Detection of rare major genes in lipid levels.

A statistical test of polygenic inheritance (TPI) against the alternative of a rare major gene is presented. It is designed for a random sample of quantitative observations on index cases and siblings of those index cases (probands) selected on the basis of the observed measurements of these probands. The test focuses on an increase of the variance of siblings of probands over its value under polygenic inheritance, such an increase being expected in the presence of a major gene producing a shift of the quantitative observations. Certain data on lipids are then analyzed by this test. A major gene can tentatively be confirmed for triglycerides but not for cholesterol. In addition, the values of all index cases are subjected to an analysis of a mixture of normal distributions (NOCOMP computer program), resulting in a significant second component for triglycerides but not for cholesterol. For both TPI and NOCOMP, the exponent in a power transformation is estimated by maximum likelihood simultaneously with all other parameters, so that these analysis methods are robust against a wide range of skewness in the data, which is demonstrated by manipulation of the observations and their reanalysis.