Modeling complex disease with demographic and environmental covariates anda candidate gene marker

We randomly chose replicates 28 and 29 of the simulated data sets of Geneti c Analysis Workshop 12 to model the dependence of affection status on covar iates, quantitative traits, and genes using all living pedigree members. Fi rst we explored the relationship of affection status to demographic and env ironmental factors using logistic regression and the Cox proportional hazar ds models. In the second stage of our analyses the generalized transmission disequilibrium test (GTDT) was applied to nuclear families with at least t wo affected siblings to select single markers and high-risk alleles, which were tested in the population association analyses including all pedigree m embers. Multiple logistic regression models were fitted to investigate the joint contributions of genetic and nongenetic factors and a block-recursive modeling approach was adopted to study inherent hierarchical dependence st ructure in the data. We found that allele 2 on marker 35 of chromosome 6 is associated with higher risk compared with the other 3 alleles of this mark er. In addition to this significant genetic effect, age at exam and four of the five quantitative traits (QT1, QT2, QT4, and QT5) had a significant as sociation with the disease. Our results were obtained without knowledge of the true disease generating models. ((C)) 2001 Wiley-Liss, Inc.