Analyzing nonsyndromic orofacial clefts GWAS data with case-parent trio design

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.

Grant Number: 7R03DE030259-04
NIH Institute/Center: NIH
Principal Investigator: Zhongxue Chen