An Evaluation of the Validity of Complex Segregation Analysis in Identifying an Individual's Genotype At a Major Locus.

The purpose of this study was to evaluate the effects of four factors on the validity of complex segregation analysis in identifying an individual's most probable genotype at a major locus of a quantitative trait. A computer simulation was performed to evaluate the effects of the following on validity: (1) pedigree size and configuration, (2) the distance between the genotypic specific means, t (as measured in units of st and ard deviations among individuals with the same major locus genotypes), (3) the frequency of the mutant allele (q) and (4) the polygenic heritability (h('2)). An analysis of cholesterol levels in a sample of 111 pedigrees (2535 individuals) collected in Muscatine, Iowa provided estimates of the parameters of the mixed genetic model used in one of the 5 simulations performed. Following the evaluation of the validity of complex segregation analysis, the assignment of genotypes to individuals in the 111 pedigrees was used to illustrate an application of this strategy. The phenotypes of individuals in at least two generations were required to achieve valid assignment of genotypes (sensitivity and specificity simultaneously above 0.90). The addition of the phenotypes of the gr and parents and /or the aunts, uncles and /or cousins of the index case to a 5 member nuclear family was associated with a statistically significant, but relatively small increase in validity. The value of t had a strong effect on validity. The validity was low when t was equal to 2.0 and high when t was equal to 3.087. The frequency of the mutant allele (values equal to 0.000137, 0.005 and 0.05 were considered) and the polygenic heritability (values equal to 0.417 and 0.750 were considered) had little effect on the validity of the strategy under the conditions simulated here. This study demonstrated that complex segregation analysis is a valid strategy for assigning genotypes at a major locus when data are available for individuals in 2 generations and t is equal to 3.087. When it is possible to identify an individual's genotype at a major locus, it then becomes possible to evaluate the role of genotype in the prediction of disease risk.PhDGeneticsUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160706/1/8520958.pd