Genetic Variations Associated with Sleep Disorders in Patients with Schizophrenia: A Systematic Review

Abstract

Background: Schizophrenic patients commonly suffer from sleep disorders which are associated with acute disease severity, worsening prognoses and a poorer quality of life. Research is attempting to disentangle the complex interplay between schizophrenia and sleep disturbances by focusing not only on demographic and clinical characteristics, but also on the identification of genetic factors. Methods: Here, we performed a systematic literature review on the topic of genetic variations in sleep-disordered schizophrenic patients in an attempt to identify high quality investigations reporting scientifically sound and clinically useful data. For this purpose, we conducted a thorough search of PubMed, ScienceDirect and GoogleScholar databases, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. Results: Our search yielded 11 eligible studies. Certain genetic variations were reported to be associated with schizophrenia-related sleep disorders. Antipsychotic-induced restless legs syndrome was linked to polymorphisms located on CLOCK, BTBD9, GNB3, and TH genes, clozapine-induced somnolence was correlated with polymorphisms of HNMT gene, while insomnia was associated with variants of the MTNR1 gene. Conclusions: There are significant genetic associations between schizophrenia and co-morbid sleep disorders, implicating the circadian system, dopamine and histamine metabolism and signal transduction pathways.

Keywords: circadian; genes; insomnia; polymorphisms; restless-legs syndrome; schizophrenia; sleep disorders; somnolence.

Figure 1

Process of articles selection.

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.