2-LOCUS MAXIMUM LOD SCORE ANALYSIS OF A MULTIFACTORIAL TRAIT - JOINT CONSIDERATION OF IDDM2 AND IDDM4 WITH IDDM1 IN TYPE-I DIABETES

To investigate the genetic component of multifactorial diseases such a s type 1 (insulin-dependent) diabetes mellitus (IDDM), models involvin g the joint action of several disease loci are important. These models can give increased power to detect an effect and a greater understand ing of etiological mechanisms. Here, we present an extension of the ma ximum lod score method of N. Risch, which allows the simultaneous dete ction and modeling of two unlinked disease loci. Genetic constraints o n the identical-by-descent sharing probabilities, analogous to the ''t riangle'' restrictions in the single-locus method, are derived, and th e size and power of the test statistics are investigated. The method i s applied to affected-sib-pair data, and the joint effects of IDDM1 (H LA) and IDDM2 (the INS VNTR) and of IDDM1 and IDDM4 (FGF3-linked) are assessed with relation to the development of IDDM. In the presence of genetic heterogeneity, there is seen to be a significant advantage in analyzing more than one locus simultaneously. Analysis of these famili es indicates that the effects at IDDM1 and IDDM2 are well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 follow a heterogeneity model.