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

S-Q Shi,P A De Verteuil,H M Borsetti,C M Ciarleglio,R C Shelton,J S Pendergast,M J White,D G Mcmahon,A G Cadar,C Cala,S M Williams,C H Johnson,A Hida

doi:10.1038/tp.2016.9

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.

Highlights

Circadian rhythms pervasively control the behavior, physiology and biochemistry of humans, including the timing of sleep
Our data indicate that polymorphisms in hClock and hPer[3] genes impact the functional activity of these proteins and, together with Functional analyses a polymorphism in hNpas[2], exhibit sex- and stress-dependent association with major depressive disorder (MDD) in humans
Undertook a candidate gene study that focused upon a small number of common polymorphisms in circadian clock genes to test an association with MDD, performing both combined and gender-stratified analyses, the latter based on the 450% higher prevalence of MDD in females

Summary

INTRODUCTION

Circadian rhythms pervasively control the behavior, physiology and biochemistry of humans, including the timing of sleep. ARNTL complex regulates rhythmic transcription of clockcontrolled genes in tissues throughout the body, and this includes at least 15% of all mammalian transcripts;[23,24] many of these gene expression patterns are disrupted in humans suffering from MDD.[8] than chi-square testing under some genetic models and was performed to provide independent evidence for association.[32] Association analysis methods are described fully in the Supplementary Materials and Methods. Our data indicate that polymorphisms in hClock and hPer[3] genes impact the functional activity of these proteins and, together with Functional analyses a polymorphism in hNpas[2], exhibit sex- and stress-dependent association with MDD in humans. The PSV40::FLuc::3′-UTR firefly luciferase reporter for the 3′-UTR of hClock (containing the major allele T) was provided by Dr Malcolm von Schantz.[33]

MATERIALS AND METHODS

Findings

DISCUSSION