Genetic linkage analysis of a dichotomous trait incorporating a tightly linked quantitative trait in affected sib pairs

Abstract

Many complex diseases are usually considered as dichotomous traits but are also associated with quantitative biological markers or quantitative risk factors. For such dichotomous traits, although their associated quantitative traits may not directly underly the diagnosis of the disease status, if the associated quantitative trait is also linked to the chromosomal regions linked to the dichotomous trait, then joint analysis of dichotomous and quantitative traits should be more efficient than consideration of them separately. Previous studies have focused on the situation when a dichotomous trait can be modeled by a threshold process acting on a single underlying normal liability distribution. However, for many complex disorders, including most psychiatric disorders, diagnosis is generally based on a set of binary or discrete criteria. These traits cannot be modeled on the basis of a threshold process acting on an underlying continuous trait. We propose a likelihood-based method that efficiently combines such a discrete trait and an associated quantitative trait in the analysis, using affected-sib-pair data. Our simulation studies suggest that joint analysis increases the power to detect linkage of dichotomous traits. We also apply the proposed new method to an asthma genome-scan data set and incorporate the total serum immunoglobulin E level in the analysis.

Figure 1

Histograms of total IgE level and its transformations. The Y-axis in each panel represents density. a, Standardized total IgE levels. b, Standardized logarithm of total IgE levels. c, Standardized square root of total IgE levels. d, Transformed total IgE levels.

Figure 2

LOD scores on chromosomes 1–12. Solid line = CLR; dotted line = MLS; dashed line = H-E

Figure 3

LOD scores on chromosomes 13–22. Solid line = CLR; dotted line = MLS; dashed line = H-E