DETECTION AND REPLICATION OF LINKAGE TO A COMPLEX HUMAN-DISEASE

Efforts to map susceptibility loci for complex human diseases frequent ly result in weak evidence for linkage, followed by failures to convin cingly replicate. If a disease locus influences both affection status (AF) and a quantitative trait, a variant of the extreme discordant sib pair (EDSP) strategy may be used to judiciously sample families for a replication study. This approach was evaluated by conducting joint se gregation and linkage analysis of four bivariate phenotypes, each comp rising AF and one quantitative trait (Q2, Q3, Q4, Q5), and undertaking a genomic scan of the GAW10 Problem 2B data set. Suggestive evidence was found for linkage of AF/Q2 to marker D8G26 (lod = 1.63, chi(2) = 7 .52, p = 3.05 x 10(-3). Sets of 23 EDSP families were selected based o n Q2 values that demarcated the bottom 1%, 2%, 5%, 10%, or 20% of the distribution. Highly significant evidence for linkage was found when t he 1% or 2% cutoffs were used (lod > 4, chi(2) > 20, p < 4 x 10(-6)), but more than 1,000 families had to be screened. Significant evidence for linkage (lod = 3.24, chi(2) = 14.91, p = 5.63 x 10(-5)) was found in the EDSP sample obtained using a 5% cutoff; about 300 families had to be screened. Only suggestive evidence for linkage (lod = 1.65, chi( 2) = 7.59, p = 2.93 x 10(-3)) was found in non-EDSP families. Use of E DSP sampling variants can permit convincing replications not otherwise obtainable in the genetic analysis of complex diseases. (C) 1997 Wile y-Liss, Inc.