Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

Monoamine oxidase (E.C.I.4.3.4) (MAO) oxidatively deaminates the biogenic amines normally present in the organism. The activities of the neurons utilizing these amines i.e. noradrenaline, dopamine and serotonin, are supposed to be involved in the pathogenesis of various psychiatric diseases. It is speculated that the MAO activity is changed as well as the monoaminergic activity in some psychiatric disorders. In the present thesis the MAO activity has been studied in brain tissue and in platelets in some psychiatric disorders. The result was as follows: MAO activities in different parts of the human brain seem to be highly intercorrelated in each individual. The brain MAO activity is also weakly correlated both to the concentration of 5-HT and of 5-HIAA, which may indicate that the MAO activity reflects the serotoninergic turnover in the brain. The MAO activity in brains from 15 suicides was compared to a control material of 20 individuals without known mental disorders, and it was found to be lower in the suicides in all 13 analysed brain parts. As eight of the patients had been chronic alcoholics, they were excluded and the remaining seven non-alcoholic suicides were tested as regards MAO activity by analysis of variance and still found to have significantly lower MAO activity than the controls. The eight chronic alcoholics in the suicide series had the most significantly (p<0.005) reduction of the MAO activity as compared to the control group. Rats were given chronic treatments with ethanol, either by 10 °/o ethanol as the only water supply or by exposition to ethanol vapor twice a day. In neither of these cases was the brain MAO activity changed as compared to control rats. The result supports the hypothesis that the low MAO activity found in alcoholic suicides most likely is related to a constitutional factor and not to a direct effect of the ethanol intake. Platelet MAO activity was found to be significantly reduced in human alcoholics as compared to matched controls. If samples were drawn from the alcoholic patients during their abstinence phase, there could be seen a transitory rise in the platelet MAO activity. This increased activity had its maximum after two weeks, and after four weeks the MAO activity had returned to the initial, low level. No difference as regards MAO activity, neither in brain tissue nor in platelets, could be registered when chronic schizophrenics were compared to matched controls. Reduced brain MAO activity was found in a group of patients diagnosed as cycloid psychoses when comparing the activity to controls or to the schizophrenic patients. The platelet MAO activity was also found to be lower in cycloid psychoses than in a group of unipolar affective psychoses, who repeatedly have been found not to differ from normals. These findings suggest that low MAO activities in brain and platelets reflect a phychic constitution in the individual making him more vulnerable for suicidal behaviour, ethanol abuse or cycloid psychosis. / digitalisering@umu.se

The general aims of this dissertation are to analyse how family situation, and especially lone parenting, influence health and life chances in Sweden and the extent to which possible relations are influenced by socioeconomic circumstances and health selection. In two population-based cohort studies we analysed overall and cause-specific mortality (1991-95), and also severe morbidity (1991-94) from different causes among lone mothers in comparison with mothers with partners. Information on the mothers was obtained from the Swedish Population and Housing censuses of 1985 and 1990. The outcomes considered were death or utilisation of (overnight) hospital care, with data taken from population-based national health registers. In the analyses we adjusted for socioeconomic and demographic circumstances, such as socioeconomic status, country of birth, receipt of social-welfare benefit, and housing situation. To take health-selection effects into account, we adjusted for previous inpatient history (1987-90). Our findings suggest that lone motherhood entails health disadvantages with regard to mortality, severe morbidity and injury. Socioeconomic circumstances were found to play a major role in accounting for increased risks, but the risks are partly independent of both socioeconomic conditions and health selection into lone motherhood. In two further studies we analysed mortality (1991-98), severe morbidity and injury (1991-99), and also educational achievement (in 1998 at ages 24-25 of offspring), of children who had lived in lone-parent families in comparison with children in two-parent families. We mainly used data from the Swedish censuses and national health-data registers. Living in a lone parent family was found to be associated with increased risks of a variety of unfavourable outcomes: psychiatric disease, suicide/suicide attempt, injury, addiction, and low educational attainment. Relatively poor educational performance and also health disadvantages are explicable to a large extent by socioeconomic conditions, especially a lack of economic resources (as measured here by receipt of social-welfare benefit and having rented accommodation). Educational achievement among children varies with cause of lone parenthood, with the best prospects found among the children of widows/widowers. In a fifth study we analysed mortality from different causes (1991-2000) among lone fathers (fathers with and without custody of their children) and childless men (with and without partners) in comparison with cohabiting fathers with children in the household. For this purpose we linked information from the Swedish censuses of 1985 and 1990 to Sweden’s Multi-Generation Register (which contains information about all known biological relations between children and parents). Lone non-custodial fathers and lone childless men suffer from the most pronounced elevated risks, especially of death from injury or addiction, but also from all-cause mortality and death from ischaemic heart disease. Being a lone custodial father also seems to entail an increased mortality risk, although generally to a much lesser degree, and not for all outcomes studied. The elevated risks for all subgroups fell when variables assumed to control health selection and socioeconomic circumstances were introduced into the initial regression model employed. However, even following adjustments, significantly increased risks, albeit greatly attenuated, remained in all the subgroups investigated. Key Words: Single parent, single mother, single father, children, risk factor, socio-economic status, mortality, morbidity, injury, psychiatric disease, education, epidemiology, longitudinal

El treball presentat en aquesta tesi és un estudi de la diversitat genètica en un conjunt de gens implicats en funcions neurològiques ("Gens cerebrals"). Hom ha examinat vint-i-dos gens implicats en els sistemes de neurotransmissió dopaminèrgic, serotoninèrgic i glutamatèrgic. L'objectiu de l'estudi té dos vessants: per una banda l'anàlisi de la diversitat genètica en un conjunt de gens implicats en malaltia humana, en aquest cas en malaltia psiquiàtrica, en poblacions humanes mundials, amb la intenció d'assentar les bases per propers esforços de mapatge genètic; i per altra banda analitzar la diversitat genètica en aquest conjunt de gens per tal de descobrir evidències d'esdeveniments històrics, incloent possibles evidències de selecció. / The work presented in this thesis is a study of the genetic variation in a set of genes related to neurological function ('Brain genes'). Twenty two genes are examined, all of which are involved in either the Dopaminergic, Serotonergic or the Glutamatergic systems of neurotransmission.The objective of the study has two aspects: on the one hand the analysis of genetic variation in a set of genes which are implicated in human disease, in this case psychiatric disease, across global human populations, towards the end of providing some new insight for gene mapping efforts, and on the other hand the study of genetic variation in this set of genes may reveal traces of the population history events undergone, including possible evidence for selection.