PROJECT SUMMARY Case-parent trio (CPT) design is widely used in genome-wide association studies (GWASs) for childhood diseases, including nonsyndromic orofacial cleft birth defects (cleft lip and cleft palate). To detect associated genetic variants, the transmission disequilibrium test (TDT)—which is known to be robust against the subpopulation stratification—is usually applied to CPT data. However, several limitations associated with TDT- based methods may result in serious power loss and failure to detect true signals; this problem shows up in current nonsyndromic orofacial cleft GWASs, as only a small portion of associated genetic variants have been identified so far. Substantially more powerful advanced statistical approaches are therefore desperately needed. We propose some cutting-edge statistical methods that circumvent the limitations of current tests and use extra information from the data to substantially gain detection power. By applying our proposed methodology to nonsyndromic orofacial cleft GWAS data with CPT design, we expect to discover many novel genetic risk factors. The long-term goal of this project is to help researchers better understand the underlying mechanisms of these conditions by using cutting-edge statistical approaches to identify genetic components of nonsyndromic orofacial cleft birth defects, leading to more refined diagnostic capabilities and ultimately better targeted therapies. The overall objective of this application is to develop robust and powerful statistical approaches and apply them to the orofacial cleft birth defects data to discover novel genetic risk factors. The central hypothesis is that powerful statistical approaches can be developed if useful information from the data is obtained and fully and efficiently used; meanwhile, through use of these powerful cutting-edge statistical methods, more disease genetic variants will be discovered. The rationale for the proposed research is that successful completion will enable us to obtain more useful genetic information for nonsyndromic orofacial clefts. The central hypothesis will be tested and the objective attained by pursuing the following specific aims: 1) Develop, test, and validate powerful and robust statistical approaches for nonsyndromic orofacial cleft GWAS with case-parent trio design; 2) Identify novel disease genetic components by applying the proposed powerful statistical approaches to the orofacial cleft birth defects data. The contribution of this project will be significant because the findings will advance knowledge of developmental biology and create new opportunities for clinical and translational research in nonsyndromic orofacial cleft birth defects. This proposed research is innovative because the proposed novel statistical approaches are more powerful than existing methods in that they harness more information from the data and use it more efficiently.