Robust methods were employed, using data from a single large pedigree, to screen serum apolipoprotein A1 and B levels, serum lipoprotein cholesterol levels, and ratios of serum lipoprotein cholesterol fractions to apolipoprotein A1 and B levels for genetic linkage to 31 polymorphic markers. Segregation analyses were performed for each of the apolipoprotein and lipoprotein cholesterol fractions to obtain estimates for use in applying likelihood methods of linkage analysis. Trait-marker combinations for which linkages were suggested from the robust methods were then reexamined for linkage using the likelihood (lod score) method. Results from the segregation analyses were consistent with major gene determination of apo B and HDL-C levels, the HDL-C to apo A1 ratio, the LDL-C to apo B ratio, and a measure of relative content of cholesterol in HDL-C and LDL-C. Linkage between haptoglobin and the HDL-C/apo A1 ratio was suggested, with a lod score of 1.72 at theta = 0.05.

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The genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels was evaluated using segregation analysis techniques in a large multigenerational kindred with a high prevalence of coronary heart disease and myocardial infarction. Univariate segregation analysis of HDL-C levels with the effects of age and sex removed by regression provided evidence of a Mendelian mode of inheritance for a portion of the variability in HDL-C levels. Subsequent analyses included low-density-lipoprotein cholesterol (LDL-C) levels and several behavioral and anthropometric variables that affect HDL-C levels. Pedigree discriminant analysis was used to find the linear functions of the variables that maximized the likelihood given the pedigree structure and assuming monogenic segregation. The best linear function was found to be approximately equivalent to the log of the HDL-C to LDL-C ratio, with concomitant and environmental effects removed by regression. Genetic hypotheses were tested by cross-validation; linear functions derived from data on each side of the kindred were used to test hypotheses on the other side of the kindred. On one side of the kindred, all hypotheses were accepted. On the other side of the kindred, only Mendelian inheritance of the linear function was indicated. Segregation of the age- and sex-adjusted HDL-C values, and of the linear function, was evaluated using a regressive model that allows for intrafamilial correlations in addition to a monogenic effect. All analyses provide evidence for levels of HDL-C being controlled by a major locus with neither dominant nor recessive expression.

Results from the study by Sherrington et a]. [1988] indicate that the maximum lod score (3.2) from a linkage analysis between narrowly defined clinical diagnostic criteria for schizophrenia and polymorphic markers on chromosome 5 is lower than that (6.5) from an analogous analysis between broadly defined clinical criteria for psychiatric illness and these same markers. Should these results be interpreted to indicate that in the families studied the narrowly defined clinical phenotype for schizophrenia is due to a single locus located on chromosome 5 , with the inclusion of other psychiatric illness spuriously inflating the lod score? Or do they indicate that a locus located on chromosome 5 is responsible, at least in part, for a spectrum of psychiatric illness that can include schizophrenia? We agree with Risch [ 19901 that current evidence indicates that single-locus segregation can account for at most a small fraction of the cases of schizophrenia in general. We further believe that there is no strong evidence that schizophrenia is largely polygenic, in the sense that many loci with additive effects are involved. The analyses performed by McGue et al. [1985], for example, although interpreted by them to indicate polygenic inheritance, really only indicate the presence of epistasis on the penetrance scale, and hence segregation at a minimum of two loci. We therefore believe that segregation and linkage analysis of schizophrenic families is not a lost cause. We further believe, perhaps in contrast to Risch, that because of the nonexperimental nature of human genetic studies, linkage will eventually provide us with the soundeset path for elucidating the genetic etiology of complex diseases.At the outset, a distinction needs to be made between two different ways in which segregation and linkage analysis can be used to investigate the genetic etiology of complex diseases or traits. In the first approach, the phenotype for a complex trait is assumed to be adequately identified, usually as a distinct clinical entity, and we try to identify the