Impact of Population Substructure on Trend Tests for Genetic Case-Control Association Studies

P>Hidden population substructure in case-control data has the potential to distort the performance of Cochran-Armitage trend tests (CATTs) for genetic associations. Three possible scenarios that may arise are investigated here: (i) heterogeneity of genotype frequencies across unidentified subpopulations (PSI), (ii) heterogeneity of genotype frequencies and disease risk across unidentified subpopulations (PSII), and (iii) cryptic correlations within unidentified subpopulations. A unified approach is presented for deriving the bias and variance distortion under the three scenarios for any CATT in a general family. Using these analytical formulas, we evaluate the excess type I errors of the CATTs numerically in the presence of population substructure. Our results provide insight into the properties of some proposed corrections for bias and variance distortion and show why they may not fully correct for the effects of population substructure.