The studies that have been published since 1990 which are dealing with the relationship of the genetic polymorphism of the dopamine D2 receptor gene (DRD2) in relation to alcoholism or other disorders or diseases have brought contradictory results. These results have led the author of this thesis to closely investigate the relationship between the genetic polymorphism of the A1 allele gene for DRD2 and hazardous alcohol consumption in the Czech Republic with a focus on the artistic area. A total of 29 participants (15 artists and 14 "non-artists") were involved in the study. The criterion for selecting the examined sample was the type of professional focus (artistic, non-artistic). A genetic analysis of blood (PCR-RFLP method) was used to determine the genotype. Only in the "non-artistic" group the presence of the genetic polymorphism of the A1 allele for DRD2 was found (a predisposition to a risk behavior in relation to alcohol). Additional parameters were found using EEG, an AUDIT test and a temperament questionnaire. A statistical analysis confirmed an association between the appearance of the A1 allele for DRD2 and a higher amplitude of the P300 component (p = 0.0000421). Statistically proven riskier alcohol consumption was found among introverted artists (n = 9) in the AUDIT test (p = 0.02298).

The variability in caffeine consumption and inconsistencies among studies linking caffeine to heart disease may be explained by genetic variation. Caffeine antagonizes adenosine receptors with downstream effects on dopamine and serotonin. The objectives of this thesis were to determine whether the DRD2 957C>T or HTR2A 102C>T polymorphisms are associated with caffeine consumption or modify the association between coffee consumption and risk of myocardial infarction (MI). DRD2 genotype was associated with caffeine consumption among non-smokers and CYP1A2 -163C allele carriers. HTR2A genotype was associated with caffeine consumption among non-smokers and subjects with the ADORA2A TT genotype. Neither polymorphism modified the association between coffee consumption and risk of MI; however, a significant coffee x HTR2A interaction was seen among subjects with the CYP1A2 -163C allele. The results suggest caffeine’s reinforcing effects may be mediated by the dopamine and serotonin receptors and implicate serotonin in caffeine’s effect on risk of MI.

The variability in caffeine consumption and inconsistencies among studies linking caffeine to heart disease may be explained by genetic variation. Caffeine antagonizes adenosine receptors with downstream effects on dopamine and serotonin. The objectives of this thesis were to determine whether the DRD2 957C>T or HTR2A 102C>T polymorphisms are associated with caffeine consumption or modify the association between coffee consumption and risk of myocardial infarction (MI). DRD2 genotype was associated with caffeine consumption among non-smokers and CYP1A2 -163C allele carriers. HTR2A genotype was associated with caffeine consumption among non-smokers and subjects with the ADORA2A TT genotype. Neither polymorphism modified the association between coffee consumption and risk of MI; however, a significant coffee x HTR2A interaction was seen among subjects with the CYP1A2 -163C allele. The results suggest caffeine’s reinforcing effects may be mediated by the dopamine and serotonin receptors and implicate serotonin in caffeine’s effect on risk of MI.

Abstract Psychotic disorders usually become evident during adolescence and early adulthood and are commonly preceded by psychosis risk states. Young people at risk for developing psychosis may already have cognitive deficits. This research examined factors associated with psychosis risk and adverse cognitive performance, particularly in those at risk for developing psychosis. We aimed to characterise genetic risk factors for psychosis risk and adverse cognitive performance. Additionally, early and later biological risk markers for adverse cognitive performance and psychosis risk were explored. Two longitudinal birth cohorts, the Northern Finland Birth Cohort 1986 (NFBC 1986, n=6,985 at 16 years) and Avon Longitudinal Study of Parents and Children (ALSPAC, n=5,217 at 17 years), two NFBC 1986 sub-studies, the Oulu Brain and Mind 1 (n=182 for these analyses) and Oulu Brain and Mind 2 (n=471 for these analyses) studies, and two Irish case control studies, the Adolescent Brain Development (n=212) and Challenging Times (n=211) studies, were utilised. Predictors of interest were selected Single Nucleotide Polymorphisms (SNPs at COMT, BDNF and DRD2), prenatal exposure to maternal cigarette smoking (PEMCS) and adolescent metabolic measures. Though not directly associated with psychotic experiences, the COMT-Val158Met Val-Val genotype interacted with experience of childhood trauma to predict more psychotic experiences. Two DRD2 SNPs were associated with poorer cognitive performance, though only in those with risk for psychotic disorders. PEMCS was associated with adult vocabulary and matrix reasoning performance in males, though not in males with adolescent psychotic experiences. Adolescent academic performance, but not psychotic experiences, were associated with metabolic measures, especially with ratios of omega-3 to total fatty acids. These findings impact on prevention strategies for long-term adverse outcomes. Some risk factors differ for those with psychotic experiences compared to the general population, while others do not. SNPs at COMT and DRD2 may be more relevant in those with psychotic experiences. Interventions targeting these groups may be particularly beneficial. Smoking in pregnancy, however, is harmful to male cognitive performance across the population, suggesting elimination of this risk is more broadly relevant. Fatty acid-related metabolic measures may mark risk for cognitive deficits or may represent a developmental feature that is potentially open to intervention. / Tiivistelmä Psykoottiset häiriöt puhkeavat tavallisesti nuoruusiässä tai varhaisessa aikuisiässä. Varsinaista psykoosijaksoa edeltää usein psykoosialttiusvaihe. Nuoruusiän psykoosialttiusvaiheeseen liittyy kognitiivisia puutoksia. Tässä tutkimuksessa selvitettiin tekijöitä, jotka liittyvät psykoosialttiuteen ja heikkoon kognitiiviseen suoriutumiseen, etenkin nuorilla, jotka olivat psykoosiriskissä. Tutkimuksessa tarkasteltiin psykoosialttiuteen ja heikkoon kognitiiviseen suoriutumiseen liittyviä geneettisiä tekijöitä. Lisäksi tutkittiin biologisia varhaisia ja myöhempiä psykoosialttiutta ja heikkoa kognitiivista suoriutumista ennustavia tekijöitä. Tutkimusaineisto käsitti kaksi pitkittäistä syntymäkohorttia: Pohjois-Suomen syntymäkohortti 1986 (n=6,985 16-vuotiaana) ja englantilainen Avon Longitudinal Study of Parents and Children (ALSPAC, n=5,217 17-vuotiaana) -tutkimukset. Pohjois-Suomen syntymäkohortti 1986:sta analysoitiin kahta ala-otosta eli Aivot ja Mieli I (n=182) ja Aivot ja Mieli II (n=471) tutkimusta. Lisäksi tutkimusaineistoon kuului kaksi irlantilaista tapaus-verrokki tutkimusta: Adolescent Brain Development (n=212) ja Challenging Times (n=211) tutkimukset. Ennustavina tekijöinä tarkasteltiin yhden nukleotidin polymorfismia (Single Nucleotide Polymorphisms, SNP; COMT, BDNF ja DRD2 -geeneissä), äidin raskaudenaikaista tupakointia, lapsuuden traumaattisia kokemuksia ja nuoruusiän metabolisia arvoja. COMT-Val158Met geenin Val-Val genotyyppi ei ollut suoraan yhteydessä psykoottisiin kokemuksiin, mutta yhdessä lapsuuden traumaattisten kokemusten kanssa ennusti suurempaa psykoosioireiden määrää. Kaksi DRD2 SNP-varianttia assosioituivat heikompaan kognitiiviseen suoriutumiseen, vaikkakin vain tutkittavilla jotka olivat psykoosialttiita. Äidin raskaudenaikainen tupakointi ennusti huonompaa kognitiivista suoriutumista pojilla, tosin ei pojilla joilla oli nuoruusiässä psykoosioireita. Metaboliset tekijät, erityisesti omega-3 rasvahapon suhde kokonaisrasvahapon määrään oli yhteydessä koulumenestykseen. Tutkimuksen tulosten perusteella voidaan mahdollisesti suunnitella ennaltaehkäiseviä toimia myöhempien haittojen ehkäisemiseksi. Jotkut tutkituista riskitekijöistä assosioituivat eri tavalla kognitioon psykoosialttiilla kuin yleisväestössä. COMT ja DRD2 geenien variantit psykoosialttiilla saattavat olla keskeisiä. Interventiot nuorille, joilla on nämä variantit ja psykoosioireita, voisivat olla erityisesti hyödyllisiä. Äidin raskauden aikaisen tupakointi ennusti poikien kognitiivista suoriutumista. Äidin raskaudenaikaisen tupakoinnin vähentämisellä olisi suotuinen vaikutus tässäkin suhteessa. Rasvahappoihin liittyvät metaboliset suureet voivat olla riski kognitiivisille puutoksille tai ne voivat merkitä kehityksellistä piirrettä, joka voisi mahdollistaa varhaisen ennaltaehkäisyn.

Genetic factors underlying alcoholism, substance abuse, antisocial and violent behaviour, psychosis, schizophrenia and psychopathy are emerging to implicate dopaminergic and cannabinoid, but also monoaminergic and glutamatergic systems through the maze of promoter genes and polymorphisms. Candidate gene association studies suggest the involvement of a range of genes in different disorders of CNS structure and function. Indices of comorbidity both complicate the array of gene-involvement and provide a substrate of hazardous interactivity. The putative role of the serotonin transporter gene in affective-dissociative spectrum disorders presents both plausible genetic variation and complication of comorbidity. The position of genetic variation is further complicated through ethnic, contextual and social factors that provide geometric progressions in the comordity already underlying diagnostic obstacles. The concept of shared biological susceptibilty to two or more disorder conditions of comorbidity seems a recurring observation, e.g., bipolar disorder with alcoholism or schizophrenia with alcohol/substance abuse or diabetes with schizopsychotic disorder. Several lines of evidence seem to suggest that the factors influencing variation in one set of symptoms and those affecting one or more disorders are observed to a marked extent which ought to facilitate the search for susceptibility genes in comorbid brain disorders. Identification of regional genetic factors is awaited for a more compelling outline that ought eventually to lead to greater efficacy of symptom-disorder arrangements and an augmentation of current pharmacological treatment therapies.

Reduction in dopamine receptor D2, has been associated with insufficient brain reward, food addiction, obesity, and type 2 diabetes (T2D). Our aim was to assess whether the genetic variability responsible for this reduction is associated with poor dietary compliance and life style habits in T2D patients. Genetic-analysis was done for 109 T2D individuals who completed a 24-week randomized clinical trial and were assigned to follow either a low-GI or a high-fibre diet. Polymorphisms of TaqIA and C957T were compared with physical and biochemical measures. Regardless of dietary treatments, individuals with the C957T-T allele and the TaqIA-A2 allele were significantly associated with blood pressure reduction. Carriers of the T allele significantly lowered their body mass index (BMI) over the 24-week trial. Our findings suggest that the presence of the TaqIA-A2 allele is associated with a decrease in blood pressure. The C957T-T allele was associated with decrease in pressure and body weight.

Reduction in dopamine receptor D2, has been associated with insufficient brain reward, food addiction, obesity, and type 2 diabetes (T2D). Our aim was to assess whether the genetic variability responsible for this reduction is associated with poor dietary compliance and life style habits in T2D patients. Genetic-analysis was done for 109 T2D individuals who completed a 24-week randomized clinical trial and were assigned to follow either a low-GI or a high-fibre diet. Polymorphisms of TaqIA and C957T were compared with physical and biochemical measures. Regardless of dietary treatments, individuals with the C957T-T allele and the TaqIA-A2 allele were significantly associated with blood pressure reduction. Carriers of the T allele significantly lowered their body mass index (BMI) over the 24-week trial. Our findings suggest that the presence of the TaqIA-A2 allele is associated with a decrease in blood pressure. The C957T-T allele was associated with decrease in pressure and body weight.