Mitochondrial genetic analyses suggest selection against maternal lineagesin bipolar affective disorder

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested tha t this disorder may be caused by mitochondrial DNA mutations. We have seque nced the mitochondrial genome in 25 BP patients with family histories of ps ychiatric disorder that suggest matrilineal inheritance. No polymorphism id entified more than once in this sequencing showed any significant associati on with BP in association studies using 94 cases and 94 controls. To determ ine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise com parisons within the BP and control groups, based on multilocus mitochondria l polymorphism haplotypes. These analyses revealed fewer closely related ha plotypes in the BP group than in the matched control group, suggesting sele ction against maternal lineages in this disease. Such selection is compatib le with recurrent mitochondrial mutations, which are associated with slight ly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study diseas e.