Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks

Abstract

An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK and hPER3 proteins, respectively. In addition, hCLOCK expression is affected by glucocorticoids, consistent with the sex-dependency of the genetic associations and the modulation of glucocorticoid-mediated stress response, providing a mechanism by which the circadian clock controls outputs that may affect psychiatric disorders. We conclude that genetic polymorphisms in circadian genes (especially hClock and hPer3, where functional assays could be tested) influence risk of developing depression in a sex- and stress-dependent manner. These studies support a genetic connection between circadian disruption and mood disorders, and confirm a key connection between circadian gene variation and major depression.

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

“…3). Many of the transcription factors predicted to bind to the motifs have links to stress-related behaviors and disorders, such as Creb1 and Clock , which are associated with schizophrenia, bipolar disorder, and major depressive disorder (see discussion) (Forero et al, 2016; Johansson et al, 2016; Shi et al, 2016; Wei et al, 2015). Subsequent examination of the sequence data for each DhMR residing in the acute stress-related differentially expressed genes revealed that the majority (>90%) of the potentially functional DhMR-associated genes contained at least one of the enriched transcription factor binding sequence motifs (Dataset 2).…”

“…Putative binding factors were predicted using SpaMo directly from the DREME suite software package and are listed in the tables shown with their putative transcription factors. The literature (Ref) links of each TF to psychiatric disorders are shown: Scz (schizophrenia); BP (Bipolar Disorder); MDD (Major Depressive Disorder); Epi (Epilepsy); ND (Neuronal Differentiation); OCD (Obsessive Compulsive Disorder) (Aston et al, 2005; Basmanav et al, 2015; Butts et al, 2014; Castilhos et al, 2014; Chen et al, 2014b; Chiang et al, 2015; Forero et al, 2016; Forrest et al, 2013; Goes et al, 2015; Grados et al, 2014; Gurung and Prata, 2015; Hattori et al, 2014; Johansson et al, 2016; Jukic et al, 2015; Keyes et al, 2015; Kim et al, 2014; Le-Niculescu et al, 2009; Lisowski et al, 2013; Mencarelli et al, 2008; Nestadt et al, 2012; Rivolta et al, 2014; Rotheram-Fuller et al, 2010; Schlaudraff et al, 2014; Shi et al, 2016; Wang et al, 2014; Wei et al, 2015; Wockner et al, 2014). …”

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

“…Involvement of the clock genes in depression is also evident from several genetic studies. It has been reported that polymorphisms of clock genes is manifested in depressed patients (Partonen et al, 2007; Kripke et al, 2009; Wang et al, 2012; Kovanen et al, 2013; Hua et al, 2014; Shi et al, 2016). …”

Depressive disorders: Processes leading to neurogeneration and potential novel treatments

“…While the role of the circadian system was discovered relatively early in seasonal affective and bipolar disorders, involvement in MDD appeared to be rather uncertain for quite some time. To date polymorphisms of Per3, Cry1, Clock and Npas2 were reported to be associated with MDD (Hua et al, 2014;Shi et al, 2016;Virginia Soria et al, 2010),…”