This study is focused on the dopamine D2 receptor and the linkage between TaqIA and - 141C Ins/Del polymorphisms in DRD2 gene and novelty seeking behaviour, as well as the linkage between Val158Met polymorphism in COMT gene and novelty seeking behaviour. Novelty seeking behaviour is characterized as a personality trait with a tendency to look for novel stimulation and extravagances at any cost of legal, physical and social risk to reward cues. DRD2 and COMT genes are associated with the function of dopamine, which is essential for motoric function and reward-motivated behaviour. Therefore, the aim of this study is to ascertain the potential linkage among the three studied polymorphisms and novelty seeking behaviour.

Delay Discounting im Sinne eines Abwertens zukünftiger Belohnungen ist ein weit verbreitetes Phänomen. Es zeigt sich z. B. in persönlichen Angelegenheiten, wie der Entscheidung für den kurzfristigen Genuss von Süßigkeiten und gegen die langfristigen, durchaus größeren Vorteile einer schlanken Figur. Auch internationale wirtschaftliche und politische Diskussionen zum Klimaschutz oder der Finanzkrise werden von der Präferenz für sofortige, kleinere Belohnungen über verzögerte, größere Belohnungen getrieben. In der Psychologie wird Delay Discounting als Maß für Impulsivität bzw. Selbstkontrolle mit dem Auftreten von Aufmerksamkeitsdefizit-Hyperaktivitäts-Syndromen und von Abhängigkeitserkrankungen in Verbindung gebracht. Bezüglich der neuronalen Grundlagen von Delay Discouting ist mithilfe von sogenannten Intertemporal Choice Tasks bereits herausgefunden worden, dass die Entscheidung für eine sofortige Belohnung stärkere neuronale Aktivierung in belohnungsspezifischen Gehirnregionen evoziert als die Entscheidung für eine verzögerte Belohnung. Außerdem wurden sowohl theoretisch wie auch empirisch ein impulsives und ein reflektives System als Grundlage des Delay Discounting beschrieben, deren Existenz jedoch von manchen Wissenschaftlern angezweifelt wird. Ebenso wird angezweifelt, ob Delay Discounting unabhängig vom Einsatz von Intertemporal Choice Tasks und der damit verbundenen Entscheidung zwischen zwei Alternativen überhaupt besteht. Da die neuronalen Grundlagen des Delay Discounting und des impulsiven und reflektiven Systems bisher nicht unabhängig von einer Entscheidungsaufgabe erfasst wurden, konnten diese Zweifel nicht ausgeräumt werden. Ebenso ist zurzeit unbekannt, ob sich die neuronalen Korrelate des Delay Discounting bei Personen mit unterschiedlichen Persönlichkeitseigenschaften, bei Männern und Frauen, bei Rauchern und Nichtrauchern und in Abhängigkeit von verschiedenen Genvarianten unterscheiden. Um diese Lücke zu schließen, ist im Rahmen der vorliegenden Arbeit ein neuartiges Delay Discounting Paradigma zum Einsatz im Magnetresonanztomographen entwickelt worden. Dieses Paradigma ähnelt einem Monetary Incentive Delay Task und ermöglicht es, neuronale Aktivierung bei der Antizipation und bei dem Erhalt einer einzelnen Belohnung zu einem Zeitpunkt zu erfassen. Außerdem kann nach der Antizipation einer Belohnung, die sich durch eine bestimmte Höhe (0,05 €, 0,50 €, 1,00 €) und eine bestimmte Auszahlungsverzögerung (0 Tage, 10 Tage, 100 Tage) auszeichnet, in einer einfachen visuellen Diskriminationsaufgabe eine Reaktionszeit erfasst werden, die als behaviorales Maß für die inzentive Motivation fungiert. Zusammen mit einer Erfassung verschiedener Persönlichkeitseigenschaften und einer Genotypisierung für den COMT Val 158 Met Polymorphismus, den DRD2 Taq 1 A Polymorphismus und den DAT 1 Polymorphismus ist das Delay Discounting Paradigma an insgesamt 90 Probanden im Magnetresonanztomographen eingesetzt worden, so dass 84 auswertbare Datensätze gewonnen werden konnten. Diese 84 Datensätze stammten insgesamt von 42 Frauen und 42 Männern bzw. von 43 strikten Nichtrauchern, 38 starken Rauchern und drei Gelegenheitsrauchern. Anhand der Auswertung der Gesamtstichprobe konnte bestätigt werden, dass das Delay Discounting Paradigma belohnungs- und verzögerungsspezifisch unterschiedliche Reaktionszeiten und unterschiedliche neuronale Aktivierung hervorruft. In belohnungsverarbeitenden Gehirnregionen wie dem ventralen Striatum zeigte sich sowohl stärkere Aktivierung für größere Belohnungen als auch für Belohnungen, die früher ausgezahlt wurden. Damit steht fest, dass Delay Discounting unabhängig von der Entscheidung zwischen zwei Alternativen auftritt. Außerdem konnte erstmalig ein Interaktionseffekt zwischen Belohnungshöhe und Belohnungsverzögerung aufgedeckt werden: Es zeigte sich eine Abnahme der Differenzen in der neuronalen Aktivierung zwischen größter und kleinster Belohnung über die Zeit, was auf eine Indifferenz gegenüber der Höhe verzögerter Belohnung hindeutet. Ein Einfluss der Belohnungsverzögerung wurde allerdings nur beim Erhalt von Belohnungen messbar, bei der Antizipation von Belohnungen zeigte sich kein Delay Discounting Effekt. Bezüglich der Kontroverse zur Existenz eines impulsiven und reflektiven Systems konnten Ergebnisse gewonnen werden, die beide Positionen integrieren. So wurde zwar die Beteiligung von zwei distinkten neuronalen Systemen beim Abwerten zukünftiger Belohnungen bestätigt, allerdings zeigte sich auch, dass beide Systeme – in einem unterschiedlichen Ausmaß – verzögerte Belohnungen abwerten. Trotzdem wird von den vorliegenden Ergebnissen die Annahme, dass sich aus der Interaktion von impulsivem und reflektivem System impulsives und selbstkontrolliertes Verhalten ergeben kann, gestützt. Im Hinblick auf die interindividuellen Unterschiede, die in der vorliegenden Arbeit aufgedeckt werden sollten, haben sich vor allem Zusammenhänge zwischen dem subjektiv berichteten allgemeinen Stress der Versuchspersonen (operationalisiert über das Selbststeuerungsinventar) und der neuronalen Aktivität von Gehirnregionen, die dem impulsiven und reflektiven System zugeordnet werden, gezeigt. So ist bei niedrigem Stress das impulsive System signifikant weniger aktiviert als das reflektive System, während sich bei hohem Stress dieser Zusammenhang umkehrt. Die relative Hyperaktivierung des impulsiven Systems bei Stress könnte erklären, warum unter Stress vermehrt Rückfälle bei abhängigkeitserkrankten Probanden beobachtet werden. Außerdem ging starkes neuronales Delay Discounting in medial präfrontalen Gehirnregionen mit hohem Stress, ebenso wie mit hoher nichtplanender Impulsivität (gemessen anhand der Barratt Impulsivitätsskala) und mit geringer Selbstkontrolle (gemäß des Selbststeuerungsinventars) einher. Dieses Ergebnis belegt unter anderem, dass das neu entwickelte Delay Discounting Paradigma neuronale Prozesse abbildet, die mit Impulsivität und Selbstkontrolle in Verbindung stehen. Darüber hinaus konnte kongruent mit entsprechenden Vorbefunden ein Einfluss des COMT Val 158 Met Polymorphismus auf das neuronale Delay Discounting im ventralen Striatum und erstmalig ein Zusammenhang zwischen dem DRD2 Taq 1 A A1-Allel und neuronalem Delay Discounting im posterioren Cingulum aufgedeckt werden. Damit ist die Bedeutung des Neurotransmitters Dopamin, der durch die untersuchten Polymorphismen beeinflusst wird, für die neuronalen Grundlagen des Delay Discounting bestätigt worden. Zusammengenommen deuten sowohl die beschriebenen Befunde als auch die sonstigen Ergebnisse der Arbeit darauf hin, dass sich neuronales Delay Discounting interindividuell unterscheidet. Im Hinblick auf Pathologien, die mit diesem Phänomen in Verbindung stehen, sollte daher weitere Forschung zu interindividuellen Unterschieden und zu spezifischen Behandlungsmethoden erfolgen.

Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

Succédant à une théorisation centrée sur le rôle des déficits des fonctions exécutives, les modèles contemporains du trouble déficit de l'attention / hyperactivité (TDAH) mettent en avant l’hétérogénéité d’une catégorie diagnostique impliquant des déficits neuropsychologiques, voies cérébrales et mécanismes étiopathogéniques multiples. En dépit de cette évolution, la majorité des études d'imagerie cérébrale des corrélats structurels du trouble menées à ce jour ont été conduites au niveau de la catégorie diagnostique, sans spécification supplémentaire. Cette approche comparant en moyenne un groupe de patients avec TDAH à un groupe de sujets sains a donné des résultats très variables d'une étude à l'autre, la comparaison inter-étude étant toutefois rendue difficile par la présence de facteurs confondants, tels que des différences en terme de régions d’intérêt examinées, de comorbidités acceptées chez les patients, de pourcentages de sujets masculins et féminins, de fenêtre d’âge sélectionnée, de méthodologie d'analyse ou encore de pourcentage de patients traités par méthylphénidate. Dans ce doctorat, nous nous sommes appuyés sur la morphométrie voxel-à-voxel pour isoler l’influence sur les volumes de matière grise de deux facteurs d’hétérogénéité intra-catégorielle dans le TDAH : le genre d’une part, et un polymorphisme génétique (Val158Met du gène Catéchol-O-méthyltransferase (COMT)) d’autre part ; ces deux facteurs présentant l’intérêt de moduler le risque associé de développer un trouble de type externalisé. Nous avons également comparé les volumes de matière grise d’enfants avec TDAH ayant reçu un traitement par méthylphénidate, de patients n'ayant jamais été exposé à la médication, et de sujet sains. Ces recherches expérimentales ont été inscrites dans une discussion plus générale de l’hétérogénéité des résultats de la littérature structurelle consacrée au TDAH et des sources neuropsychologiques de cette hétérogénéité. Dans notre étude des effets du genre sur les volumes de matière grise dans le TDAH, nous reportons pour la première fois une interaction entre genre et diagnostic, avec des corrélats structurels du trouble différents chez les garçons et les filles avec TDAH dans des régions de la ligne médiane du cerveau, impliquées à la fois dans la régulation émotionnelle et dans le fonctionnement du mode de réseau par défaut. Nous suggérons que ces différences structurelles pourraient contribuer aux différences de risque associé pour les troubles internalisés et externalisés présentées par les garçons et filles avec TDAH. Dans notre étude explorant l'influence du polymorphisme Val158Met sur les volumes de matière grise, nous mettons en évidence une modulation génétique des corrélats structurels du trouble : les sujets homozygotes pour l'allèle Val158, identifiés dans la littérature comme à risque pour le développement d'un trouble des conduites, présentent des volumes de matière grise supérieurs dans le noyau caudé comparativement aux sujets sains, tandis que les patients avec TDAH porteurs d'un allèle Met158 présentent des volumes de matière grise plus faibles dans le cortex préfrontal inférieur droit, une région cruciale pour les processus de contrôle attentionnel. Enfin, dans notre étude des corrélats structurels de l'exposition au méthylphénidate, nous reportons un effet potentiellement normalisateur du traitement sur les volumes de matière grise de l'insula et du pole temporal, des volumes de matière grise plus faibles chez les patients traités comparativement aux sujets sains dans le gyrus frontal moyen et dans le gyrus précentral, et une association entre volume de matière grise dans le nucleus accumbens gauche et durée d'exposition au méthylphénidate chez les sujets traités. (...) / Previous models of Attention Deficit / Hyperactivity Disorder (ADHD) such as Barkley’s or Brown’s conceptualized ADHD as essentially a developmental impairment of executive function. Against this view, it is now recognized that ADHD is a heterogeneous disorder, involving multiple deficits and multiple neuronal pathways. Despite this current theoretical framework, most structural brain imaging studies in ADHD have compared groups of children with ADHD with typically developing children, without trying to identify subgroups within the diagnostic category. This approach has yielded heterogeneous findings, possibly due to inter-studies variations in the type and number of comorbidities, the percentage of medicated participants included, the number of girls included, and/or methodological and statistical differences. Patients participating in these studies were also often exposed to methylphenidate, and potential medication effects on grey matter volumes are still unclear in certain brain regions such as the frontal lobe, despite a therapeutic action involving the preferential activation of catecholamine neurotransmission within the prefrontal cortex. In this thesis, we used voxel-based morphometry to study the influence of two important risk factors for the development of comorbid conditions in ADHD. The first of these two factors was gender, and the second a genetic polymorphism of the Catechol-O-methyltransferase gene known to put children with ADHD at risk for developing a conduct disorder (Val158Met). We also compared grey matter volumes in children with ADHD exposed to methylphenidate, never-medicated children with ADHD and typically developing children. These experimental studies were part of a more general discussion of ADHD neuropsychological and neurobiological heterogeneity. In our study exploring the influence of gender on the structural correlates of ADHD, we report for the first time a gender-by-diagnosis interaction, with grey matter volume differences in boys and girls with ADHD in midline cortical structures, involved in emotional regulation and part of the default mode network. We propose that these differences may contribute to explain why girls with ADHD more often develop inattentive and internalizing symptoms, whereas externalizing symptoms are predominant in boys with ADHD. In our study investigating the effects of Val158Met in ADHD, we report the first evidence of a COMT-related genetic modulation of ADHD-related grey matter volume alterations. Indeed, children with ADHD at higher risk for developing a conduct disorder (children homozygotes for the Val158 allele) presented increased grey matter volumes in the caudate nucleus when compared with typically developing children, whereas children carrying a Met158 allele presented with decreased grey matter volumes in the right inferior frontal cortex, a region known for its key role in attention. Finally, we measured grey matter volumes in medicated children with ADHD, never-medicated children with ADHD and typically developing children using both whole-brain voxel-based morphometry and automated tracing procedures in chosen regions of interest. We document potential methylphenidate-related grey matter volume normalization and deviation in previously unexplored frontal and temporal regions, and report a positive association between treatment history and grey matter volume in the nucleus accumbens, a key region for reward processing. Our first two experimental studies therefore contribute to a better understanding of the influence of important sources of within-category heterogeneity, while the third helps clarifying the potential confounding effect of medication exposure in previous structural brain imaging studies in ADHD.

Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

Delay Discounting im Sinne eines Abwertens zukünftiger Belohnungen ist ein weit verbreitetes Phänomen. Es zeigt sich z. B. in persönlichen Angelegenheiten, wie der Entscheidung für den kurzfristigen Genuss von Süßigkeiten und gegen die langfristigen, durchaus größeren Vorteile einer schlanken Figur. Auch internationale wirtschaftliche und politische Diskussionen zum Klimaschutz oder der Finanzkrise werden von der Präferenz für sofortige, kleinere Belohnungen über verzögerte, größere Belohnungen getrieben. In der Psychologie wird Delay Discounting als Maß für Impulsivität bzw. Selbstkontrolle mit dem Auftreten von Aufmerksamkeitsdefizit-Hyperaktivitäts-Syndromen und von Abhängigkeitserkrankungen in Verbindung gebracht. Bezüglich der neuronalen Grundlagen von Delay Discouting ist mithilfe von sogenannten Intertemporal Choice Tasks bereits herausgefunden worden, dass die Entscheidung für eine sofortige Belohnung stärkere neuronale Aktivierung in belohnungsspezifischen Gehirnregionen evoziert als die Entscheidung für eine verzögerte Belohnung. Außerdem wurden sowohl theoretisch wie auch empirisch ein impulsives und ein reflektives System als Grundlage des Delay Discounting beschrieben, deren Existenz jedoch von manchen Wissenschaftlern angezweifelt wird. Ebenso wird angezweifelt, ob Delay Discounting unabhängig vom Einsatz von Intertemporal Choice Tasks und der damit verbundenen Entscheidung zwischen zwei Alternativen überhaupt besteht. Da die neuronalen Grundlagen des Delay Discounting und des impulsiven und reflektiven Systems bisher nicht unabhängig von einer Entscheidungsaufgabe erfasst wurden, konnten diese Zweifel nicht ausgeräumt werden. Ebenso ist zurzeit unbekannt, ob sich die neuronalen Korrelate des Delay Discounting bei Personen mit unterschiedlichen Persönlichkeitseigenschaften, bei Männern und Frauen, bei Rauchern und Nichtrauchern und in Abhängigkeit von verschiedenen Genvarianten unterscheiden. Um diese Lücke zu schließen, ist im Rahmen der vorliegenden Arbeit ein neuartiges Delay Discounting Paradigma zum Einsatz im Magnetresonanztomographen entwickelt worden. Dieses Paradigma ähnelt einem Monetary Incentive Delay Task und ermöglicht es, neuronale Aktivierung bei der Antizipation und bei dem Erhalt einer einzelnen Belohnung zu einem Zeitpunkt zu erfassen. Außerdem kann nach der Antizipation einer Belohnung, die sich durch eine bestimmte Höhe (0,05 €, 0,50 €, 1,00 €) und eine bestimmte Auszahlungsverzögerung (0 Tage, 10 Tage, 100 Tage) auszeichnet, in einer einfachen visuellen Diskriminationsaufgabe eine Reaktionszeit erfasst werden, die als behaviorales Maß für die inzentive Motivation fungiert. Zusammen mit einer Erfassung verschiedener Persönlichkeitseigenschaften und einer Genotypisierung für den COMT Val 158 Met Polymorphismus, den DRD2 Taq 1 A Polymorphismus und den DAT 1 Polymorphismus ist das Delay Discounting Paradigma an insgesamt 90 Probanden im Magnetresonanztomographen eingesetzt worden, so dass 84 auswertbare Datensätze gewonnen werden konnten. Diese 84 Datensätze stammten insgesamt von 42 Frauen und 42 Männern bzw. von 43 strikten Nichtrauchern, 38 starken Rauchern und drei Gelegenheitsrauchern. Anhand der Auswertung der Gesamtstichprobe konnte bestätigt werden, dass das Delay Discounting Paradigma belohnungs- und verzögerungsspezifisch unterschiedliche Reaktionszeiten und unterschiedliche neuronale Aktivierung hervorruft. In belohnungsverarbeitenden Gehirnregionen wie dem ventralen Striatum zeigte sich sowohl stärkere Aktivierung für größere Belohnungen als auch für Belohnungen, die früher ausgezahlt wurden. Damit steht fest, dass Delay Discounting unabhängig von der Entscheidung zwischen zwei Alternativen auftritt. Außerdem konnte erstmalig ein Interaktionseffekt zwischen Belohnungshöhe und Belohnungsverzögerung aufgedeckt werden: Es zeigte sich eine Abnahme der Differenzen in der neuronalen Aktivierung zwischen größter und kleinster Belohnung über die Zeit, was auf eine Indifferenz gegenüber der Höhe verzögerter Belohnung hindeutet. Ein Einfluss der Belohnungsverzögerung wurde allerdings nur beim Erhalt von Belohnungen messbar, bei der Antizipation von Belohnungen zeigte sich kein Delay Discounting Effekt. Bezüglich der Kontroverse zur Existenz eines impulsiven und reflektiven Systems konnten Ergebnisse gewonnen werden, die beide Positionen integrieren. So wurde zwar die Beteiligung von zwei distinkten neuronalen Systemen beim Abwerten zukünftiger Belohnungen bestätigt, allerdings zeigte sich auch, dass beide Systeme – in einem unterschiedlichen Ausmaß – verzögerte Belohnungen abwerten. Trotzdem wird von den vorliegenden Ergebnissen die Annahme, dass sich aus der Interaktion von impulsivem und reflektivem System impulsives und selbstkontrolliertes Verhalten ergeben kann, gestützt. Im Hinblick auf die interindividuellen Unterschiede, die in der vorliegenden Arbeit aufgedeckt werden sollten, haben sich vor allem Zusammenhänge zwischen dem subjektiv berichteten allgemeinen Stress der Versuchspersonen (operationalisiert über das Selbststeuerungsinventar) und der neuronalen Aktivität von Gehirnregionen, die dem impulsiven und reflektiven System zugeordnet werden, gezeigt. So ist bei niedrigem Stress das impulsive System signifikant weniger aktiviert als das reflektive System, während sich bei hohem Stress dieser Zusammenhang umkehrt. Die relative Hyperaktivierung des impulsiven Systems bei Stress könnte erklären, warum unter Stress vermehrt Rückfälle bei abhängigkeitserkrankten Probanden beobachtet werden. Außerdem ging starkes neuronales Delay Discounting in medial präfrontalen Gehirnregionen mit hohem Stress, ebenso wie mit hoher nichtplanender Impulsivität (gemessen anhand der Barratt Impulsivitätsskala) und mit geringer Selbstkontrolle (gemäß des Selbststeuerungsinventars) einher. Dieses Ergebnis belegt unter anderem, dass das neu entwickelte Delay Discounting Paradigma neuronale Prozesse abbildet, die mit Impulsivität und Selbstkontrolle in Verbindung stehen. Darüber hinaus konnte kongruent mit entsprechenden Vorbefunden ein Einfluss des COMT Val 158 Met Polymorphismus auf das neuronale Delay Discounting im ventralen Striatum und erstmalig ein Zusammenhang zwischen dem DRD2 Taq 1 A A1-Allel und neuronalem Delay Discounting im posterioren Cingulum aufgedeckt werden. Damit ist die Bedeutung des Neurotransmitters Dopamin, der durch die untersuchten Polymorphismen beeinflusst wird, für die neuronalen Grundlagen des Delay Discounting bestätigt worden. Zusammengenommen deuten sowohl die beschriebenen Befunde als auch die sonstigen Ergebnisse der Arbeit darauf hin, dass sich neuronales Delay Discounting interindividuell unterscheidet. Im Hinblick auf Pathologien, die mit diesem Phänomen in Verbindung stehen, sollte daher weitere Forschung zu interindividuellen Unterschieden und zu spezifischen Behandlungsmethoden erfolgen.

A cana-de-açúcar é uma monocotiledônea poliplóide, alógama que possui baixa taxa reprodutiva devido a dificuldade de florescimento. Devido estas características genéticas e fisiológicas os programas de melhoramento são longos e laboriosos. Alternativamente, modernas aplicações da biotecnologia visam contribuir com o desenvolvimento de novos cultivares. Neste trabalho estudou-se a metodologia de cultura de tecidos a partir de discos de folhas imaturas para o estabelecimento da cultura de calos embriogênicos e regeneração de plantas a partir dos calos embriogênicos e diretamente, a partir de folhas imaturas. O objetivo principal foi contribuir para o desenvolvimento de métodos eficientes para produção de plantas transgênicas a partir de calos e folhas imaturas, considerando-se a crescente necessidade de produção de novos cultivares com características agronômicas específicas. Diversas concentrações de 2,4-D e cinetina em meio MS foram testadas para o estabelecimento de calos altamente embriogênicos e para a indução da desdiferenciação celular nos discos foliares antecedendo a regeneração de plantas. Meios de cultura sem reguladores de crescimento (MS) e com a adição de BAP e ANA foram testados para a regeneração de plantas a partir de discos foliares. Calos embriogênicos com 12 a 20 semanas de cultivo produziram em média 3 a 5 plantas, em meio de regeneração MS. Folhas imaturas apresentaram elevado potencial de regeneração de plantas quando se utilizou 2,4-D em concentrações de 5 e 8 mg/L nos períodos de 5 e 8 dias no escuro. Houve indução a formação de embriões somáticos que resultaram em média 12 a 16 plantas por explante no período total de 7 a 10 semanas. Além disso, foi testado o pré-tratamento dos discos foliares em meio MS3K, contendo 2,4-D (3mg/L) e cinetina (0,1 mg/L), antes da transferência do discos para meio de regeneração MS. Os discos submetidos a este pré-tratamento durante 14, 21 e 28 dias apresentaram aumento significativo na eficiência de regeneração de plantas, variando em média de 41 a 50 plantas por disco foliar nas variedades RB835089 e RB855156. A redução no tempo para obtenção de plantas aliado ao aumento na média de plantas obtidas é a base para aumentar a eficiência de transformação genética de plantas. Experimentos de cotransformação dos genes neo e comt(AS), foram realizados por biolística. Em plantas regeneradas a partir de folhas imaturas da variedade RB835486, as análises de PCR confirmaram a incorporação do gene marcador neo em 57 e 90% das plantas em meio seletivo com geneticina (30 mg/L), sendo que a maior eficiência de regeneração de transgênicos (90%) foi obtida no pré-tratamento com o meio MS3K. Das plantas transgênicas para o gene neo, 7 e 38% também foram confirmadas para a incorporação do gene comt(AS). Nas plantas regeneradas a partir de calos embriogênicos em meio seletivo, as análises de PCR detectaram somente a incorporação do gene neo, o que ocorreu em 52% das plantas analisadas. Os resultados obtidos mostram que a cultura de discos de folhas imaturas para o processo de transformação genética por biolística é uma metodologia viável, rápida e menos onerosa, quando comparada com a cultura de calos embriogênicos. / Sugarcane is a polyploidy monocot and allogamous species that has low reproductive rate due to the difficulty of flowering. Because of these genetic and physiological characteristics breeding program takes long time and demand hard labor. Alternatively, modern biotechnology approaches contribute to the development of new cultivars. In this work we studied the methodology of plant tissue culture from immature leaf discs to establish callus culture and plant regeneration from those calli and from immature leaves, directly. The main objective was to contribute to the development of efficient methods to produce transgenic plants from callus and immature leaves, due to the growing need to produce new cultivars with specific agronomics traits. MS medium with different concentrations of 2,4-D and kinetin were tested to obtain highly embryogenic calli and to induce cellular dedifferentiation in the immature leaf discs prior to plant regeneration. Culture media without growth regulators (MS) and with the addition of BAP and NAA were tested for plant regeneration from leaf discs. Callus culture with 12 to 20 weeks resulted on average 3 to 5 plants on regeneration medium designed as MS. Immature leaves showed a high potential for plant regeneration when 2,4-D at concentrations of 5 and 8 mg/L in periods of 5 and 8 days in the dark. There were inducing of somatic embryos that resulted in average 12 to 16 plants per explant in the total period of 7 to 10 weeks. In addition, we tested the pre-treatment of leaf discs in MS3K medium which contain 2,4-D (3 mg/L) and kinetin (0.1 mg/L) before transfering to plant regeneration MS medium . The discs submitted to this pretreatment for 14, 21 and 28 days showed significant increase in the efficiency of plant regeneration, with on average of 41 to 50 plants per leaf disc in varieties RB835089 and RB855156. The reduction of time to obtain plants coupled with the increase of plants obtained is the basis for increasing the efficiency of plant genetic transformation. Co-transformation with genes neo and comt(AS), were performed by biolistics. Plants regenerated from immature leaves of the variety RB835486, PCR analysis confirmed the incorporation of the neo selection marker gene in 57 and 90% of the plants on selective medium with geneticin (30 mg/L), the higher efficiency of transgenic plants (90%) was obtained on pre-treatment in MS3K medium. Transgenic plants for the neo gene, 7 and 38% were also confirmed for the incorporation of comt (AS). PCR analysis of candidates transgenic plants from callus growing on selective medium, revelled only the insertion of the neo gene, which occurred in 52% of the analyzed plants. The results of this work showed that the approach of using immature leaf discs to obtain plant genetic transformation by biolistics methodology is a viable, cheaper and faster than using embryogenic callus.

Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). As part of this disorder the myelin sheath undergoes degeneration, leading to alterations in the conductivity of axons, and impaired function. The onset of the disease occurs in young adults and clinical pathology is characterised by varying severity. These include i) Relapsing Remitting MS (RR-MS), ii) Secondary Progressive MS (SP-MS) and iii) Primary Progressive MS (PP-MS). MS is more prevalent in women and accounts for more than two thirds of all MS sufferers. MS is considered to be a multifactorial disorder with both genetic and environmental components. The prevalence of MS is dependent on geographical localisation, with lower sunlight exposure linked to higher prevalence. Also, studies show an increased risk in close relatives, or in identical twins, indicating a significant genetic component to the disorder. There are a number of genes that may plausibly be involved in MS pathophysiology. These include myelin-related genes, such as the myelin basic protein (MBP), immune-related genes, such FC receptor and osteopontin, and heat shock proteins such as xb crystallin. These candidate genes have been implicated in a variety of ways but usually through immunological and/or genetic studies. One of the most consistent findings in recent years has been the association of disease with alterations in the specific major histocompatibility complex (MHC) localised to chromosome 6p21.3, and includes MHC I, II, III. Genome wide screens have permitted the identification of loci in the genome, which are associated with MS susceptibility. The number of genes involved in MS is unknown and several case-control association studies have been undertaken to reveal the involvement of potential candidate genes. In general terms, current research is aimed at determining allelic variation of candidate genes. Such genes have been implicated in MS because they reside within susceptible regions of the chromosome associated with MS or they have a plausible potential pathophysiological role in MS. Candidate loci investigated in this study, for association with MS susceptibility, include members of the nitric oxide synthase family of metabolic proteins (inducible NOS, iNOS/NOS2A and neuronal NOS, nNOS), methylenetetrahydrofolate reductase (MTHFR), catechol-O-methyl transferase (COMT), and vitamin D receptor (VDR). The MS population used in all studies consisted of over 100 MS cases and gender, age and ethnicity matched controls. In our study of inducible and neuronal NOS genes, PCR based assays were developed to amplify a region of both promoters that contained known microsatellite variation. Supporting phyisological data suggests that the neuroinflammatory aspects of MS are associated with aberrant NO production, which may be due to aberrant regulation of NOS activity. Specific amplified products were identified by fluorescent capillary electrophoresis and allele frequencies were statistically compared using chi-squared analysis. In the nNOS and iNOS study, no association was identified with allele frequency variation and MS susceptibility (nNOS: ?2=5.63, P=0.962; iNOS: ?2=3.4; P=0.082). Similarly, no differences in allele frequencies were observed for gender or clinical course for both markers (Pvalue greater than 0.05). In short, results from this study indicate that the NOS promoter variations studied do not play a significant role in determining susceptibility to MS in the tested population. The COMT and MTHFR genes are localised at 22q12-13 and 1p36.3 respectively, regions of the genome that have been found to be positively associated with MS susceptibility. In our research, we set out to examine the G158A change in the 4th exon of the COMT gene. This functional mutation leads to an amino acid change (valine to methionine) that is directly associated with changes in the activity of COMT. The MTHFR enzyme plays a role in folate metabolism, and can be implicated in the turnover of homocysteine. Previous investigations have shown that high levels of homocysteine are encountered in MS patients, where it is also linked to demyelination in the CNS. In our study the aim was to examine the C677T variation (alanine to valine amino acid change) in the exon 4 coding region of the MTHFR gene and the G158A variation in the COMT gene. Restriction fragment length polymorphism (RFLP) analysis and gel electrophoresis was used to identify specific alleles for both COMT and MTHFR. However, as with the NOS study, no specific association was identified between MS susceptibility and variation for either of the tested COMT or MTHFR (Pvalue greater than 0.05) variants. In a final genomic investigation of the MS population, three variations in the VDR gene were analysed for association with MS susceptibility and pathology. Using RFLP analysis, three VDR variants were investigated with genotypes detected using the Taq I, Apa I and Fok I restriction enzymes. In contrast to previous genotypic analyses, this study did show a positive association, specifically between the functional variation in exon 9 of the VDR gene and MS (Taq I, 2= 7.22, P= 0.0072). Interestingly, the Apa I variant of VDR was also found to be associated with MS ( 2=4.2, P=0.04). The Taq I and Apa I variants were also found to be in very strong and significant linkage disequilibrium (D'=0.96, Pvalue less than 0.0001) and their associations were more prominent with the progressive forms of MS (SP-MS and PP-MS). In addition to genotypic analysis of a clinical population, additional research was undertaken to identify novel targets for MS susceptibility studies. Global gene expression analysis was undertaken using comparative subtractive fluorescent microarray technology to examine differences in gene activity (expression) in age and sex matched MS plaque tissue and anatomically matched normal white matter (NWM). MS plaques were obtained post mortem from MS sufferers with no drug history in the last two months before death and matched anatomically to healthy white matter from donors with no previous neurological disorders. Target arrays consisted of 5000 cDNAs and analysis was conducted using the Affymetrix 428 scanner. In this way, 139 genes were shown to be differentially regulated in MS plaque tissue compared to NWM. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue less than 0.0001, a=0.73); while 70 transcripts were uniquely differentially expressed ( 1.5-fold) in either acute or chronic active lesions. To validate the gene expression profile results, quantitative real time reverse transcriptase (RT) PCR (Q-PCR) analysis was performed. 12 genes were selected because they were shown to be differentially expressed by array analysis in this study, or because of their involvement in MS pathology. These included transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), glutathione S-transferase pi (GSTP1), crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1), tubulin beta-5 (TBB5), inositol 1,4,5-trisphosphate 3-kinase B (ITPKB), calpain 1 (CAPNS1), osteopontin (SPP1 or OPN), as well as the signal transducer and activator of transcription 1 (STAT1) and protein inhibitor of activated STAT1 (PIAS1). Both absolute (copy number) and comparative differences in the relative levels of expression in MS lesions and NWM were determined for each gene. The results from this study revealed a significant correlation of real time PCR results with the microarray data, while a significant correlation was also found between comparative and absolute determinations of fold. As with the results of array analysis, a significant difference in gene expression patterning was identified between chronic active and acute plaque pathologies. For example, a up to 50-fold increase in SPP1 and ITPKB levels in acute plaques contrasted with the 5-fold or less increase in chronic active plaques (P less than 0.0.1, unpaired t-Test). Of particular note, gamma-amino butyric acid receptor ?2 (GABG2), integrin ?5 (ITGB5), complement component 4B (C4B), parathyroid hormone receptor 1 (PTHR1) were found up-regulated in MS and glial derived neurotropic factor ?2 (GDNFA2), insulin receptor (INSR), thyroid hormone receptor ZAKI4 (ZAKI4) were found down-regulated in MS. Data also revealed a decreased expression of the immune related genes STAT1 and PIAS1 in acute plaques. In conclusion, this research used both genomic analysis and technologies in gene expression to investigate both known and novel markers of MS pathology and susceptibility. The study developed tools that may be used for further investigation of clinical pathology in MS and have provided interesting initial expression data to further investigate the genes that play a role in MS development and progression.

A cana-de-açúcar é uma monocotiledônea poliplóide, alógama que possui baixa taxa reprodutiva devido a dificuldade de florescimento. Devido estas características genéticas e fisiológicas os programas de melhoramento são longos e laboriosos. Alternativamente, modernas aplicações da biotecnologia visam contribuir com o desenvolvimento de novos cultivares. Neste trabalho estudou-se a metodologia de cultura de tecidos a partir de discos de folhas imaturas para o estabelecimento da cultura de calos embriogênicos e regeneração de plantas a partir dos calos embriogênicos e diretamente, a partir de folhas imaturas. O objetivo principal foi contribuir para o desenvolvimento de métodos eficientes para produção de plantas transgênicas a partir de calos e folhas imaturas, considerando-se a crescente necessidade de produção de novos cultivares com características agronômicas específicas. Diversas concentrações de 2,4-D e cinetina em meio MS foram testadas para o estabelecimento de calos altamente embriogênicos e para a indução da desdiferenciação celular nos discos foliares antecedendo a regeneração de plantas. Meios de cultura sem reguladores de crescimento (MS) e com a adição de BAP e ANA foram testados para a regeneração de plantas a partir de discos foliares. Calos embriogênicos com 12 a 20 semanas de cultivo produziram em média 3 a 5 plantas, em meio de regeneração MS. Folhas imaturas apresentaram elevado potencial de regeneração de plantas quando se utilizou 2,4-D em concentrações de 5 e 8 mg/L nos períodos de 5 e 8 dias no escuro. Houve indução a formação de embriões somáticos que resultaram em média 12 a 16 plantas por explante no período total de 7 a 10 semanas. Além disso, foi testado o pré-tratamento dos discos foliares em meio MS3K, contendo 2,4-D (3mg/L) e cinetina (0,1 mg/L), antes da transferência do discos para meio de regeneração MS. Os discos submetidos a este pré-tratamento durante 14, 21 e 28 dias apresentaram aumento significativo na eficiência de regeneração de plantas, variando em média de 41 a 50 plantas por disco foliar nas variedades RB835089 e RB855156. A redução no tempo para obtenção de plantas aliado ao aumento na média de plantas obtidas é a base para aumentar a eficiência de transformação genética de plantas. Experimentos de cotransformação dos genes neo e comt(AS), foram realizados por biolística. Em plantas regeneradas a partir de folhas imaturas da variedade RB835486, as análises de PCR confirmaram a incorporação do gene marcador neo em 57 e 90% das plantas em meio seletivo com geneticina (30 mg/L), sendo que a maior eficiência de regeneração de transgênicos (90%) foi obtida no pré-tratamento com o meio MS3K. Das plantas transgênicas para o gene neo, 7 e 38% também foram confirmadas para a incorporação do gene comt(AS). Nas plantas regeneradas a partir de calos embriogênicos em meio seletivo, as análises de PCR detectaram somente a incorporação do gene neo, o que ocorreu em 52% das plantas analisadas. Os resultados obtidos mostram que a cultura de discos de folhas imaturas para o processo de transformação genética por biolística é uma metodologia viável, rápida e menos onerosa, quando comparada com a cultura de calos embriogênicos. / Sugarcane is a polyploidy monocot and allogamous species that has low reproductive rate due to the difficulty of flowering. Because of these genetic and physiological characteristics breeding program takes long time and demand hard labor. Alternatively, modern biotechnology approaches contribute to the development of new cultivars. In this work we studied the methodology of plant tissue culture from immature leaf discs to establish callus culture and plant regeneration from those calli and from immature leaves, directly. The main objective was to contribute to the development of efficient methods to produce transgenic plants from callus and immature leaves, due to the growing need to produce new cultivars with specific agronomics traits. MS medium with different concentrations of 2,4-D and kinetin were tested to obtain highly embryogenic calli and to induce cellular dedifferentiation in the immature leaf discs prior to plant regeneration. Culture media without growth regulators (MS) and with the addition of BAP and NAA were tested for plant regeneration from leaf discs. Callus culture with 12 to 20 weeks resulted on average 3 to 5 plants on regeneration medium designed as MS. Immature leaves showed a high potential for plant regeneration when 2,4-D at concentrations of 5 and 8 mg/L in periods of 5 and 8 days in the dark. There were inducing of somatic embryos that resulted in average 12 to 16 plants per explant in the total period of 7 to 10 weeks. In addition, we tested the pre-treatment of leaf discs in MS3K medium which contain 2,4-D (3 mg/L) and kinetin (0.1 mg/L) before transfering to plant regeneration MS medium . The discs submitted to this pretreatment for 14, 21 and 28 days showed significant increase in the efficiency of plant regeneration, with on average of 41 to 50 plants per leaf disc in varieties RB835089 and RB855156. The reduction of time to obtain plants coupled with the increase of plants obtained is the basis for increasing the efficiency of plant genetic transformation. Co-transformation with genes neo and comt(AS), were performed by biolistics. Plants regenerated from immature leaves of the variety RB835486, PCR analysis confirmed the incorporation of the neo selection marker gene in 57 and 90% of the plants on selective medium with geneticin (30 mg/L), the higher efficiency of transgenic plants (90%) was obtained on pre-treatment in MS3K medium. Transgenic plants for the neo gene, 7 and 38% were also confirmed for the incorporation of comt (AS). PCR analysis of candidates transgenic plants from callus growing on selective medium, revelled only the insertion of the neo gene, which occurred in 52% of the analyzed plants. The results of this work showed that the approach of using immature leaf discs to obtain plant genetic transformation by biolistics methodology is a viable, cheaper and faster than using embryogenic callus.

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.