摘要：About one fourth of patients with bipolar disorders (BD) have depressive episodes with a seasonal pattern (SP) coupled to a more severe disease. However, the underlying genetic influence on a SP in BD remains to be identified. We studied 269 BD Caucasian patients, with and without SP, recruited from university-affiliated psychiatric departments in France and performed a genetic single-marker analysis followed by a gene-based analysis on 349 single nucleotide polymorphisms (SNPs) spanning 21 circadian genes and 3 melatonin pathway genes. A SP in BD was nominally associated with 14 SNPs identified in 6 circadian genes: NPAS2 , CRY2 , ARNTL , ARNTL2 , RORA and RORB . After correcting for multiple testing, using a false discovery rate approach, the associations remained significant for 5 SNPs in NPAS2 (chromosome 2:100793045–100989719): rs6738097 (pc = 0.006), rs12622050 (pc = 0.006), rs2305159 (pc = 0.01), rs1542179 (pc = 0.01), and rs1562313 (pc = 0.02). The gene-based analysis of the 349 SNPs showed that rs6738097 ( NPAS2 ) and rs1554338 ( CRY2 ) were significantly associated with the SP phenotype (respective Empirical p-values of 0.0003 and 0.005). The associations remained significant for rs6738097 (NPAS2) after Bonferroni correction. The epistasis analysis between rs6738097 ( NPAS2 ) and rs1554338 ( CRY2 ) suggested an additive effect. Genetic variations in NPAS2 might be a biomarker for a seasonal pattern in BD.
