Age‐of‐onset heterogeneity in Huntington disease families

Abstract

Ten Huntington disease (HD) families are analyzed using maximum likelihood methods to study age-of-onset (AO) heterogeneity. Both age of onset and age at examination are used in calculating an individual's likelihood of being affected; familial correlations and family structure are not included in the model. The model allows for differences in current age distributions by considering the distribution of age of onset conditional on age at examination. Families are grouped according to family type (ie, juvenile-onset families and adult-onset families) and then analyzed within each family type as well as between the two types, using both a chi-square test for heterogeneity and F-ratios. The results of the chi-square analyses indicate heterogeneity in AO among the individual families as well as between the two family types. However, the results of the F-ratios show no significant difference between the two family types, indicating that the difference in the chi-square analysis between the two family types is mostly owing to variation among the families. Thus, the results demonstrate that the existing variation in age of onset between these two family types is dwarfed by the magnitude of the variation among the families within each type. This implies that families of sufficient size should be evaluated individually for age-of-onset data for the purpose of either genetic counseling or linkage studies.

Genetic Dissection of Complex Traits

“…Late-onset Alzheimer's disease provides an excellent example. Initial linkage studies found weak evidence of linkage to chromosome 19q, but they were dismissed by many observers because the lod score (logarithm of the likelihood ratio for linkage) remained relatively low, and it was difficult to pinpoint the linkage with any precision (25). The confusion was finally resolved with the discovery that the apolipoprotein E type 4 allele appears to be the major causative factor on chromosome 19.…”

Familial alzheimer's disease in american descendants of the volga germans: Probable genetic founder effect

“…In human genetics this is known as the fozlnder effect. The large number of affected siblings in generation IV (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) of the R family could be explained through the chance occurrence of autosomal dominant inheritance. Also, if the gene for AD is common in the general population (or in the extended Volga German population), it is possible that the wife of family member 111-1 also carried the gene for AD and increased the probability that the children of that mating would be affected.…”

A review of the 'Statistical Analysis for Genetic Epidemiology' (SAGE) software package

“…• AGEON fits an age-of-onset distribution [25] to sibship data comprising both affected and unaffected sibs, allowing for covariates that can influence the mean, variance or skewness of the onset distribution. It then calculates two new traits that can be used to achieve more power in Haseman-Elston regression linkage analysis: disease susceptibility allowing for age [26] and a measure of age of onset [27].…”