Biomedical subjects

Marsha A Wilcox

Publications and source records attributed to Marsha A Wilcox.

12 recordsLinked to original sources

PubMed2006

Serum heat shock protein 70 level as a biomarker of exceptional longevity.

Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. In contrast, extracellular heat shock protein 70 (Hsp70) has been shown to have both protective and deleterious effects. In this study, we assessed heat shock protein 70 for its potential role in human longevity. Because of the importance of HSP to disease processes, cellular protection, and inflammation, we hypothesized that: (1) Hsp70 levels in centenarians and centenarian offspring are different from controls and (2) alleles in genes associated with Hsp70 explain these differences. In this cross-sectional study, we assessed serum Hsp70 levels from participants enrolled in either the New England Centenarian Study (NECS) or the Longevity Genes Project (LGP): 87 centenarians (from LGP), 93 centenarian offspring (from NECS), and 126 controls (43 from NECS, 83 from LGP). We also examined genotypic and allelic frequencies of polymorphisms in HSP70-A1A and HSP70-A1B in 347 centenarians (266 from the NECS, 81 from the LGP), 260 NECS centenarian offspring, and 238 controls (NECS: 53 spousal controls and 106 septuagenarian offspring controls; LGP: 79 spousal controls). The adjusted mean serum Hsp70 levels (ng/mL) for the NECS centenarian offspring, LGP centenarians, LGP spousal controls, and NECS controls were 1.05, 1.13, 3.07, 6.93, respectively, suggesting that a low serum Hsp70 level is associated with longevity; however, no genetic associations were found with two SNPs within two hsp70 genes.

Aged↗

PubMed2005

Multifactor-dimensionality reduction versus family-based association tests in detecting susceptibility loci in discordant sib-pair studies.

Complex diseases are generally thought to be under the influence of multiple, and possibly interacting, genes. Many association methods have been developed to identify susceptibility genes assuming a single-gene disease model, referred to as single-locus methods. Multilocus methods consider joint effects of multiple genes and environmental factors. One commonly used method for family-based association analysis is implemented in FBAT. The multifactor-dimensionality reduction method (MDR) is a multilocus method, which identifies multiple genetic loci associated with the occurrence of complex disease. Many studies of late onset complex diseases employ a discordant sib pairs design. We compared the FBAT and MDR in their ability to detect susceptibility loci using a discordant sib-pair dataset generated from the simulated data made available to participants in the Genetic Analysis Workshop 14. Using FBAT, we were able to identify the effect of one susceptibility locus. However, the finding was not statistically significant. We were not able to detect any of the interactions using this method. This is probably because the FBAT test is designed to find loci with major effects, not interactions. Using MDR, the best result we obtained identified two interactions. However, neither of these reached a level of statistical significance. This is mainly due to the heterogeneity of the disease trait and noise in the data.

Chromosome Mapping↗

PubMed2005

Whole-genome variance components linkage analysis using single-nucleotide polymorphisms versus microsatellites on quantitative traits of derived phenotypes from factor analysis of electroencephalogram waves.

Alcohol dependence is a serious public health problem. We studied data from families participating in the Collaborative Study on the Genetics of Alcoholism (COGA) and made available to participants in the Genetic Analysis Workshop 14 (GAW14) in order to search for genes predisposing to alcohol dependence. Using factor analysis, we identified four factors (F1, F2, F3, F4) related to the electroencephalogram traits. We conducted variance components linkage analysis with each of the factors. Our results using the Affymetrix single-nucleotide polymorphism dataset showed significant evidence for a novel linkage of F3 (factor comprised of the three midline channel EEG measures from the target case of the Visual Oddball experiment ttdt2, 3, 4) to chromosome 18 (LOD = 3.45). This finding was confirmed by analyses of the microsatellite data (LOD = 2.73) and Illumina SNP data (LOD = 3.30). We also demonstrated that, in a sample like the COGA data, a dense single-nucleotide polymorphism map provides better linkage signals than low-resolution microsatellite map with quantitative traits.

Chromosome Mapping↗

PubMed2005

Genome-wide linkage analysis for alcohol dependence: a comparison between single-nucleotide polymorphism and microsatellite marker assays.

Both theoretical and applied studies have proven that the utility of single nucleotide polymorphism (SNP) markers in linkage analysis is more powerful and cost-effective than current microsatellite marker assays. Here we performed a whole-genome scan on 115 White, non-Hispanic families segregating for alcohol dependence, using one 10.3-cM microsatellite marker set and two SNP data sets (0.33-cM, 0.78-cM spacing). Two definitions of alcohol dependence (ALDX1 and ALDX2) were used. Our multipoint nonparametric linkage analysis found alcoholism was nominal linked to 12 genomic regions. The linkage peaks obtained by using the microsatellite marker set and the two SNP sets had a high degree of correspondence in general, but the microsatellite marker set was insufficient to detect some nominal linkage peaks. The presence of linkage disequilibrium between markers did not significantly affect the results. Across the entire genome, SNP datasets had a much higher average linkage information content (0.33 cM: 0.93, 0.78 cM: 0.91) than did microsatellite marker set (0.57). The linkage peaks obtained through two SNP datasets were very similar with some minor differences. We conclude that genome-wide linkage analysis by using approximately 5,000 SNP markers evenly distributed across the human genome is sufficient and might be more powerful than current 10-cM microsatellite marker assays.

Alcoholism↗

PubMed2005

Comparison of single-nucleotide polymorphisms and microsatellite markers for linkage analysis in the COGA and simulated data sets for Genetic Analysis Workshop 14: Presentation Groups 1, 2, and 3.

The papers in presentation groups 1-3 of Genetic Analysis Workshop 14 (GAW14) compared microsatellite (MS) markers and single-nucleotide polymorphism (SNP) markers for a variety of factors, using multiple methods in both data sets provided to GAW participants. Group 1 focused on data provided from the Collaborative Study on the Genetics of Alcoholism (COGA). Group 2 focused on data simulated for the workshop. Group 3 contained analyses of both data sets. Issues examined included: information content, signal strength, localization of the signal, use of haplotype blocks, population structure, power, type I error, control of type I error, the effect of linkage disequilibrium, and computational challenges. There were several broad resulting observations. 1) Information content was higher for dense SNP marker panels than for MS panels, and dense SNP markers sets appeared to provide slightly higher linkage scores and slightly higher power to detect linkage than MS markers. 2) Dense SNP panels also gave higher type I errors, suggesting that increased test thresholds may be needed to maintain the correct error rate. 3) Dense SNP panels provided better trait localization, but only in the COGA data, in which the MS markers were relatively loosely spaced. 4) The strength of linkage signals did not vary with the density of SNP panels, once the marker density was approximately 1 SNP/cM. 5) Analyses with SNPs were computationally challenging, and identified areas where improvements in analysis tools will be necessary to make analysis practical for widespread use.

Alcoholism↗

PubMed2005

Cancer in the oldest old.

Our previous work revealed that 88% of centenarians delay or escape the age-related lethal diseases cardiac disease, stroke and diabetes. In the cases of those having a history of cancer we have observed anecdotes of centenarians presenting with large primary tumors that would have otherwise been expected to have metastasized and to have been lethal. However, these tumors were removed without consequence. To better understand the relationship between cancer and exceptional longevity, we quantified age of cancer diagnoses, life-time clinically evident cancer prevalence, tobacco use and family histories through medical record review and interviews. One thousand one hundred and forty-three subjects were studied revealing 20% (N=152) of female and 22% (N=80) of male centenarians with a history of non-skin cancer. The most common cancers were prostate (11.7% of males), breast (8.2% of females), and colon (5.7%). The average age of diagnosis was 80.5 years compared to 63.2 years in the general population according to National Cancer Institute SEER data. Similar delays were noted when age of onset was examined according to specific type of cancer. In conclusion, the age of diagnosis of cancer is relatively delayed in those who live to 100 years. Some cancers are very rare among these individuals suggesting that there are certain cancers that may be incompatible with survival to extreme old age.

Age Factors↗

PubMed2005

Psychiatric genetics: a survey of psychiatrists' knowledge, opinions, and practice patterns.

OBJECTIVE: Knowledge about the genetic basis of psychiatric illness is growing rapidly, and psychiatrists may be called upon to incorporate this information into clinical practice. The goal of this study was to assess psychiatrists' familiarity with and attitudes toward genetic information. METHOD: We surveyed 844 participants, the majority of whom were psychiatrists, attending a continuing medical education course in the fall of 2002 and measured knowledge, opinions, and current practice patterns in regard to psychiatric genetics. RESULTS: Responses were received from 352 psychiatrists (54% of those surveyed). Most psychiatrists correctly answered fewer than half of survey items assessing general and psychiatric genetic knowledge. While 83% considered it their role to discuss genetic information with patients and families, fewer than 25% felt prepared or competent to do so. In response to hypothetical questions regarding genetic testing, a substantial proportion of psychiatrists indicated willingness to use such tests for diagnostic clarification, as well as presymptomatic and even prenatal risk prediction. The majority of respondents expressed interest in further genetics education. CONCLUSIONS: Our results suggest that psychiatrists view genetic information as clinically relevant, but have limitations in knowledge that may impact the incorporation of psychiatric genetics into clinical practice.

Attitude of Health Personnel↗

PubMed2004

Cardiovascular disease delay in centenarian offspring.

BACKGROUND: Previously, the authors have shown that an important component of the ability to survive to exceptionally old age is family health history. This study assessed the age at onset of age-related diseases in centenarian offspring. METHODS: The health histories of 177 offspring of centenarians enrolled in the nationwide New England Centenarian Study, and 166 controls were assessed from 1997 to 2000. Controls were the offspring of parents born in the same years as the centenarians but at least one of whom died at average life expectancy. Ages at onset of heart disease, hypertension, diabetes, cancer, osteoporosis, cataracts, glaucoma, macular degeneration, depression, thyroid disease, and stroke were compared in the two groups. RESULTS: The median ages of onset for coronary heart disease (p <.001), hypertension (p <.001), diabetes (p =.002), and stroke (p =.017) were significantly delayed in the centenarian offspring by 5.0, 2.0, 8.5, and 8.5 years, respectively, compared with the age-matched controls. Adjusted hazard ratios were 0.388 (p =.0004), 0.39 (p <.0001), 0.302 (p =.008), and 0.328 (p =.06). No differences were found in the ages of onset for the other diseases investigated. CONCLUSIONS: The offspring of centenarians show a marked delay in the age of onset for cardiovascular disease, diabetes, hypertension, and stroke but not for other age-related diseases such as cancer, osteoporosis, and thyroid disease. These results suggest that the children of centenarians may be following in their parents' footsteps, markedly delaying the onset of lethal diseases that commonly affect older persons.

Aged↗

PubMed2004

Lower all-cause, cardiovascular, and cancer mortality in centenarians' offspring.

OBJECTIVES: To assess the cause of death for centenarians' offspring and controls. DESIGN: Cross-sectional study. SETTING: Community-based, nationwide sample. PARTICIPANTS: Family pedigree information was collected on 295 offspring of centenarians (from 106 families with a parent already enrolled in the nationwide New England Centenarian Study) and on 276 controls (from 82 control families) from 1997 to 2000. Controls were individuals whose parents were born in the same year as the centenarians but at least one of whom died at the average life expectancy. MEASUREMENTS: Age at death and cause of death. RESULTS: Centenarians' offspring had a 62% lower risk of all-cause mortality (P<.001), a 71% lower risk of cancer-specific mortality (P=.002), and an 85% lower risk of coronary heart disease-specific mortality (P<.001). Significant differences were not found for other causes of death. However of those who died centenarian offsprings dead at a significantly younger age than controls. CONCLUSION: These findings suggest that centenarians' offspring have lower all-cause mortality rates and cause-specific mortality rates for cancer and coronary heart disease. These results suggest that mechanisms for survival to exceptional old age may go beyond the avoidance or delay of cardiovascular disease and also include the avoidance or delay of cancer. Moreover survival advantage of centenarian offsprings may not be due to factors related to childhood mortality. Ultimately, survival to exceptional old age may involve lower susceptibility to a broad range of age-related diseases, perhaps secondary to inhibition of basic mechanisms of aging.

Adult↗

PubMed2003

Empirically derived phenotypic subgroups - qualitative and quantitative trait analyses.

BACKGROUND: The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits. METHODS: Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis. RESULTS: We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 x 10(-6)) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23). CONCLUSION: This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.

Adult Children↗

PubMed2003

Genetic analysis of phenotypes derived from longitudinal data: Presentation Group 1 of Genetic Analysis Workshop 13.

The participants of Presentation Group 1 used the GAW13 data to derive new phenotypes, which were then analyzed for linkage and, in one case, for association to the genetic markers. Since the trait measurements ranged over longer time periods, the participants looked at the time dependence of particular traits in addition to the trait itself. The phenotypes analyzed with the Framingham data can be roughly divided into 1) body weight-related traits, which also include a type 2 diabetes progression trait, and 2) traits related to systolic blood pressure. Both trait classes are associated with metabolic syndrome. For traits related to body weight, linkage was consistently identified by at least two participating groups to genetic regions on chromosomes 4, 8, 11, and 18. For systolic blood pressure, or its derivatives, at least two groups obtained linkage for regions on chromosomes 4, 6, 8, 11, 14, 16, and 19. Five of the 13 participating groups focused on the simulated data. Due to the rather sparse grid of microsatellite markers, an association analysis for several traits was not successful. Linkage analysis of hypertension and body mass index using LODs and heterogeneity LODs (HLODs) had low power. For the glucose phenotype, a combination of random coefficient regression models and variance component linkage analysis turned out to be strikingly powerful in the identification of a trait locus simulated on chromosome 5. Haseman-Elston regression methods, applied to the same phenotype, had low power, but the above-mentioned chromosome 5 locus was not included in this analysis.

Cardiovascular Diseases↗

PubMed2002

Genome scan of three quantitative traits in schizophrenia pedigrees.

BACKGROUND: Twin and adoption studies have consistently implicated genes in the etiology of schizophrenia. Molecular genetic studies have found some consistent support for linkage to many regions of the genome. Despite these encouraging results, none of these findings have achieved genome-wide levels of statistical significance, and none have been consistently replicated. METHODS: This report is a follow-up of a genome scan that analyzed linkage to the diagnosis of schizophrenia in a series of sibling pairs in the National Institute of Mental Health Genetics Initiative for Schizophrenia data. In this report, we use the same sample to assess linkage to three quantitative traits developed from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms: positive, negative, and disorganized symptoms. RESULTS: We show suggestive linkage to chromosomes 6, 9, and 20 for the disorganized trait and to chromosome 12 for the negative trait. We also show weak association with PAH (phenylalanine hydroxylase) on that chromosome. CONCLUSIONS: The findings on chromosome 6 replicate some prior findings, the other loci are novel. A larger sample would provide more power to detect both linkage and association for this complex disorder.

Alleles↗