Measuring the genetic influence in modulating the human life span: gene-environment interaction and the sex-specific genetic effect

New approaches are needed to explore the different ways in which genes affe ct the human life span. One needs to assess the genetic effects themselves, as well as gene-environment interactions and sex dependency. In this paper . we present a new model that combines both genotypic and demographic infor mation in the estimation of the genetic influence on life spans. Based on C ox's proportional hazard assumption, the model measures the risks for each gene as well as for gene-environment and gene-sex interactions, while contr olling for confounding factors. A two-step MLE is introduced to obtain a no n-parametric form of the baseline hazard function. The model is applied to genotypic data from Italian centenarian studies to estimate relative risks of candidate genes, risks due to interactions and initial frequencies of di fferent genes in the population. Results from models that either do or do n ot take into consideration individual heterogeneity are compared. It is sho wn that ignoring the existence of heterogeneity can lead to a systematic un derestimation of genetic effects and effects due to interactions.