An Association Analysis of Circadian Genes in Anxiety Disorders

Sipilä, Tessa; Kananen, Laura; Greco, Dario; Donner, Jonas; Silander, Kaisa; Terwilliger, Joseph D.; Auvinen, Petri; Peltonen, Leena; Lönnqvist, Jouko; Pirkola, Sami; Partonen, Timo; Hovatta, Iiris

doi:10.1016/j.biopsych.2009.12.011

Cited by 82 publications

(56 citation statements)

References 62 publications

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“…In addition, the association was not replicated in the replication sample. Our results are consistent with previous studies that found no association between Per2 and anxiety disorders, including PD in a Finnish population 15 and PD in our previous genome-wide association study 20 (rs2304672, allele P¼0.44 and genotype P¼0.71). One possible reason for this is the small magnitude of effect size, which is likely to be typical of single gene effects on complex phenotypes.…”

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confidence: 93%

“…Per2 was nominally associated with bipolar disorder, 13 whereas no associations of Per2 with mood disorders and anxiety disorders have also been observed. 14,15 To find the possible involvement of Per2 in PD, we conducted a two-stage case-control association study in the Japanese population.The study was approved by the Ethical Committee of the Graduate School of Medicine, University of Tokyo. The objective of the present study was clearly explained and written informed consent was obtained from all subjects.…”

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An association analysis of Per2 with panic disorder in the Japanese population

et al. 2011

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Panic disorder (PD) is a severe and chronic psychiatric disorder, with genetic components underlying in its etiology. The PERIOD2 (Per2) gene has been reported to be associated with familial advanced sleep phase syndrome. Considering the high frequency of sleep disturbance in PD, Per2 may be a candidate gene for PD. Therefore, we conducted a two-stage case-control association study in the Japanese population. In the first screening sample of 203 patients and 409 controls, we investigated three single-nucleotide polymorphisms in Per2. We found a potential association in the screening sample (rs2304672, genotype P¼0.046, uncorrected), whereas we could not replicate the association in the second sample of 460 patients and 460 controls. Our results suggest that Per2 may not have a major role in the pathogenesis of PD in the Japanese population. Keywords: case-control study; Japanese population; panic disorder; Per2Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety, with a lifetime prevalence of 1-3% and a female:male ratio of 2:1. 1 PD frequently takes a chronic course, with many remissions and relapses, occasionally complicated by comorbidity with other psychiatric disorders, such as agoraphobia and major depression. 2 Twin and family studies have provided evidence for both genetic and environmental factors, contributing to susceptibility to PD. 3,4 Heritability of PD has been estimated about 40% on the basis of the meta-analyses of twin studies. 5 Because of the phenotypic and genetic heterogeneity of PD and the small effect size of individual variants, only a few candidate genes have been identified so far. 6 Sleep disturbance is frequently present among psychiatric patients and has been incorporated in the diagnostic criteria for major depression, post-traumatic stress disorder and generalized anxiety disorder. Several studies demonstrated that individuals with PD report significant sleep disturbances. 7,8 The sleep-wake cycle, as well as other rhythmic variations in physiological and metabolic processes (hormone production, feeding behavior and brain activity), is generated by an endogenous pacemaker. In mammals, the principal circadian clock, which coordinates peripheral clocks in the body, is located in the suprachiasmatic nucleus and produces a nearly 24-h cycle through interacting positive/negative feedback loops. It is comprised of the positive regulators (CLOCK/ARNTL complexes) and the negative regulators (PER1, PER2, PER3, CRY1 and CRY2). 9 A polymorphism of PERIOD2 (Per2) has been reported to be associated with familial advanced sleep phase syndrome. 10 Carpen et al. 11 founded that the 111G allele of Per2 (rs2304672) was associated with extreme morning preference. Lee et al. 12 reported that the G3853A single-nucleotide polymorphism (SNP) of Per2 (rs934945) was associated with diurnal preference in Korean subjects. Per2 was nominally associated with bipolar disorder, 13 whereas no associations of Per2 with mood disorders and anxiety disorders have also b...

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An association analysis of Per2 with panic disorder in the Japanese population

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“…Similarly, bcl2l2 has been shown to play a role in cell survival in cell lines (27). Similar to ntrk3, an SNP in bcl2 has been found to be associated with generalized anxiety disorder (28). These results suggest that the bcl2 family may both regulate cell survival and play a role in anxiety disorders.…”

Section: Discussionmentioning

confidence: 84%

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

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Thompson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety-and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders. elevated plus maze | gene expression microarray H uman postmortem studies suggest a role for the fibroblast growth factor (FGF) system in the pathophysiology of mood disorders. The expression of several members of the FGF family was altered in the forebrain of patients with major depressive disorder (MDD). Specifically, FGF2 mRNA expression was down-regulated in cortical areas and the hippocampus in MDD compared with controls (1, 2). The hippocampus seems to be particularly affected in MDD (3). A potential role for FGF2 in depression and anxiety disorders was first suggested by pharmacological studies in rodents, which showed that administration of antidepressant and anxiolytic drugs can increase FGF2 expression in the hippocampus (3-6). We then asked whether FGF2 is a modulator of emotionality in rodents and discovered that repeated administration of FGF2 was both antidepressant and anxiolytic (7,8).Using rats selectively bred for differences in novelty-seeking, we found that hippocampal expression of FGF2 mRNA was higher in high responders to novelty (bHRs) than in the low responders to novelty (bLRs). The bHRs have higher FGF2 levels and exhibit less anxiety-like behavior, whereas the bLRs exhibit more anxiety-like behavior. FGF2 seems to be a protective factor against anxiety-like behavior in the adult (7). Th...

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“…Genetic variations in circadian rhythm genes are significantly associated with a large variety of neuropsychiatric disorders, such as Major Depressive Disorder (MDD) (Levebratt et al 2010;Hua et al 2014), winter depression (Partonem et al 2007), dysthymia (Kovanen et al 2013), anxiety (Sipila et al 2010) and schizophrenia (Mansour et al 2009). Polymorphisms associated with important genes of serotonergic transmission are also constantly associated with predisposing factors for such condition (Petito et al 2016;Wang et al 2016).…”

Section: Introductionmentioning

confidence: 99%