A comparison of univariate, bivariate, and trivariate whole-genome linkage screens of genetically correlated electrophysiological endophenotypes.

We used a maximum-likelihood based multipoint linkage approach implemented in SOLAR to examine simultaneously linkage for three electrophysiological endophenotypes from the Collaborative Study of the Genetics of Alcoholism: TTTH1, TTTH2, and TTTH3. These endophenotypes have been identified as markers of alcohol dependence susceptibility. Data were from 905 individuals in 143 families. Measured covariates considered included sex, age at electrophysiology data collection, habitual smoking status, and the maximum number of drinks consumed in a 24-hour period. Comparisons were made among genome-wide univariate, bivariate, and trivariate linkage analyses using genotypes based on microsatellite markers supplied by the Center for Inherited Disease Research, and genotypes based on single-nucleotide polymorphism markers provided by Illumina. All LODs were corrected to a standard equivalent to 1 degree of freedom. Using the trivariate approach and the microsatellite-based genotypes, we estimated a maximum multipoint linkage signal of LOD = 2.66 on chromosome 7q at 157 cM. Analyses using the Illumina SNP genotypes produced similar results, yielding a maximum multipoint LOD of 2.95 on 7q at 174 cM. These regions of interest correspond to those identified in the univariate and bivariate linkage screens. Our results suggest that trivariate multipoint linkage analyses have utility in the further characterization of chromosomal regions potentially containing genes influencing the phenotypes being examined. Based on a comparison of the number of LOD scores achieving statistical significance, our results suggest that the microsatellite- and Illumina SNP-based genotypes have similar utility for detecting genomic regions of interest.