title: Genetic association study of circadian genes with seasonal pattern in bipolar disorders.
abstract: 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.
authors.affiliation: 1] Inserm, U1144, Paris, F-75006, France [2] AP-HP, GH Saint-Louis - Lariboisière - Fernand Widal, Pôle Neurosciences, 75475 Paris Cedex 10, France [3] Université Paris Descartes, UMR-S 1144, Paris, F-75006, France [4] Fondation FondaMental, Créteil, 94000, France.
authors.forename: Pierre Alexis
authors.initials: PA
authors.lastname: Geoffroy
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] INSERM, U955, Psychiatrie génétique, Créteil, 94000, France [3] AP-HP, Hôpitaux Universitaires Albert Chenevier-Henri Mondor , DHU PePSY, Pôle de Psychiatrie, Créteil, 94000, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lajnef
authors.affiliation: 1] Inserm, U1144, Paris, F-75006, France [2] AP-HP, GH Saint-Louis - Lariboisière - Fernand Widal, Pôle Neurosciences, 75475 Paris Cedex 10, France [3] Université Paris Descartes, UMR-S 1144, Paris, F-75006, France [4] Fondation FondaMental, Créteil, 94000, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bellivier
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] INSERM, U955, Psychiatrie génétique, Créteil, 94000, France [3] Université Paris Est, Faculté de médecine, Créteil, 94000, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Jamain
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] Hôpital Charles Perrens, Centre Expert Trouble Bipolaire, Service de psychiatrie adulte, Pôle 3-4-7, Bordeaux, 33000, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gard
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] Service de Psychiatrie et Psychologie Clinique, CHU de Nancy, Hôpitaux de Brabois, Vandoeuvre Les Nancy, 54500, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kahn
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] INSERM, U955, Psychiatrie génétique, Créteil, 94000, France [3] AP-HP, Hôpitaux Universitaires Albert Chenevier-Henri Mondor , DHU PePSY, Pôle de Psychiatrie, Créteil, 94000, France [4] Université Paris Est, Faculté de médecine, Créteil, 94000, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Henry
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] INSERM, U955, Psychiatrie génétique, Créteil, 94000, France [3] AP-HP, Hôpitaux Universitaires Albert Chenevier-Henri Mondor , DHU PePSY, Pôle de Psychiatrie, Créteil, 94000, France [4] Université Paris Est, Faculté de médecine, Créteil, 94000, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.affiliation: 1] Fondation FondaMental, Créteil, 94000, France [2] INSERM, U955, Psychiatrie génétique, Créteil, 94000, France [3] AP-HP, Hôpitaux Universitaires Albert Chenevier-Henri Mondor , DHU PePSY, Pôle de Psychiatrie, Créteil, 94000, France [4] Université Paris Est, Faculté de médecine, Créteil, 94000, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Etain
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D056926:CLOCK Proteins / Q000235:genetics*; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics; D005260:Female; D005602:France; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008550:Melatonin / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012621:Seasons
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D056931:Cryptochromes; D005819:Genetic Markers; D008550:Melatonin; D009419:Nerve Tissue Proteins; C538966:CRY2 protein, human; C104264:NPAS2 protein, human