Dr. McMahon and colleagues reply to Mitochondrial DNA polymorphisms and bipolar disorder

We thank Dr. Kato for his kind letter commenting on our report of a nominal association between a mitochondrial DNA variant at nucleotide position 10398 and bipolar disorder. We are intrigued by his finding that this same variant may also be associated with bipolar disorder in a Japanese population. The association of the same mitochondrial DNA variant with bipolar disorder in two ethnically distinct populations increases the likelihood that the association is genuine rather than due to the ethnic particulars of a single study population. These data show that the differences between probands with bipolar disorder and comparison subjects observed within Dr. Kato’s and our studies are small compared to the differences between the populations from which the subjects were drawn. Furthermore, the A allele occurred less frequently in both groups of clinical comparison subjects than in the corresponding population sample for each ethnicity. Although the population samples presumably included some people carrying susceptibility alleles for bipolar disorder, the meaning of these differences is not immediately apparent. Could this reflect a common susceptibility allele of low penetration? A recently published study of a British population R1587CIHEJDIB also failed to show an association between bipolar disorder and the nucleotide position 10398 polymorphism. On the basis of these data, we stand by our original conclusion that a pathogenic role of the nucleotide position 10398 polymorphism in bipolar disorder appears unlikely, but we agree that it cannot be entirely ruled out, especially in light of Dr. Kato’s new results. More data from larger groups of Europeans and Asians might clarify the situation.