Pattern Of Familial Correlations Research Articles

Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder which displays considerable inter- and intra-familial variability in phenotypic expression. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including five quantitative traits (number of café-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous and plexiform neurofibromas) and seven binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the five quantitative traits ranged from 0.26 to 0.62. Moreover, we investigated for the first time the role of the normal NF1 allele in the variable expression of NF1 through a family-based association study. Nine tag SNPs in NF1 were genotyped in 1132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. Taken together, our results provided evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease.

Statistical designs for familial aggregation.

In the past two decades, it has become increasingly clear that genetic factors contribute to the aetiology of many common diseases including cancers, coronary disease, allergy and psychiatric disorders. While one goal of genetic epidemiological studies is to locate susceptibility genes for these complex diseases, it is important that strong evidence of familial aggregation be established at an early stage of research. In this paper, we discuss several study designs useful to address some issues such as (1) detecting familial aggregation, (2) testing for gene-environment interaction, (3) identifying homogeneous subgroups and (4) measuring magnitude and patterns of familial correlations. These designs include the conventional case-control design and the family case-control design. For each of these two study designs, we discuss analytical strategies as well as their strengths and weaknesses. Throughout, several examples from real studies are used for illustrative purposes.

Familial resemblance for physique: heritabilities for somatotype components

Primary objective: To examine familial resemblance in the Heath-Carter anthropometric somatotype in a sample of 328 participants from 103 nuclear families in Northern Ontario (Canada). Methods and procedures: The three somatotype components (endomorphy, mesomorphy, ectomorphy) were subjected to principal components analysis and the resulting first principal component (PC1) was used as an additional index of physique. The four phenotypes were adjusted for age, sex and generation effects, while each of the three somatotype components was further adjusted for the effects of the other two components using regression procedures. A familial correlation model was fit to the data and used to estimate the degree of familial resemblance in somatotype. Main outcome and results: For all somatotype variables, the most parsimonious model was one in which there was no spouse resemblance and no sex or generation effects in the familial correlations. Maximal heritabilities were 56%, 68%, 56% and 64% for endomorphy, mesomorphy, ectomorphy and PC1, respectively, indicating significant familial resemblance for the Heath-Carter anthropometric somatotype. Further, the pattern of familial correlations suggests the role of genetic factors in explaining variation in human physique. Conclusions: In general, a pattern of no spouse but significant parent-child correlations implicates the role of genes on human physique, provided that mating is random with regard to these traits.

Psychometric detection of schizotypy: Perceptual aberration and physical anhedonia in relatives of schizophrenics.

We administered scales of Perceptual Aberration (PERAB) and Physical Anhedonia (PHYSAN), traits that may be related to risk for schizophrenia, to 54 schizophrenics, 146 of their first-degree relatives (evaluated for schizophrenia-related disorders), and 178 normal subjects (screened for psychotic disorders in them or their relatives). For both scales, there was a significant effect of group membership. For the PERAB scale, the schizophrenics had higher scores than the normal subjects, who had higher scores than the relatives. For the PHYSAN scale, schizophrenics had higher scores than their relatives, who had higher scores than the normal subjects. Patterns of familial correlations also suggested that physical anhedonia, but not perceptual aberration, may be familial among schizophrenics and their relatives. The PHYSAN scale, but not the PERAB one, may be a useful indicator of liability for schizophrenia among the relatives of affected probands.

Sex-Linked Determinants for IgM?

Evidence for a sex-linked determinant of immunoglobulin M levels was sought using correlational and commingling analyses in a sample of 174 randomly selected nuclear families. While mean IgM levels in females were approximately 25% higher than that in males, the pattern of familial correlations did not follow the expectations under a sex-linked model, and there was no commingling in the distribution of IgM levels as expected when a trait is under the influence of a major gene.