Supplementary Material for: Detection of Phenotype Modifier Genes Using Two-Locus Linkage Analysis in Complex Disorders Such as Major Psychosis

<b><i>Objective:</i></b> To increase power to detect modifier loci conferring susceptibility to specific phenotypes such as disease diagnoses which are part of a broader disorder spectrum by jointly modeling a modifier and a broad susceptibility gene and to identify modifier loci conferring specific susceptibility to schizophrenia (SZ) or to bipolar disorder (BP) using the approach. <b><i>Methods:</i></b> We implemented a two-locus linkage analysis model where a gene 1 genotype increases the risk of a broad phenotype and a gene 2 genotype modifies the expression of gene 1 by conferring susceptibility to a specific phenotype. <b><i>Results:</i></b> Compared to a single-locus analysis within the broad phenotype, the proposed approach had greater power to detect the modifier gene 2 (0.96 vs. 0.54 under a simulation scenario including heterogeneity). In a sample of 12 mixed SZ and BP Eastern Quebec kindreds, D8S1110 at 8p22 showed the strongest evidence of linkage to a gene determining a specific phenotype (SZ or BP) among subjects susceptible to major psychosis because of putative genes at 10p13 (D10S245, conditional maximized LOD (cMOD) = 4.20, p = 0.0003) and 3q21–q23 (D3S2418, cMOD = 4.09, p = 0.0005). <b><i>Conclusion:</i></b> The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.