Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the National Institute of Mental Health Genetics Initiative pedigrees

Background: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p. Methods: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6 Nonparametric linkage analysis was performed. Results. Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p = .006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6-p22.2 (r = .26; p < .0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p < .0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from .35 to 2.26 on 6p22.2. Conclusions. These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.