Consanguinity and the transmission/disequilibrium test for allelic association

Consanguineous marriages, usually between first cousins or between uncle an d niece, are common in certain societies. The transmission/disequilibrium t est (TDT) compares the transmission from parents to an affected child of al leles at a marker locus, and differential transmission indicates linkage an d allelic association between the marker locus and a disease locus. We inve stigate the consequences for the TDT, as a test for allelic association, of consanguineous marriages. For each parental marker mating type, we calcula te the frequency of each disease mating type, and the associated probabilit y that an offspring is affected. We use Bayes' Theorem to estimate the prob ability that an affected child inherits the given allele from a heterozygou s parent, then combine our results across marker mating types. The effect o f consanguineous marriage is usually small. For candidate genes, the effect s were greater for uncle-niece marriages, for rare disease alleles, and for high genotype relative risk. For markers, the effects were generally negli gible. The Type I error probability of the TDT is essentially unchanged by intermarriage, except for a purely recessive disease allele. The power of t he TDT is increased for a recessive allele and decreased for a dominant all ele. However, consideration of levels of consanguinity that arise in practi ce indicates that standard power calculations for the TDT will usually need only minor modification. (C) 2001 Wiley-Liss. Inc.