An Association Analysis of Circadian Genes in Anxiety Disorders Tessa Sipilä, Laura Kananen, Dario Greco, Jonas Donner, Kaisa Silander, Joseph D. Terwilliger, Petri Auvinen, Leena Peltonen, Jouko Lönnqvist, Sami Pirkola, Timo Partonen, Iiris Hovatta  Biological Psychiatry  Volume 67, Issue 12, Pages 1163-1170 (June 2010) DOI: 10.1016/j.biopsych.2009.12.011 Copyright © 2010 Society of Biological Psychiatry Terms and Conditions

Figure 1 A candidate gene signaling pathway connecting circadian rhythmicity and anxiety behavior. Light has been shown to regulate expression levels of both DRD2 (27) and NR4A1 (24). PAWR directly interacts with DRD2 via the calmodulin binding motif. Mutant mice that lack this interaction domain exhibit enhanced dopamine cyclic adenosine monophosphate (cAMP)/cAMP–responsive element binding protein signaling and increased depression-like behavior (26). PAWR also regulates the expression of BCL2 through a Wilms' tumor 1 gene (WT1) binding site on the BCL2 promoter (25). In vitro, BCL2 has been shown to interact with NR4A1 through the N-terminal loop region of BCL2 (23). In addition to these genes that can be directly linked by function, we also detected some evidence for association to ARNTL2, which has been associated with bipolar disorder (60). ARNTL2 can be indirectly linked to the pathway through a circadian gene PAI-1 as CLOCK/ARNTL2 heterodimer induces the expression of PAI-1 (62). In contrast, deficiency of PAI-1 led to decreased Bcl2 mRNA in neuronally differentiated rat PC-12 cells (63), linking ARNTL2 to the BCL2 pathway through PAI-1. NR4A1 is the only gene described in the figure for which we did not find any evidence of association. NR4A1, ARNTL2, and PAWR are transcription factors; DRD2 is a G protein–coupled receptor; and BCL2 a mitochondrial protein. ARNTL2, aryl hydrocarbon receptor nuclear translocator-like 2; BCL2, B-cell CLL/lymphoma 2; DRD2, dopamine receptor D2; NR4A1, nuclear receptor subfamily 4, group A, member 1; PAWR, PRKC, apoptosis, WT1, regulator; PAI-1, plasminogen activator inhibitor-1. Biological Psychiatry 2010 67, 1163-1170DOI: (10.1016/j.biopsych.2009.12.011) Copyright © 2010 Society of Biological Psychiatry Terms and Conditions