RESUMO
Using the simulated data set from Genetic Analysis Workshop 13, we explored the advantages of using longitudinal data in genetic analyses. The weighted average of the longitudinal data for each of seven quantitative phenotypes were computed and analyzed. Genome screen results were then compared for these longitudinal phenotypes and the results obtained using two cross-sectional designs: data collected near a single age (45 years) and data collected at a single time point. Significant linkage was obtained for nine regions (LOD scores ranging from 5.5 to 34.6) for six of the phenotypes. Using cross-sectional data, LOD scores were slightly lower for the same chromosomal regions, with two regions becoming nonsignificant and one additional region being identified. The magnitude of the LOD score was highly correlated with the heritability of each phenotype as well as the proportion of phenotypic variance due to that locus. There were no false-positive linkage results using the longitudinal data and three false-positive findings using the cross-sectional data. The three false positive results appear to be due to the kurtosis in the trait distribution, even after removing extreme outliers. Our analyses demonstrated that the use of simple longitudinal phenotypes was a powerful means to detect genes of major to moderate effect on trait variability. In only one instance was the power and heritability of the trait increased by using data from one examination. Power to detect linkage can be improved by identifying the most heritable phenotype, ensuring normality of the trait distribution and maximizing the information utilized through novel longitudinal designs for genetic analysis.
Assuntos
Doenças Cardiovasculares/genética , Mapeamento Cromossômico/estatística & dados numéricos , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 9/genética , Estudos de Coortes , Simulação por Computador/estatística & dados numéricos , Estudos Transversais , Feminino , Ordem dos Genes/genética , Ligação Genética/genética , Humanos , Escore Lod , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Característica Quantitativa HerdávelRESUMO
OBJECTIVE: To determine whether longitudinal changes in personality as measured by the Minnesota Multiphasic Personality Inventory (MMPI) can be detected among clinically presymptomatic individuals carrying the expanded Huntington disease (HD) allele. BACKGROUND: Emotional symptoms are considered one of the cardinal features of HD. However, the literature is replete with conflicting reports of psychiatric symptoms in presymptomatic HD gene carriers. METHODS: A longitudinal, case-control, double-blind study comparing presymptomatic gene carriers and nongene carriers at risk for HD evaluated with an abbreviated MMPI and a quantified neurologic rating scale examined an average of 3.7 years apart. RESULTS: Presymptomatic gene carriers (PSGC) had a greater increase in abnormality over time for the MMPI scales, cynical hostility (repeated-measures ANOVA, = 0.04) and irritability (repeated measures ANOVA, = 0.005), when compared with the nongene carriers (NGC). Among both the PSGCs and NGCs, no significant correlation was found between the number of CAG repeats and the change in MMPI score between visits. CONCLUSIONS: This study provides significant evidence for increasing irritability and cynical hostility in presymptomatic gene carriers before the onset of overt clinical symptoms.