Detecting QTLs for uni- and bipolar disorder using a variance component method.

The objective of this study was to use a robust variance component method to analyse unipolar and bipolar disorder in a large Scottish extended family (n = 168) in which linkage between markers and disease has been previously reported on the short arm of chromosome 4. Data consisted of diagnosed clinical uni- or bipolar disorder on 143 individuals, with microsatellite marker information on 109 of these individuals. The incidence of unipolar and bipolar disorder in the family was 17/143, and 11/143, respectively. Eleven linked markers on chromosome 4, spanning a region of approximately 26 cM, were used in the analysis. The statistical analysis was performed in two steps. First, pairwise identify-by-descent (IBD) coefficients for all individuals in the pedigree were calculated at 1 cM intervals, using all marker data simultaneously, with a Monte Carlo Markov Chain algorithm. Second, the variance in the trait of interest was partitioned using residual maximum likelihood (REML). Three components of variance were estimated: (i) a genetic component associated with the average relationship between individuals using the numerator relationship matrix, (ii) a genetic component associated with a chromosome location using the estimated IBD coefficients, and (iii) a residual component. The test statistic (LOD score) was calculated from the maximum likelihood of the full model, fitting all three variance components, and the maximum likelihood value from the reduced model, fitting a polygenic and residual component. The largest LOD scores (maximum LOD = 5.9), were found in a region spanning about 10 cM, when the trait was defined as the occurrence of either uni- or bipolar disorder. The putative QTL explained about 25% of the total variation in the trait.