Confounding by linkage disequilibrium

Linkage disequilibrium (LD) and confounding are two widely discussed concepts in Genetics and in Epidemiology, yet their relationship has received only intuitive or no considerations. Taken in the narrow sense, LD refers to the nonrandom association of alleles at two or more linked genetic loci. The degree to which these alleles are associated is the basis behind genetic association studies whereby the genetic variation across target chromosomal intervals or over the entire genome is captured by a set of representative genetic markers (tagging markers). The denomination of ‘linkage’ is somehow misleading because LD is a special case of the more general gametic phase disequilibrium (GPD), 1 which also occurs between variants at the mitochondrial and nuclear loci in the form of cytonuclear disequilibrium. 2