Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.
Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3' near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.
Soria
Virginia
V
CIBERSAM (CIBER en Salud Mental), Mood Disorders Clinical and Research Unit, Psychiatry Department, Bellvitge University Hospital, Barcelona, Spain.
Martínez-Amorós
Erika
E
Escaramís
Geòrgia
G
Valero
Joaquín
J
Pérez-Egea
Rosario
R
García
Cecilia
C
Gutiérrez-Zotes
Alfonso
A
Puigdemont
Dolors
D
Bayés
Mònica
M
Crespo
José M
JM
Martorell
Lourdes
L
Vilella
Elisabet
E
Labad
Antonio
A
Vallejo
Julio
J
Pérez
Víctor
V
Menchón
José M
JM
Estivill
Xavier
X
Gratacòs
Mònica
M
Urretavizcaya
Mikel
M
D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D021081:Chronobiology Disorders / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics; D004252:DNA Mutational Analysis; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014660:Vasoactive Intestinal Peptide / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D056931:Cryptochromes; D009419:Nerve Tissue Proteins; D014660:Vasoactive Intestinal Peptide; C538963:CRY1 protein, human; C104264:NPAS2 protein, human; C538943:CLOCK protein, human