CL/P: Utilizing Advanced Analytic Approaches to Identify Etiologic Genes

Objective: Our group and others have demonstrated that common craniofacial and dental genetic traits and diseases like cleft lip with/out cleft palate (CL/P) possess a complex etiology, with heterogeneity in prevalence influenced by a variety of factors including geographic origin. These discoveries, in turn, have been facilitated by, and continue to fuel the development and use of sophisticated statistical approaches in our continuing effort to untangle the genetics of such complex traits. The posterior probability of linkage (PPL) is a class of likelihood-based, model-free statistics developed specifically to meet the challenge presented by complex traits. The PPL is a measure of the strength of evidence in favor of, or against, linkage and it accommodates inter- and intra-population heterogeneity using Bayesian sequential updating over datasets.

Method: This IRB approved study carried out a multipoint PPL genome scan for 556 families from five population-groups (Colombia, India, Philippines, China, USA) on 401 microsatellite markers, 10cM apart, genotyped by CIDR. Using the program KELVIN, multipoint PPLs were generated for each group using population-specific genetic maps, and then they were sequentially updated over all groups to produce the composite genome scan.

Result: PPL<0.10 observed for 95% of the genome; 67% of the genome gave evidence against linkage (PPL<0.02). Peak PPL by chromosomal region: 0.60 12p11.2-12; 0.32 15q22; 0.20 8p22-23; 0.18 6q22-23, 2p21, 2q37(q-ter), 1q44.

Conclusion: These findings not only support prior linkage results, particularly confirming the role of ancestry in observed heterogeneity of CL/P, they also provide stronger evidence in favor of novel chromosomal regions and genes. While it is expected that analyses currently underway that incorporate additional phenotypic information along with patterns of linkage disequilibrium will further refine the regions for follow-up and/or fine mapping, the current results demonstrate the potential power of this approach to facilitate identification of genes associated with complex traits.