Background. Multiple lines of evidence suggest that the circadian clock contributes to the pathogenesis of winter depression or seasonal affective disorder (SAD). We hypothesized that sequence variations in three genes, including Per2, Arntl, and Npas2, which form a functional unit at the core of the circadian clock, predispose to winter depression. Methods. In silico analysis of the biological effects of allelic differences suggested the target single-nucleotide polymorphisms (SNPs) to be analyzed in a sample of 189 patients and 189 matched controls. The most relevant SNP in each gene was identified for the interaction analysis and included in the multivariate assessment of the combined effects of all three SNPs on the disease risk.