Influence of birth weight on the risk and clinical presentation of schizophrenia

Pre- and perinatal environmental factors have been associated with increased schizophrenia risk, particularly in combination with genetic liability. Both low and high birth weight have been associated with an increased risk of autism spectrum disorders and schizophrenia. The interaction of specific schizophrenia susceptibility genes and specified pre- and perinatal environmental factors have recently been described in relation to augmented schizophrenia risk. In this thesis, the relationship between birth weight and schizophrenia risk was investigated as part of a large Finnish schizophrenia family study sample based on the Genetic Epidemiology and Molecular Genetics of Schizophrenia in Finland study, in which genetic susceptibility for schizophrenia is known to be elevated relative to the general population (Study I). The study sample consisted of two subsamples having at least one sibling with a diagnosis of schizophrenia. The associations between birth weight and symptom severity of schizophrenia and psychotic disorders (Study II) and cognitive functioning in schizophrenia (Study III) were also characterized. A gene-environment interaction, focusing on birth weight and specific genes from the DISC1 network (Study IV), which had previously been found to be associated with increased schizophrenia risk in the same cohort, was also investigated in relation to schizophrenia risk. A 1.68-fold increase in schizophrenia risk was observed in subjects presenting with a high birth weight (>4000 g) relative to subjects with an intermediate birth weight of 3000-4000 g (Study I). In particular, schizophrenia risk was elevated among high birth weight individuals in combination with specific variants of the NDE1 gene (Study IV). Both low and high birth weight were found to be associated with increased severity of disorganized and negative symptom dimensions, whereas birth weight was not associated with symptoms of reality distortion (Study II). Both low and high birth weight, compared with the intermediate birth weight range, were associated with a slight decrease in cognitive performance among both subjects with schizophrenia and their unaffected first-degree relatives (Study III). The observations in the thesis corroborate existing findings describing an association between high birth weight and increased schizophrenia risk. An association between low birth weight and increased schizophrenia risk, a finding widely documented in the literature, was not seen here. Birth weight was found to influence both symptom severity and cognitive performance in schizophrenia. The findings also suggest that the functions of NDE1 during the early stages of neurodevelopment are vulnerable to the influence of pre- and perinatal environmental factors associated with high birth weight, with the propensity to augment subsequent schizophrenia susceptibility among offspring. The mechanisms underlying the association between high birth weight and schizophrenia risk are speculative, but may involve factors such as pre- or perinatal hypoxia, maternal metabolic and immunological mechanisms during pregnancy.Graviditets- och förlossningsfaktorer påverkar vår predisposition för schizofreni, framför allt i kombination med ett ärftligt anlag för sjukdomen. I denna doktorsavhandling undersöks sambandet mellan födelsevikten och risken för att utveckla schizofreni samt schizofrenisjukdomens kliniska symtombild i finländska familjer med ett känt anlag för schizofreni. Avhandlingen undersöker även hur DISC1-genvarianter, som deltar i utvecklingen av det centrala nervsystemet, tillsammans med födelsevikten påverkar predispositionen för schizofreni. Doktorsavhandlingen är en del av forskningsprojektet Genetisk epidemiologi och molekylärgenetisk bakgrund vid allvarliga psykiska störningar i regi av Institutet för hälsa och välfärd. Undersökningen påvisade förhöjd predisposition för schizofreni hos individer med hög födelsevikt (> 4000 g). Dessutom upptäcktes ett samband mellan hög och låg födelsevikt å ena sidan och svårare symtombild och en lägre kognitiv kapacitet å andra sidan, i jämförelse med normal födelsevikt. Förhöjd predisposition för schizofreni förelåg framför allt hos individer med vissa NDE1-genvarianter av DISC1-gentypen och hög födelsevikt. Födelsevikten anses avspegla graviditets- och förlossningsmiljöns inverkan på det växande fostret. Dessa forskningsrön stödjer uppfattningen om att födelsevikten har ett samband med utvecklingen av det centrala nervsystemet och med en förhöjd disposition för schizofreni samt bl.a. att NDE1-genen påverkas av graviditets- och förlossningsfaktorer. Även om denna avhandling inte undersökte de direkta förklaringarna bakom dessa observationer är det känt att födelsevikten har ett samband med metabola och immunologiska faktorer hos modern under graviditeten samt med syrebrist hos barnet i samband med förlossning. Detta är så vitt det är känt den mest omfattande undersökningen av sambanden mellan födelsevikten och en genetisk predisposition för schizofreni och det är en ny upptäckt att samspelet mellan graviditets- och förlossningsfaktorer och genen som deltar i utvecklingen av det centrala nervsystemet innebär en förhöjd predisposition för schizofreni. Dessa resultat bidrar till en ökad förståelse av schizofrenisjukdomens långsiktiga natur och utveckling där predisponerande biologiska faktorer för schizofreni aktiveras i ett mycket tidigt utvecklingsstadium. Dessa forskningsrön väcker frågor om huruvida graviditets- och förlossningsfaktorer bör uppmärksammas mer som en del av utvecklingen av mödra- och barnrådgivningsverksamheten för psykiatriska riskgrupper. Genetisk forskning kommer i framtiden att bidra med ökad kunskap om biologiska riskfaktorer för psykiatriska sjukdomar samtidigt som forskningen erbjuder utökade möjligheter för att undersöka sambanden mellan de genetiska och miljömässiga faktorer som ger upphov till psykiatriska sjukdomar

Digital health technologies in the psychosocial treatment of core symptoms of psychotic disorders - literature review and practical aspects

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An interaction between NDE1 and high birth weight increases schizophrenia susceptibility

Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISCI pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b = 1.26, SE= 0.5, p = 0.012) and one of its constituent SNPs rs4781678 (b = 1.33, SE = 0.51, p = 0.010). Specifically, high birth weight (> 4000 g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Differences in psychosocial functioning between psychotic disorders in the Finnish SUPER study

Background: Psychotic disorders differ in their impact on psychosocial functioning. However, few studies have directly compared psychosocial functioning and its determinants between schizophrenia, schizoaffective disorder (SAD), bipolar disorder (BD), and major depressive disorder with psychotic features (psychotic MDD). Objective: We compared rates of independent living, employment, marriage, and having children between these diagnostic groups in a large national sample of participants with psychotic disorders in Finland. Methods: A cross-sectional substudy of participants (N = 9148) aged 18 to 65 years in the Finnish SUPER study, recruited nationwide from health-and social care settings and with advertisements. Psychosis diagnoses, age of onset, and hospitalizations were collected from healthcare registers. Participants were interviewed for psychosocial functioning. Associations of age of onset, hospitalizations, gender, and education with psychosocial functioning were analyzed using logistic regression models. Results: Of participants, 13.8% were employed or studying, 72.0% living independently and 32.5% had children. Overall, BD was associated with best, SAD and psychotic MDD with intermediate, and schizophrenia with worst level of psychosocial functioning. Greatest differences were found in independent living (OR 4.06 for BD vs. schizophrenia). In multivariate models, gender and number of hospitalizations predicted employment, marriage, and independent living in all diagnostic categories, and age of onset in some diagnostic categories. Conclusions: Level of functioning and psychosocial outcomes differed markedly between psychotic disorders, particularly in independent living. Outcomes were worst for schizophrenia and best for BD. Across all psychotic disorders, female gender and lifetime number of hospitalizations had strong independent associations with marriage, employment, and independent living.Peer reviewe

Substance Use and Sleep Problems in Patients With Psychotic Disorders

sgac073Substance use and sleep problems are common in patients with psychotic disorders, but their associations in these patients have not been evaluated. We aimed to investigate associations between substance use and sleep problems in a large nationwide cohort of patients with a psychotic disorder.This study is part of the Finnish SUPER study, which belongs to the Stanley Global Neuropsychiatric Genomics Initiative. In this cross-sectional, multicenter study, participants (N = 8616) were recruited from primary and specialized healthcare. Patients with schizophrenia, schizoaffective disorder, bipolar disorder, and psychotic depression were included. Information on current alcohol (Alcohol Use Disorders Identification Test-Concise) and cigarette use as well as on lifetime illicit drug use, including cannabis, benzodiazepines, amphetamines, and opioids, was collected using questionnaires. The sleep outcomes in our logistic regression analysis were short (≤6 h) and long sleep (≥10 h) duration, difficulties initiating asleep, early morning awakenings, fatigue, and poor sleep quality (SQ).Self-reported substance use was associated with a higher prevalence of sleep problems. After adjustments with age, gender, diagnostic group, and living status, hazardous alcohol use (eg, poor SQ odds ratio [OR] = 1.80, 95\ 1.49 to 2.16, P \lt; .001), current smoking (short sleep duration OR = 1.28, 95\ 1.08 to 1.52, P = .005), and lifetime benzodiazepine misuse (difficulties initiating sleep OR = 2.00, 95\ 1.55 to 2.48, P \lt; .001) were associated with sleep problems.Substance use was associated with sleep problems. Our findings underline the potential benefits of screening substance use when treating sleep problems in patients with psychotic disorders.Peer reviewe

Sleep in psychotic disorders: Results from nationwide SUPER Finland study

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Reaction Time and Visual Memory in Connection with Alcohol Use in Schizophrenia and Schizoaffective Disorder

The purpose of this study was to explore the association between cognition and hazardous drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognition is more or less compromised in schizophrenia, and schizoaffective disorder and alcohol use might aggravate this phenomenon. The study population included 3362 individuals from Finland with diagnoses of schizophrenia or schizoaffective disorder. Hazardous drinking was screened with the AUDIT-C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Alcohol use disorder (AUD) diagnoses were obtained from national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: The Five-Choice Serial Reaction Time Task (5-CSRTT) or the reaction time (RT) test and the Paired Associative Learning (PAL) test. The association between alcohol use and the RT and PAL tests was analyzed with log-linear regression and logistic regression, respectively. After adjustment for age, education, housing status, and the age at which the respondents had their first psychotic episodes, hazardous drinking was associated with a lower median RT in females and less variable RT in males, while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores (TEASs) in females. Our findings of positive associations between alcohol and cognition in schizophrenia and schizoaffective disorder are unique.Peer reviewe

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.Peer reviewe

Reaction Time and Visual Memory in Connection with Alcohol Use in Schizophrenia and Schizoaffective Disorder

The purpose of this study was to explore the association between cognition and hazardous drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognition is more or less compromised in schizophrenia, and schizoaffective disorder and alcohol use might aggravate this phenomenon. The study population included 3362 individuals from Finland with diagnoses of schizophrenia or schizoaffective disorder. Hazardous drinking was screened with the AUDIT-C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Alcohol use disorder (AUD) diagnoses were obtained from national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: The Five-Choice Serial Reaction Time Task (5-CSRTT) or the reaction time (RT) test and the Paired Associative Learning (PAL) test. The association between alcohol use and the RT and PAL tests was analyzed with log-linear regression and logistic regression, respectively. After adjustment for age, education, housing status, and the age at which the respondents had their first psychotic episodes, hazardous drinking was associated with a lower median RT in females and less variable RT in males, while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores (TEASs) in females. Our findings of positive associations between alcohol and cognition in schizophrenia and schizoaffective disorder are unique