Nonsyndromic cleft lip with or without cleft palate (CUP) is a disease of complex etiology. Although significant work has been done, with many important findings, the genetics of CUP is poorly understood. Herein we present a plan for a novel set of analyses on a CUP pedigree sample of unprecedented size and an independent set of 1000 CUP trios. Importantly, this dataset has CIDR genome scan data available, has been accepted for an Illumina fine-mapping project with CIDR and has many candidate loci already genotyped. Our analysis plan will consist of three distinct approaches to CUP gene discovery. First, we will use a non-parametric linkage approaches to detecting gene-gene interaction, incorporating either a previous linkage finding or candidate gene marker in the model. Second, we will use association approaches to detect interaction at a set of candidate genes. Lastly, we will use empirical information to inform a novel approach to linkage analysis incorporating a parameter representing diagnostic uncertainty. Overall, the proposed analytical approaches applied in this large dataset will shed significant light on the contribution of specific genes, and their interactions, to CUP. ? ? ?
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