Multilocus linkage tests based on affected relative pairs

Abstract

For complex diseases, recent interest has focused on methods that take into account joint effects at interacting loci. Conditioning on effects of disease loci at known locations can lead to increased power to detect effects at other loci. Moreover, use of joint models allows investigation of the etiologic mechanisms that may be involved in the disease. Here we present a method for simultaneous analysis of the joint genetic effects at several loci that uses affected relative pairs. The method is a generalization of the two-locus LOD-score analysis for affected sib pairs proposed by Cordell et al. We derive expressions for the relative risk, lambdaR, to a relative of an affected individual, in terms of the additive and epistatic components of variance at an arbitrary number of disease loci, and we show how these can be used to fit a likelihood model to the identity-by-descent sharing among pairs of affected relatives in extended pedigrees. We implement the method by use of a stepwise strategy in which, given evidence of linkage to disease at m-1 locations on the genome, we calculate the conditional likelihood curve across the genome for an mth disease locus, using multipoint methods similar to those proposed by Kruglyak et al. We evaluate the properties of our method by use of simulated data and present an application to real data from families with insulin-dependent diabetes mellitus.

Figure 1

Structure of pedigrees used for the simulation study. Families were included in the study if they had at least three affected members in generation III, including at least one affected individual in each sibship. Individuals in generation I were assumed to be unavailable for genotyping.

Figure 2

Single-locus and two-locus MLS results against chromosomal location (in cM), for data simulated under a three-locus recessive model. Dotted lines indicate additive MLS; dashed lines, multiplicative or single-locus MLS; and solid lines, general MLS.

Figure 3

Two-locus MLS results (conditional on IDDM1) for IDDM data against chromosomal location in cM for chromosomes 6, 8, 10, 11, 15, 16, 18, and 21 and for the pseudo autosomal region. Dotted lines indicate additive MLS, solid lines indicate general MLS, and dashed lines indicate multiplicative or single-locus MLS (apart from chromosome 6, where dashed lines indicate multiplicative MLS only).