alzheimer's disease cases between the ages of 64 and 71, while the epsilon4 allele was associated with incident Alzheimer's disease cases from age 64 until at least age 80., Conclusions: These results indicate that increased platelet membrane fluidity is not produced by the APOE epsilon4 allele. Instead, increased platelet membrane fluidity and the epsilon4 allele appear to make significant independent contributions to the risk of developing Alzheimer's disease among the first-degree relatives of patients with this disorder. Moreover, the age ranges over which these risk factors operate appear to be different.

We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target new risk genes for Alzheimer disease (AD) by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from autopsy-confirmed cases with AD and matched controls. Allelic associations with AD were observed for 6 of the 391 SSTRPs in the CHLC Human Screening Set/Weber Version 6 (Research Genetics, Inc., Huntsville, AL): D1S518, D1S547, D10S1423, D12S1045, D19S178, and DXS1047. These allelic associations were replicated in an independent sample of autopsied AD cases and controls recruited from a geographically disparate site. The association of the large D19S178 alleles with AD appeared to arise from linkage disequilibrium with the APOE epsilon 4 allele, whose effect on increasing the risk of AD has been established. None of the remaining SSTRPs was in close proximity to loci previously reported to influence the risk of developing AD. Instead, they may identify five novel AD susceptibility loci.

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45 +/- S.E. 0.06) than controls (0.22 +/- S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29 +/- S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

We have conducted a population-based association study of substance abuse and a microsatellite at the dopamine D5 receptor locus (DRD5) in a sample of European-American males and females with substance dependence (SA) or without any psychiatric disorder. Overrepresentation of the most frequent allele (148 bp) was found in males in the SA group (OR = 2.2, P = .02); this finding was reproduced in females (OR = 5.4, p < .001). The difference in the frequencies of this allele between SA males and SA females was statistically significant. The genotype coded in accordance with the dose of this allele correlated with substance abuse liability in males and females (stronger in females) and with novelty seeking in females. There was no evidence of correlation between the genotypes of spouses that could be induced by assortative mating for the liability to substance abuse. The data suggest that the DRD5 locus is involved in the variation and sex dimorphism of substance abuse liability.

Consistent with previous reports, we observed a significant association of the APOE epsilon 4 allele with Alzheimer's Disease (AD) in a series of 91 autopsy-confirmed cases. The epsilon 4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 +/- 0.07), although the epsilon 4 allele frequency in the AD cases with a negative family history (0.38 +/- 0.05) remained significantly greater than that for the non-AD control group (0.13 +/- 0.03). A similar increase in epsilon 4 allele frequency (0.54 +/- 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.36 +/- 0.04). Contrary to previous reports, no effect of the dosage of the epsilon 4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of epsilon 4 and atherosclerosis, the epsilon 4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of epsilon 4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the epsilon 4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an epsilon 4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the epsilon 4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE epsilon 4 allele.

Three missense mutations in exon 17 of the beta-amyloid precursor protein (APP) gene have been reported to cosegregate in families with early onset Alzheimer's disease (AD). All three mutations result in amino acid substitutions at codon 717 and may produce AD by altering the structure of the transmembrane domain of APP. Alternatively, the mutations may destabilize the stem of a putative iron-responsive element (IRE) in which they lie and confer pathogenicity by inactivating this negative regulatory element. We have detected a clinically-silent mutation in codon 716 that would also be expected to disrupt the putative IRE but results in no amino acid substitution. This result strongly suggests that the missense mutations at codon 717 produce AD by altering the amino acid sequence of APP rather than the IRE. Furthermore, the identification of a clinically-silent mutation among four point mutations that span only three nucleotides of exon 17 suggests that this region may be a mutational "hot" spot.

The genetic basis of various subtypes of the affective disorders has been investigated by family, twin, and adoption studies, as well as by segregation and linkage analysis. Linkage analyses of bipolar disorder with the chromosome 11p15 DNA markers HRAS1 and INS, and the chromosome Xq28 markers for color blindness and G6PD have been reported. We have used restriction fragment length polymorphisms as markers to examine linkage in three extended families with unipolar affective illness, ascertained through probands with either recurrent unipolar or bipolar II illness. Using an inclusive definition of the affected phenotype, linkage could be excluded up to 28cM around the HRAS1-INS linkage group on chromosome 11p15, and up to 5 cM around the DNA marker DXS52 on Xq28. Negative linkage results were also obtained for two more restrictive definitions of affective illness. Thus, we find no evidence for the involvement of the chromosomal regions 11p15 and Xq28 with unipolar affective disorder in these three families.