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

Thursday, March 22, 2012: 8 a.m. - 9:30 a.m.
Presentation Type: Oral Session
M. GOVIL1, N. MUKHOPADHYAY1, Y. HUANG2, W. VALENTINE-COOPER2, L.L. FIELD3, A. LIDRAL4, J. MURRAY5, M.L. MARAZITA6, and V.J. VIELAND7, 1Center for Craniofacial & Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, 2Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH, 3Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada, 4Orthodontics, University of Iowa, Iowa, IA, 5Dept. of Pediatrics, University of Iowa, Iowa City, IA, 6Center for Craniofacial and Dental Genetics, Department of Oral Biology, Department of Human Genetics, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 7Battelle Center for Mathematical Medicine, Department of Pediatrics, Department of Statistics, The Research Institute at Nationwide Children's Hospital & The Ohio State University, Columbus, OH
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.

This abstract is based on research that was funded entirely or partially by an outside source: NIH/NIDCR K99/R00DE018085, NIH/NIDCR K99DE018085-01A2S1, NIH/NIMH R01MH086117, NIH/NIDCR R01-DE016148, NIH/NIDCR R01-DE009886, NIH/NIDCR R37-DE008559, NIH/NIDCR R01-DE014677, genotyping through CIDR NIH contract N01-HG-65403

Keywords: Biostatistics, Cleft lip-palate, Gene Mapping, Genetics and Methodology
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