Exploring the impact of extended phenotype in stratified samples

We have performed initial nonparametric sib-pair genome scans in the early (N = 52) and late (N = 53) onset subgroups of the COGA pedigrees, stratifie d near the median value of pedigree mean age of onset for ALDX1 diagnosis o f alcoholism. Because the early group contained a higher proportion of smok ers, traits of alcoholism, smoking, and addiction (defined as either alcoho lism or smoking) were examined. Subgroups and phenotypic definitions influe nced initial linkage results, corrected for the number of analyzed traits. Evidence for linkage to the ALDX1 alcoholism phenotype at the ADH3 function al candidate gene was increased in the late onset subgroup (Bonferroni corr ected significance level < 0.002), as compared with the unstratified sample that replicated COGA linkage obtained in the same analysis; there was no e vidence for linkage at this locus in the early onset subgroup. The theoreti cal implication of this result is that the loss of power due to contracting sample size through stratification may in some cases be more than offset b y extraction of a more homogenous subgroup from the etiologically complex t rait. (C) 1999 Wiley-Liss, Inc.