Recent genomic studies using a variety of techniques have revealed that copy number polymorphism (CNP) is common in the human genome, and there are preliminary reports of CNP associated with complex human diseases. One of the first regions implicated in linkage mapping studies of complex disorders was the NIDDM1 region of chromosome 2q37 in type 2 diabetes (T2D) in Mexican Americans. Similarly, the first gene identified as a susceptibility locus for T2D in the context of a positional cloning study was CAPN10, in the NIDDM1 region (Horikawa et al., 2000). The model characterizing the relationship of genetic variation at CAPN10 and the risk of T2D is complex. The original report identified a combination of two different 3-locus haplotypes as conferring the largest increase in risk for T2D. These results have been replicated in some studies, but many studies have not been able to reproduce the originally reported associations. Because a variety of observations made in the context of the original studies on CAPN10 are reminiscent of observations more recently made on CNP, we initiated some preliminary studies to assess the possibility that CAPN10 contains CNP that has not been detected with conventional genotyping and sequencing methods. Results of these preliminary studies provide sufficiently compelling evidence for CPN in CAPN10 that we propose the following specific aims: 1) Test the hypothesis that CAPN10 contains copy-number polymorphisms that have not been detected with conventional genotyping and sequencing methods and devise approaches for reliably characterizing such CAPN10 polymorphisms; 2) Test the hypothesis that CNP at CAPN10 is associated with risk of T2D; and 3) Adapt existing simulation software using coalescent models to allow for CNPs to enable tests of alternative statistical approaches to aid in identifying and characterizing CNP and testing associations with disease.
