Molecular and bioinformatics evaluation of PRNP as a candidate gene for successful suicidal behavior

Abstract

Contemplating suicide, suicide attempts, and successful suicides represent the suicidal behavior accompanied by depression and hopelessness. Suicide is among the major causes of death worldwide. According to obtained data, it has been reported that approximately 800,000 suicide deaths occur worldwide every year and the frequency of suicide varies from country to country. Many suicide attempts or the contemplation of suicide are associated with psychological disorders such as depression and schizophrenia as well as alcoholism and drug abuse. It has been demonstrated that depression, which affects nearly 350 million people worldwide is strongly linked to suicidal behavior, as it is the most common disorder in people who die from suicide. There are several major hypotheses in the pathogenesis of depression. One of them is the monoamine hypothesis and the insufficiency of monoamine neuromediators such as serotonin, norepinephrine, and dopamine in the central nervous system is considered to be a triggering factor for the development of depression. Another hypothesis is the stress hypothesis, and chronic stress and stressful life events are accepted as a predictor in the onset of depression. The third one is the disturbance of neurogenesis and neuroplasticity caused by especially brain-derived neurotrophic factors (BDNF) in nervous tissue. Another depression development related theory is the cytokine theory explained by the activation of the inflammatory response system inducing the various behavioral, neuroendocrine, and neurochemical alterations. Finally, the circadian rhythm theory that is responsible for regulating many physiological and behavioral processes and sleep disorders are reported to occur in most of the individuals suffering from depression. The findings about physiological roles or normal functions of the prion protein are very limited but there are several studies showing the possible role of prion protein in circadian rhythm, sleep deprivation and development of depression using mice devoid of prion protein. Relying on these findings, we sequenced the prion protein coding genes in a cohort of individuals who had successfully committed suicide (n = 75) and compared allele and genotype frequencies with a control group (n = 44). We also applied bioinformatics analysis to detect the interaction between the prion protein Met/Val allele and DRD2, PER2, PER3, and COMT proteins, which are very present in the brain and related to depression, stress, and circadian rhythm. Among the individuals who died by suicide, although the frequency of the homozygous Met/Met genotype (45/75; 60%) was higher compared to the control group (20/44; 45.45%), no statistically significant difference was found (X² = 2.530; P = 0.282). Parallel to this, the frequency (76.6%) of Met allele detected in the individuals who died by suicide was also higher than that of (67%) the control group, but no statistically significant difference was found (X² = 4.338; P = 0.114). Docking analysis also showed that the prion protein with Val allele had a higher binding affinity with proteins analyzed according to the Met allele. In conclusion, the Met/Met genotype and Met allele frequencies were detected to be higher in the completed suicidal group. Also, the interaction between the prion protein with the M allele and proteins analyzed was lower. Based on these findings, it was thought that carriers of the prion Met allele may be more prone to suicide.