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, stratified near the median value of pedigree mean age of onset for ALDX1 diagnosis of alcoholism. Because the early group contained a higher proportion of smokers, traits of alcoholism, smoking, and addiction (defined as either alcoholism or smoking) were examined. Subgroups and phenotypic definitions influenced initial linkage results, corrected for the number of analyzed traits. Evidence for linkage to the ALDX1 alcoholism phenotype at the ADH3 functional candidate gene was increased in the late onset subgroup (Bonferroni corrected significance level < 0.002), as compared with the unstratified sample that replicated COGA linkage obtained in the same analysis; there was no evidence for linkage at this locus in the early onset subgroup. The theoretical 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 by extraction of a more homogeneous subgroup from the etiologically complex trait.