Norway has several large epidemiological studies with genetic bio-banks that may be used in etiologic research. Examples are the CONOR-cohort and the MoBa-cohort of children with mothers and fathers. Optimal analysis of such studies requires integration o f both genetic and environmental effects. Relevant methodology for such integrated approaches to genetic and environmental effects, or gene-environment interaction, is however lacking. We propose to use a large case-control study on oral clefts and data f rom the MoBa cohort to develop such approaches. Oral clefts represent a particularly interesting model, since these birth defects have a relatively high prevalence in Norway and since there are known environmental as well as genetic effects. We are buildi ng on new methodology for haplotype reconstruction and genetic analysis of family triad data or nested case-control data. Estimation of environmental affects and gene-environment interaction will be incorporated for a variety of scenarios. We will develop new analytic tools and investigate specific hypotheses of oral clefts etiology.