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Posttraumatski stresni poremećaj (PTSP) je stresom izazvan poremećaj koji se razvija nakon izlaganja traumatskom događaju. Patofiziologija PTSP-a uključuje poremećaje dopaminergičke funkcije. Funkcionalni polimorfizam rs4680 (Val108/158Met) katehol-o-metil transferaze (COMT) je zbog utjecaja na aktivnost samog enzima, važan za regulaciju degradacije dopamina, posebice u prefrontalnom korteksu. Oblik enzima s valinom se povezuje s njegovom povećanom aktivnošću. Cilj ovog diplomskog rada bilo je ispitati povezanost genotipa obzirom na polimorfizam rs4680 gena COMT i težine simptoma PTSP-a procijenjenih kliničkom ljestvicom pozitivnih i negativnih simptoma (PANSS). Studija je uključila 573 muškarca oboljelih od PTSP-a izazavnog ratnim iskustvom kod kojih je težina simptoma prema PANSS-u ovisila o tome jesu li pušači. Istraživanje je pokazalo značajnu povezanost genotipa Met/Met s manjim brojem bodova ostvarenih na PANSS podljestvicama za kogniciju, psihotične simptome i agitaciju kod nepušača te s većim brojem bodova ostvarenih na općoj psihopatološkoj ljestvici kod pušača. Zaključno, polimorfizam rs4680 gena COMT je povezan s težinom pojedinih simptoma procjenjenih prema PANSS-u. Posttraumatic Stress Disorder (PTSD) is a stress-related disorder caused by an exposure to a traumatic event. Pathophysiology of PTSD involves dysfunctions in dopaminergic system. A functional polymorphism rs4680 (Val108/158Met) of catechol-o-methyltransferase (COMT), due to its effect on the activity of the enzyme, plays an important role in dopamine degradation, especially in prefrontal cortex. The valine variant is associated with increased enzymatic activity. The aim of this thesis was to examine the association of COMT rs4680 genotypes and severity of PTSD symptoms according to positive and negative syndrome scale (PANSS). The study included 573 men with combat related PTSD, whose symptoms' severity according to the PANSS was related to their smoking status. Results indicated a significant association of Met/Met genotype with lower scores on PANSS cognitive, psychosis and excitement subscales in nonsmokers and with higher scores on general psychopathology scale in smokers. In conclusion, the COMT rs4680 polymorphism contributes to the severity of individual PTSD symptoms assessed using the PANSS.

Shizofrenija je teška psihička bolest koja zahvaća 1% opće populacije. Dijagnoza se postavlja prema kliničkoj slici i prisutnim simptomima. Premda sama biološka osnova nije razjašnjena, danas je najprihvaćenija dopaminska hipoteza prema kojoj dopamin ima centralnu ulogu u nastanku shizofrenije. Dopaminske puteve u mozgu velikim dijelom prati serotoninski put za koji je utvrđeno da ima inhibitorni učinak na dopaminski sustav. Djelovanje dopamina regulira dopaminski transporter i katekol-o-metil transferaza, a djelovanje serotonina regulira serotoninski transporter i monoamino-oksidaza A, koja osim što sudjeluje u metabolizmu serotonina, sudjeluje i u metabolizmu dopamina. Hipoteza ovog istraživanja je da bi funkcionalni polimorfizmi dopaminskog transportera (DAT-VNTR), katekolo- metil transferaze (COMT Val158Met), serotoninskog transportera (5-HTTLPR) i monoamino-oksidaze A (MAOA-uVNTR) mogli biti povezani sa pojavom simptoma shizofrenije. Ciljevi ovog istraživanja su: Ispitati povezanost pojedinih polimorfizama i kombinacija genotipova sa shizofrenijom. U skupini ispitanika sa shizofrenijom ispitati povezanost polimorfizama sa simptomima bolesti. Uspostaviti regresijski model za predviđanje shizofrenije. U istraživanje je uključeno 314 zdravih ispitanika i 306 ispitanika sa dijagnozom shizofrenije. Za ispravnu klasifikaciju zdravih ispitanika korišten je MINI upitnik i fizikalni pregled. Dijagnoza shizofrenije postavljena je prema DSM IV standardu, a simptomi shizofrenije ocijenjeni su PANSS i Calgary skalom. Genotipizacija ispitivanih polimorfizama rađena je PCR reakcijom uz elektroforetsko razdvajanje dobivenih fragmenata odnosno PCR-RFLP metodom za genotipizaciju COMT Val158Met polimorfizma. Usporedbom zdravih i ispitanika sa shizofrenijom utvrđeno je sljedeće: na ukupnom uzorku utvrđena je statistički značajna razlika u distribuciji DAT-VNTR polimorfizma. U podskupini žena utvrđena je statistički značajna razlika u distribuciji COMT Val158Met polimorfizma a u podskupini muškaraca utvrđena je povezanost MAOA-uVNTR polimorfizma sa shizofrenijom. U skupini ispitanika sa shizofrenijom utvrđena je povezanost COMT Val158Met polimorfizma sa obiteljskim hereditetom. Utvrđen je logistički model za predviđanje shizofrenije. Schizophrenia is severe psychiatric disorder which affects 1% of general population. Diagnosis of schizophrenia is based on presence of clinical symptoms but its exact pathophysiology is still unknown. However, according to extensive research the most accepted is dopamine hypothesis by which dopamine plays central role in development of schizophrenia. Dopamine pathways in brain are followed by serotonin pathway which has inhibitory effect on dopamine. Dopamine action is regulated by dopamine transporter and catechol-o-methyltranspherase, while serotonin action is regulated by serotonin transporter and monoamine-oxidase A which is also included in dopamine metabolism. Hypothesis of this research is that polymorphisms of dopamine transporter (DAT-VNTR), catechol-omethyltranspherase (COMT Val158Met), serotonin transporter (5-HTTLPR) and monoamine oxidase A (MAOA-uVNTR) might be associated with symptoms of schizophrenia. The aims of this research were: To test association of polymorphisms and genotype combinations with schizophrenia. In group of patients with schizophrenia, test association of polymorphisms with schizophrenia symptoms. To establish regression model for prediction of schizophrenia. 314 healthy volunteers and 306 patients with schizophrenia were included in this research. Healthy volunteers were included based on MINI psychiatric questioner and physical exam. Schizophrenia was diagnosed based on DSM IV standard and symptoms of schizophrenia were assessed by PANSS and Calgary scale. For detection of polymorphisms we used PCR followed by electrophoresis with exception of COMT Val158Met polymorphism for which we used PCR-RFLP method. Comparing healthy volunteers and patients with schizophrenia, the following was established: In overall sample there was statistically significant difference in distribution of DAT-VNTR polymorphisms. In female population we found statistically significant difference in distribution of COMT Val158Met polymorphism. In male population we found statistically significant distribution of MAOA-uVNTR polymorphism. In group of patients with schizophrenia we found association of COMT Val158Met polymorphism with family heritage of schizophrenia. Logistic regression model was established for predicting schizophrenia.

Attention deficit hyperactivity disorder (ADHD) is a multifactorial, highly heritable developmental disorder characterized by behavioral symptoms of impulsivity, hyperactivity and/or inattention. The enzyme cathecol-O-methyl transferase (COMT), which is responsible for the degradation of catecholamines, could have an important role in genetic susceptibility to ADHD. COMT could play a significant role in modulating dopamine levels in the prefrontal cortex which was implicated in ADHD etiology. We aimed to analyze the association of COMT Val108/158Met (rs4680) polymorphism which affects COMT activity with ADHD features since genetic studies of the functional Val158Met polymorphism in ADHD have been inconsistent. The study included 113 medication free children with ADHD diagnosed according to the DSM-IV criteria and 187 children without psychiatric diagnoses and free of medication that served as control group. Genotyping was done using the TaqMan SNP Genotyping Assay. We found an association between Val108/158Met polymorphism and the symptoms of ADHD in male, but not in female children. Lack of association in female children is probably due to a small number of female patients with ADHD, which represents the limitation of this study. We also found an association with ADHD features when comparing Val carriers to Met/Met homozygotes in male children. These differences were especially significant when comparing male patients with combined type of ADHD with healthy control subjects. Our results confirmed the association between COMT variants and ADHD in male children, which was due to the higher frequency of Met/Met homozygotes in children with ADHD compared to healthy controls. These results suggest that carriers of the high activity COMT variant are less prone to develop ADHD. This study also suggests that COMT Val108/158Met polymorphism is associated with the ADHD combined subtype.