Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression.
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.


RESULTS
SAD was associated with variations in each of the three genes in gene-wise logistic regression analysis. In combination analysis of variations of Per2, Arntl, and Npas2, we found additive effects and identified a genetic risk profile for the disorder. Carriers of the risk genotype combination had the odds ratio of 4.43 of developing SAD as compared with the remaining genotypes, and of 10.67 as compared with the most protective genotype combination.


CONCLUSIONS
Variations in the three circadian clock genes Per2, Arntl, and Npas2 are associated with the disease, supporting the hypothesis that the circadian clock mechanisms contribute to winter depression.
Partonen
Timo
T
Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland. timo.partonen@ktl.fi
Treutlein
Jens
J
Alpman
Asude
A
Frank
Josef
J
Johansson
Carolina
C
Depner
Martin
M
Aron
Liviu
L
Rietschel
Marcella
M
Wellek
Stefan
S
Soronen
Pia
P
Paunio
Tiina
T
Koch
Andreas
A
Chen
Ping
P
Lathrop
Mark
M
Adolfsson
Rolf
R
Persson
Maj-Liz
ML
Kasper
Siegfried
S
Schalling
Martin
M
Peltonen
Leena
L
Schumann
Gunter
G
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D056950:Period Circadian Proteins; D020641:Polymorphism, Single Nucleotide; D016574:Seasonal Affective Disorder / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D014157:Transcription Factors; C538960:BMAL1 protein, human; C104264:NPAS2 protein, human; C421902:PER2 protein, human