Gene-gene and gene-environment interactions govern a substantial portion of the variation in complex traits and diseases. In convention, a set of either unrelated or family samples are used in detection of such interactions; even when both kinds of data are available, the unrelated and the family samples are analyzed separately, potentially leading to loss in statistical power. In this report, to detect gene-gene interactions we propose a generalized multifactor dimensionality reduction method that unifies analyses of nuclear families and unrelated subjects within the same statistical framework. We used principal components as genetic background controls against population stratification, and when sibling data are included, within-family control were used to correct for potential spurious association at the tested loci. Through comprehensive simulations, we demonstrate that the proposed method can remarkably increase power by pooling unrelated and offspring's samples together as compared with individual analysis strategies and the Fisher's combining p value method while it retains a controlled type I error rate in the presence of population structure. In application to a real dataset, we detected one significant tetragenic interaction among CHRNA4, CHRNB2, BDNF, and NTRK2 associated with nicotine dependence in the Study of Addiction: Genetics and Environment sample, suggesting the biological role of these genes in nicotine dependence development. © 2013 Springer-Verlag Berlin Heidelberg.