Background: Most genome-wide association studies assumed an additive model of inheritance which may result in significant loss of power when there is a strong departure from additivity. The General Regression Model (GRM), which allows performing an assumption-free test for association by testing for both additive effect and deviation from additive effect, may be more appropriate for association tests. Additionally, GRM allows testing the underlying genetic model. We compared the power of GRM association test to additive and other Cochran-Armitage Trend (CAT) tests through simulations and by applying GRM to a large case/control sample, the bipolar Welcome Trust Case Control Cohort data. Simulations were performed on two sets of case/control samples (1000/1000 and 2000/2000), using a large panel of genetic models. Four association tests (GRM and additive, recessive and dominant CAT tests) were applied to all replicates. Results: We showed that GRM power to detect association was similar or greater than the additive CAT test, in particular in case of recessive inheritance, with up to 67% gain in power. GRM analysis of genome-wide bipolar disorder Welcome Trust Consortium data (1998 cases/3004 controls) showed significant association in the 16p12 region (rs420259; P = 3.4E-7) which has not been identified using the additive CAT test. As expected, rs42025 fitted a non-additive (recessive) model. Conclusions: GRM provides increased power compared to the additive CAT test for association studies and is easily applicable.