We sought to identify quantitative trait loci (QTLs) by genome-wide linkage analysis for BMI and waist circumference (WC) exploring various strategies to address heterogeneity including covariate adjustments and complex models based on epistatic components of variance. Because cholesterol-lowering drugs and diabetes medications may affect adiposity and risk of coronary heart disease, we excluded subjects medicated for hypercholesterolemia and hyperglycemia. The evidence of linkage increased on 2p25 (BMI: lod = 1.59 vs. 2.43, WC: lod = 1.32 vs. 2.26). Because environmental and/or genetic components could mask the effect of a specific locus, we investigated further whether a QTL could influence adiposity independently of lipid pathway and dietary habits. Strong evidence of linkage on 2p25 (BMI: lod = 4.31; WC: lod = 4.23) was found using Willet's dietary factors and lipid profile together with age and sex in adjustment. It suggests that lipid profile and dietary habits are confounding factors for detecting a 2p25 QTL for adiposity. Because evidence of linkage has been previously detected for BMI on 7q34 and 13q14 in National Heart, Lung, and Blood Institute Family Heart Study (NHLBI FHS), and for diabetes on 15q13, we investigated epistasis between chromosome 2 and these loci. Significant epistatic interactions were found between QTLs 2p25 and 7q34, 2q37 and 7q34, 2q31 and 13q14, and 2q31-q36 and 15q13. These results suggest multiple pathways and factors involving genetic and environmental effects influencing adiposity. By taking some of these known factors into account, we clarified our linkage evidence of a QTL on 2p25 influencing BMI and WC. The 2p25, 2q24-q31, and 2q36-q37 showed evidence of epistatic interaction with 7q34, 13q14, and 15q13. © 2009 The Obesity Society.