## 4 Discussion  
In conducting the current review, our systematic search of the literature labored over a limited but non-negligible number of studies in order to detect genetic variations in sleep-disordered schizophrenic patients. All included studies possessed a sound and well-elaborated methodological design, however their sample sizes were relatively small thus reducing the statistical value of their conclusions. Moreover, all participants were either of Asian or Caucasian descent, originating from three single geographic regions; in this respect, the existing findings cannot be generalized to other populations with different racial characteristics. To our knowledge, there has been no previous systematic review on this topic, and our findings could constitute an important and novel contribution in the field of schizophrenia and sleep disorders research. The current review's major finding was that certain sleep disorders in schizophrenic patients are associated with specific genetic variations. More specifically, in a series of studies conducted in a Korean sample, it was found that antipsychotic-induced RLS is more frequent in patients carrying certain polymorphisms of _CLOCK_, _BTBD9_, _GNB3_ and _TH_ genes. It should be noted that in all these studies, participants were carefully controlled for a variety of confounding variables, a methodological characteristic which adds further strength to the above findings. In a similar vein, another research group showed that polymorphisms of _MTRN1_ gene (melatonin receptor 1) may be associated with increased frequency of insomnia in patients with schizophrenia. However, a significant limitation of this study was that data analysis did not take into account the  
Figure 2: IPA pathway analysis, in which specific genes emerged throughout our review, are shown in purple. As can be seen, GNB3 enhances APP (Amyloid precursor protein) expression, which has been suggested to have growth promoting properties and a role in neuron plasticity. APP is linked with the expression of TGFB1, which encodes a protein that regulates various cell activities including proliferation, differentiation, motility of cells, and apoptosis. TGFB1 is possibly related to an increase in the expression of TH, which is the rate limiting enzyme in the synthesis of dopamine [28]. Tyrosine hydroxylase is a crucial enzyme for converting tyrosine to DOPA in the pathway of the catecholamine biosynthesis. Diurnal expression of TH is mirrored by the diurnal availability of dopamine in the central nervous system. The protein product of the CLOCK gene is a transcription factor with a crucial role in circadian rhythm regulation, which is suggested to be positively linked to the expression of another transcription factor, the protein of the NF-kB gene. The latter also exhibits a central role in circadian and immune mechanisms. type and dosage of antipsychotic medication, and in this respect the observed differences in insomnia prevalence cannot be definitely attributed to differences in genetic variations, but could also be the result of variations in medication dosage. Furthermore, clozapine-related daytime somnolence was correlated with variants of the _HNMT_ gene. Variants of other genes which have been examined did not correlate with the emergence of RLS or somnolence, a finding which could be attributed to the relatively small sample size included in these studies. For this reason, larger-scale studies should be undertaken in order to further address this issue. It should be noted that the associations we detected involve genes implicated either in the circadian system (_CLOCK_ and _MTNR1_) or in signal transduction (_BTBD9_ and _GNB3_), and neurotransmitters' metabolism (_TH_ and _HNMT_). The circadian clock is an innate biological system which synchronizes human physiology and behavior with the day/night cycle, thus achieving energy equilibrium and promoting adjustment to environmental demands [29].