Significance levels in complex inheritance

Abstract

A LOD score ≤3 is necessary but not sufficient to make a linkage test reliable, and this applies to complex inheritance as well as to major loci. Factors that affect this threshold are considered here. A LOD score as small as 2 is suggestive but is unreliable except as confirmation of either a significant linkage or a strong candidate locus. A threshold as great as 4 is unnecessarily conservative if multipoint tests are used sensibly. Marker density is not a major factor, and biases in the evaluation of LOD scores - specially inadequate allowance for estimation of nuisance parameters in multiple models - are paramount. Allelic association increases resolution for oligogenes within a candidate region and remains the only practical method to locate polygenes. The method sketched here combines multipoint linkage and allelic association to test efficiently for a regional candidate locus.