Columbia University, Department of Psychiatry and Columbia Genome Center, New York State Psychiatric Institute, Department of Neuroscience, New York, USA

Correspondence to: Joseph D Terwilliger PhD, Columbia University, 60 Haven Avenue No. 15-C, New York, NY 10032, USA. Fax: +1 212 304 5515; E-mail: jdt3@columbia.edu

The admixture test of linkage heterogeneity is the most often and most successfully applied oligogenic-model linkage and/or LD analysis method. Full two-locus model linkage analysis is possible, but can be computationally intensive and difficult to interpret because of the need to specify so many indeterminate parameters. A novel, computationally efficient method is proposed for combining single locus lod scores which can allow for varying degrees of epistatic interaction. This method can be applied to two-point or multipoint (using complex-valued recombination fractions) linkage and/or linkage disequilibrium analysis to jointly test for multiple unlinked disease loci. Unlike the traditional admixture test, this algorithm permits joint analysis of multiple disease loci with different modes of inheritance for each, and can be applied to 'model-free' analysis as well through the use of 'pseudomarkers'. Software is available for computation of the various likelihood ratio tests described, for comparison of a variety of possible hypotheses regarding locus homogeneity, locus heterogeneity, and epistasis. European Journal of Human Genetics (2000) 8, 399-406.

oligogenic inheritance; admixture test; linkage heterogeneity; two-locus models; linkage disequilibrium analysis; complex disease