DETECTION OF VULNERABILITY LOCI BY ASSOCIATION AND SIB-PAIR METHODS

A haplotype-based haplotype relative risk (HHRR) analysis of simulated data for 200 affected offspring and their parents (Genetic Analysis W orkshop 9, Problem 1) detected linkage disequilibrium at 2 of 360 mark er loci. An additive model was suggested but not proven by haplotypes of affected vs. unaffected offspring. These findings were consistent w ith the generating model. Affected sib pair analysis failed to detect additional loci. Discussion among workshop participants suggested that the chi-square test used here (2 [transmitted vs. nontransmitted] x n [alleles] for each locus) was invalid because of the nonindependence of proportions of transmitted alleles. In post-workshop analyses, tran smission disequilibrium tests (TDTs) for each allele at each locus det ected only the true associations if p values were corrected by one of two methods: Bonferroni correction for 2,035 TDTs, or correcting each test for n (number of tests at the locus) minus 1 and then for the num ber of loci tested. Screening loci for linkage disequilibrium requires careful attention to correction for multiple comparisons. (C) 1995 Wi ley-Liss, Inc.