TESTING FOR CONTRIBUTIONS OF MITOCHONDRIAL-DNA MUTATIONS TO COMPLEX DISEASES

Several complex disorders are suspected of being associated with mitoc hondrial DNA (mtDNA) mutations. We studied the statistical properties of a test based on proband-relative pairs to identify potential mtDNA mutation involvement in a complex disorder. The test compares the recu rrence risk of relatives of probands along the mitochondrial lineage w ith that of relatives along the nonmitochondrial lineage. If mtDNA mut ations are involved, the recurrence risk will be higher among relative s in the mitochondrial lineage. The form of the test is independent of the assumed models of inheritance and interaction of the nuclear auto somal mutations with mtDNA mutations. The power of the test, however, differs among the different models and by the type of proband-relative pairs used in the test. We considered heterogeneity models with and w ithout phenocopies, a three-state heteroplasmic mtDNA transmission mod el, and a multiplicative epistasis model. Under the heterogeneity mode l, the power of the test increases as the relationship between the pro band and the relative becomes more distant. Under the multiplicative e pistasis model, the power of the test decreases as the relationship be tween the proband and the relative becomes more distant. Genet. Epidem iol. 15:451-469, 1998. (C) 1998 Wiley-Liss, Inc.