Exploring the impact of extended phenotype in stratified samples

Abstract

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 homogenous subgroup from the etiologically complex trait.

Genome-wide Linkage of Forced Mid-expiratory Flow in Chronic Obstructive Pulmonary Disease

“…Colilla and colleagues suggest that stratification by tobacco smoke exposure may lead to less heterogeneity of the phenotypes of interest, with a resultant increase in power to detect susceptibility loci (20). The utility of stratification for revealing novel loci has been corroborated by other authors using simulated data (21)(22)(23). Stratification may be a useful analytic strategy to use when there are known environmental risk factors and likely multiple susceptibility loci contributing to disease.…”

Haplotype-sharing analysis for alcohol dependence based on quantitative traits and the Mantel statistic

“…More precisely, Daw et al [11] and Jacobs et al [12] had detected the region on chromosome 4, Kovac et al [13] and Macciardi et al [14] on chromosome 16, and Palmer et al [15] and Zinn-Justin et al [9] on chromosome 20. We detected an additonal signal with our method on chromosome 8, which has not been reported before.…”

Subtyping schizophrenia: implications for genetic research

“…In contrast, subtyping strategies are supported by mounting evidence that sample stratification, particularly using quantitative traits as covariates, can reduce heterogeneity and substantially increase power. [316][317][318][319][320][321] This approach has scored successes in the genetics of other complex diseases and its application to schizophrenia genetics will bring the disorder into the mainstream of current research into the common genetic diseases.…”