A Novel Haplotype-Sharing Approach for Genome-Wide Case-Control Association Studies Implicates the Calpastatin Gene in Parkinson's Disease

The large number of markers considered in a genome-wide association study (GWAS) has resulted in a simplification of analyses conducted. Most studies are analyzed one marker at a time using simple tests like the trend test. Methods that account for the special features of genetic association studies, yet remain computationally feasible for genome-wide analysis, are desirable as they may lead to increased power to detect associations. Haplotype sharing attempts to translate between population genetics and genetic epidemiology. Near a recent mutation that increases disease risk, haplotypes of case participants should be more similar to each other than haplotypes of control participants; conversely, the opposite pattern may be found near a recent mutation that lowers disease risk. We give computationally simple association tests based on haplotype sharing that can be easily applied to GWASs while allowing use of fast (but not likelihood-based) haplotyping algorithms and properly accounting for the uncertainty introduced by using inferred haplotypes. We also give haplotype-sharing analyses that adjust for population stratification. Applying our methods to a GWAS of Parkinson's disease, we find a genome-wide significant signal in the CAST gene that is not found by single-SNP methods. Further, a missing-data artifact that causes a spurious single-SNP association on chromosome 9 does not impact our test. Genet. Epidemiol. 33:657-667, 2009. Published 2009 Wiley-Liss, Inc.(dagger)