Mitochondrial Genetic Analyses Suggest Selection against Maternal Lineages in Bipolar Affective Disorder

Abstract

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly 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 disease.

New variants in the mitochondrial genomes of schizophrenic patients

“…In this respect, we also found two other missense variants that had previously been described as polymorhisms in patients with bipolar disorder. 25 These were the MTND5 C12403T (Leu23Phe) and MTND5 A12950C (Asn105Thr), and they were identified in two out of 23 and 24 bipolar patients, respectively. However, they were not found in QJ;a subsequent analysis of 94 control individuals.…”

Mitochondrial involvement in psychiatric disorders

“…Two subjects shared 25 polymorphisms and these subjects belonged to the sub-haplogroup F1ba of the macro-haplogroup N, leading the authors to speculate that this haplotype may be a risk factor for atypical psychosis. However, Kirk et al (1999) resequenced the mitochondrial genome from 25 subjects with bipolar affective disorder who had family histories suggestive of inheritance from the maternal side, but they did not find a relationship between haplotype frequency in subjects with bipolar affective disorder compared to controls (85).…”

The other, forgotten genome: mitochondrial DNA and mental disorders

“…Kirk et al 116 sequenced the whole mitochondrial genome in 25 patients with bipolar disorder and demonstrated differences in the mitochondrial genetic distances within the bipolar and control groups. They determined these by making all the pairwise comparisons possible of mtDNA haplotypes in the bipolar or control groups and found that the bipolar group had fewer closely related haplotypes than controls, suggesting selection against certain haplotypes in the bipolar cases.…”