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PurposeSUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland.Participants10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018.Findings to date5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death.Future plansCompare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.

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.

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol-related disorder in persons with bipolar disorder (BD). The study population included 1268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol-related disorder including alcohol use disorder (AUD). Hazardous drinking was screened with the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) screening tool. Alcohol-related disorder diagnoses were obtained from the national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on A tablet computer: the 5-choice serial reaction time task, or reaction time (RT) test and the Paired Associative Learning (PAL) test. Depressive symptoms were assessed with the Mental Health Inventory with five items (MHI-5). However, no assessment of current manic symptoms was available. Association between RT-test and alcohol use was analyzed with log-linear regression, and eβ with 95% confidence intervals (CI) are reported. PAL first trial memory score was analyzed with linear regression, and β with 95% CI are reported. PAL total errors adjusted was analyzed with logistic regression and odds ratios (OR) with 95% CI are reported. After adjustment of age, education, housing status and depression, hazardous drinking was associated with lower median and less variable RT in females while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores in females. Our findings of positive associations between alcohol use and cognition in persons with bipolar disorder are difficult to explain because of the methodological flaw of not being able to separately assess only participants in euthymic phase.

The purpose of this study was to explore the association of cognition with hazardous drinking Polygenic Scores (PGS) in 2649 schizophrenia, 558 schizoaffective disorder, and 1125 bipolar disorder patients in Finland. Hazardous drinking PGS was computed using the LDPred program. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: the 5-choice serial reaction time task, or Reaction Time (RT) test, and the Paired Associative Learning (PAL) test. The association between hazardous drinking PGS and cognition was measured using four cognition variables. Log-linear regression was used in Reaction Time (RT) assessment, and logistic regression was used in PAL assessment. All analyses were conducted separately for males and females. After adjustment of age, age of onset, education, household pattern, and depressive symptoms, hazardous drinking PGS was not associated with reaction time or visual memory in male or female patients with schizophrenia, schizoaffective, and bipolar disorder.

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population ( n  = 485,930). We identify eight genes ( ADGRB2 , KDM5B , GIGYF1 , ANKRD12 , SLC8A1 , RC3H2 , CACNA1A and BCAS3 ) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population. Analysis of rare coding variants in the UK Biobank identifies eight genes associated with adult cognitive function, including KDM5B . Rare and common variant signals overlap and contribute additively to the phenotype.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants’ past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23–1.43], p  = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia ( n  = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden ( p  = 1.00e-04 and p  = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

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.

BackgroundSchizophrenia patients have been found to have long lasting, clinical state independent impairments in intellectual abilities as well as in specific cognitive domains of which visual learning and memory are central to our current study.The main aim of this study was to investigate the sociodemographic and lifestyle factors associated with good visual learning and memory in patients with schizophrenia in a sample of patients.MethodsThe basic population for this study consists of Finnish SUPER study on genetic mechanisms of psychotic disorders (SUPER), part of the Stanley Global Neuropsychiatric Genomics Initiative. The Northern Finland Birth Cohort 1966 (NFBC 1966) functioned as a reference group to define good cognitive performance.The Finnish SUPER study on genetic mechanisms of psychotic disorders is a part of the international Stanley Global Neuropsychiatric Genomics Initiative. The objective of the study is to understand the genetic and biological background of psychotic disorders.The participants of the present study were patients with clinical diagnosis of schizophrenia who were born between 1950–1979 (N=1,907). The reference group of members of the NFBC 1966 consisted 5,506 individuals aged 46–47 years.Paired Associates Learning (PAL) was used both in SUPER and NFBC 1966 studies. PAL test measures visual memory and new learning. We used the primary outcome variable of ‘total errors adjusted’ (TEA) which assesses learning over repeated attempts. Lower than the mean score of TEA of NFBC 1966 was used as cut-off for good performance in PAL test. SUPER participants with good performance in the PAL test were compared to other SUPER participants.Participants in SUPER study were interviewed and filled in a questionnaire about general mental wellbeing, subjective health and lifestyle factor. The association of following sociodemographic and lifestyle factors were investigated: education, age, marital status, self-rated memory, psychotropic medication use, alcohol consumption and cigarette smoking.ResultsOf the SUPER participants, 129 (6,9 %) performed at least on the level on which 50% of the participants of the NFBC 1966 performed. Of SUPER participant males 5,9 % and of the females 8,1 % performed on this level.Performing above the NFBC 1966 50% level in the PAL test was associated with higher educational level and higher use of alcohol in males, and with higher educational level and being married in females.DiscussionIn previous studies age, education, duration of illness, severity of symptoms have been found to count for some of the overall impairments found in schizophrenia. We found a subgroup of schizophrenia patients with good visual learning and memory and sociodemographic and lifestyle factors that were associated with good performance. In our study education and marital status in women and alcohol use in men was associated with better performance in PAL test.

Non-adherence and negative attitudes towards medication are major problems in treating psychotic disorders. Cytochrome P450 2D6 (CYP2D6) contributes to the metabolism of aripiprazole and risperidone, and variations in CYP2D6 activity may affect treatment response or adverse effects. However, the impact of these variations on adherence and medication attitudes is unclear. This study investigates the relationships between CYP2D6 phenotype, self-reported adherence, adverse effects, and attitudes among aripiprazole and risperidone users. The study analysed data from the SUPER-Finland cohort of 10,474 adults with psychotic episodes, including 1,429 aripiprazole and 828 risperidone users. The Attitudes towards Neuroleptic Treatment (ANT) questionnaire assessed adherence and adverse effects in all patients, while medication-related attitudes were examined in a subgroup of 1,000 participants. Associations between CYP2D6 phenotypes and outcomes were analysed using logistic regression and beta regression in aripiprazole and risperidone groups separately. Among risperidone users, we observed no association between CYP2D6 phenotypes and adherence, adverse effects, or attitudes. Similarly, we found no link between adherence and CYP2D6 phenotypes among aripiprazole users. However, aripiprazole users with the ultrarapid CYP2D6 phenotype had more adverse effects (OR = 1.71, 95 % CI 1.03–2.90, p = 0.041). Among aripiprazole users, CYP2D6 ultrarapid phenotype was associated with less favourable attitudes towards antipsychotic treatment (β = −0.48, p = 0.023). These findings provide preliminary evidence that the ultrarapid CYP2D6 phenotype is associated with increased adverse effects and negative attitudes towards antipsychotic medication among aripiprazole users. CYP2D6 phenotype did not influence adherence, adverse effects, or attitudes among risperidone users.

Abstract Background People with psychotic disorders demonstrate a wide spectrum of sleep abnormalities. Abnormalities include changes in total sleep time, increased sleep onset latency, increased wake-up time after sleep onset and abnormalities in sleep architecture. The study aimed to characterize the sleep difficulties in a large sample of persons with psychotic disorders and to examine association with age and gender. Methods Altogether, 5046 persons with a major psychiatric disorder (schizophrenia: 2972, schizoaffective disorder: 640, bipolar disorder: 1097 and psychotic depression: 330) and aged 18–80 participated in a nationwide Super project. The Finnish SUPER (Finnish acronym for “Finnish study on genetic mechanisms of psychotic disorders”) study is a part of the international Stanley Global Neuropsychiatric Genomics Initiative. The results were compared with a representative general population sample of 8018 adults (Health 2000). Sleep was assessed in a self-report questionnaire. In the present study we used total sleep time, tiredness (defined as feeling more tired than other people of the same age during day time at least weakly, yes/no), difficulties in getting sleep without sleep medication often or almost daily (yes/no) and early morning or night awakenings occurring either often or nearly every night (yes/no). Results Long sleep (> 10h) was most common in persons with schizophrenia or schizoaffective disorder reported by approximately 30% when age was 18–40. The corresponding proportion was approximately 15% in persons with bipolar disorder or psychotic depression and less than 1% in the general population. Tiredness, difficulties in getting sleep and early morning or night awakenings were reported most by persons with bipolar disorder and psychotic depression, but also persons with schizophrenia reported those more than the general population in people with under 60 years of age. Schizoaffective disorder was between schizophrenia and affective psychoses in the sleep variables. In persons over 60, the difference between the groups was smaller than in persons under 60 years of age, because sleeping long and tiredness decreased in all patient groups, and difficulties getting sleep and awakenings increased in the general population sample more than in psychosis patients. Discussion Sleep disorders seem to be prominent in persons with major psychiatric disorders. Tiredness was common in all diagnosis groups. Long sleep was most common in schizophrenia and difficulties in getting sleep and early morning or night awakenings in affective psychoses. More research is needed on possibilities to prevent and treat sleep disorders in major psychiatric disorders.