Mood-incongruent psychosis in bipolar disorder: conditional linkage analysis shows genome-wide suggestive linkage at 1q32.3, 7p13 and 20q13.31

Objective: The majority of research into functional psychosis has proceeded under the assumption that schizophrenia and bipolar disorder are distinct entities with separate underlying disease processes and treatments. This view has been increasingly challenged in both clinical and genetic studies. Findings in recent association studies at two specific genes suggest that the occurrence of mood-incongruent psychotic features may indicate a relatively homogeneous subset of the bipolar phenotype. We examined this hypothesis. Methods: Caucasian affected individuals were ascertained from Europe (the United Kingdom, the Republic of Ireland, Germany, Italy and Andalusia). Consensus best-estimate diagnoses were assigned by two independent raters according to all available information. There was no cross-site evaluation of inter-rater reliability. Families multiply affected by bipolar spectrum mood disorder were selected, comprising 383 affected relative pairs. Individuals were considered to be affected if they were diagnosed with DSM-IV bipolar I disorder or schizoaffective disorder, bipolar type. Multipoint, affected relative pair covariate linkage analysis was performed. Results: Significant familiality of incongruent psychosis was observed [intra-class correlation coefficient (ICC) = 0.309; p = 0.001, one-tail]. Covariate linkage analysis provided three regions with genome-wide suggestive evidence for linkage on chromosomes 1q32.3 (LOD = 4.15, expected 0.12 times per genome scan), 7p13 (LOD = 3.32) and 20q13.31 (LOD = 2.98). No region in our analysis met criteria for genome-wide significance. Conclusion: Our results provide molecular support for the hypothesis that genes may exist for specific forms of bipolar illness, dependent on the presence or absence of incongruent psychosis. Our findings suggest that researchers should take account of mood-congruence/incongruence of psychotic features in studies of bipolar disorder.