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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.
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Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1ß) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.
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Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2',7'-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.
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Transportador 1 de Anión Orgánico Específico del Hígado , Trastornos Psicóticos , Humanos , Finlandia , Células HEK293 , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Rosuvastatina CálcicaRESUMEN
Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)-derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron-astrocyte co-cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.
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Células Madre Pluripotentes Inducidas , Esquizofrenia , Animales , Astrocitos/metabolismo , Predisposición Genética a la Enfermedad/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Prosencéfalo/metabolismo , Esquizofrenia/genéticaRESUMEN
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.
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Citocromo P-450 CYP2D6 , Trastornos Psicóticos , Citocromo P-450 CYP2D6/genética , Finlandia , Frecuencia de los Genes , Genotipo , Humanos , Variantes FarmacogenómicasRESUMEN
We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06-1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07-1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Trastornos Psicóticos , Esquizofrenia , Endofenotipos , Finlandia , Humanos , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/genética , Esquizofrenia/genéticaRESUMEN
BACKGROUND: There is little information on lung function and respiratory diseases in people with psychosis. AIMS: To compare the respiratory health of people with psychosis with that of the general population. METHOD: In a nationally representative sample of 8028 adult Finns, lung function was measured by spirometry. Information on respiratory diseases and symptoms was collected. Smoking was quantified with serum cotinine levels. Psychotic disorders were diagnosed utilising the Structured Clinical Interview for DSM-IV (SCID-I) and medical records. RESULTS: Participants with schizophrenia and other non-affective psychoses had significantly lower lung function values compared with the general population, and the association remained significant for schizophrenia after adjustment for smoking and other potential confounders. Schizophrenia was associated with increased odds of pneumonia (odds ratio (OR) = 4.9), chronic obstructive pulmonary disease (COPD, OR = 4.2) and chronic bronchitis (OR = 3.8); and with high cotinine levels. CONCLUSIONS: Schizophrenia is associated with impaired lung function and increased risk for pneumonia, COPD and chronic bronchitis.
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Bronquitis Crónica/epidemiología , Neumonía/epidemiología , Esquizofrenia/complicaciones , Fumar/epidemiología , Espirometría/estadística & datos numéricos , Adulto , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Finlandia , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , AutoinformeRESUMEN
Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
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Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 6/genética , Proteínas de Unión al ADN/genética , Marcadores Genéticos/genética , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Complejo Mayor de Histocompatibilidad/genética , Neurogranina/genética , Esquizofrenia/inmunología , Factor de Transcripción 4 , Factores de Transcripción/genéticaRESUMEN
Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
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Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Eliminación de Secuencia/genética , China , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 15/genética , Europa (Continente) , Dosificación de Gen/genética , Genoma Humano/genética , Genotipo , Humanos , Pérdida de Heterocigocidad , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/genéticaRESUMEN
BACKGROUND: This study investigated the epidemiology of eating disorders in a population-based sample of young adults. METHOD: A mental health questionnaire was sent to a nationally representative two-stage cluster sample of 1863 Finns aged 20-35 years. All screen-positives and a random sample of screen-negatives were invited to participate in a Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) interview. Case records from all lifetime mental health treatments were also obtained and were used to complement the diagnostic assessment. RESULTS: The lifetime prevalence of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified and any eating disorder among women were 2.1%, 2.3%, 2.0% and 6.0%, respectively, while there was only one man with an eating disorder. Unlike other mental disorders, they are associated with high education. Of women diagnosed with lifetime eating disorder, 67.9% had at least one comorbid Axis I psychiatric disorder, most commonly depressive disorder. While 79.3% of women with lifetime eating disorder had had a treatment contact, only one third of persons with current eating disorder had a current treatment contact. Women whose eating disorder had remitted still experienced more psychological distress and had lower psychosocial functioning that women without lifetime Axis I disorders. CONCLUSION: Eating disorders are the fourth largest group of mental disorders among young women. They tend to be comorbid, often remain untreated and are associated with residual symptoms after the remission of eating disorder symptoms.
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Trastorno Depresivo/epidemiología , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Trastornos Relacionados con Sustancias/epidemiología , Adolescente , Adulto , Anorexia Nerviosa/complicaciones , Anorexia Nerviosa/diagnóstico , Anorexia Nerviosa/epidemiología , Bulimia Nerviosa/complicaciones , Bulimia Nerviosa/diagnóstico , Bulimia Nerviosa/epidemiología , Análisis por Conglomerados , Comorbilidad , Trastorno Depresivo/complicaciones , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Trastornos de Alimentación y de la Ingestión de Alimentos/complicaciones , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Femenino , Finlandia/epidemiología , Humanos , Entrevistas como Asunto , Masculino , Prevalencia , Proyectos de Investigación , Trastornos Relacionados con Sustancias/complicaciones , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Mental disorders influence diet and food consumption, but there is a lack of consistent findings. AIMS: To investigate food consumption, nutrient intakes and serum metabolic biomarkers in depressive, anxiety and alcohol use disorders in comparison with the remaining from a population-based nationwide sample. METHODS: The study was based on the Health 2000 Survey data of which 5504 subjects aged 30 and over (3009 women and 2495 men) were used for the analysis. Depressive disorder, anxiety disorders and alcohol use disorders were diagnosed using the Composite International Diagnostic Interview (M-CIDI). The consumption of food and beverage items, and nutrient intakes were measured with a validated food frequency questionnaire, and the concentrations of biomarkers were determined in blood samples. RESULTS: Overall, no similar differences with both genders were found in the intakes of energy, dietary fibre or macronutrients or in biomarkers in depressive or anxiety disorders. Women suffering from depressed disorder consumed more soft drinks (P = 0.034) and women suffering from anxiety disorders consumed more oils (P = 0.001), polyunsaturated fatty acids (P = 0.001) and less potatoes (P = 0.002) than the remaining participants. Men suffering from depressive disorder consumed less sweets and chocolate (P = 0.001) and men with anxiety disorder consumed more tea (P = 0.033) compared with the remaining participants. In alcohol use disorders, the intake of carbohydrate was lower in both genders (P = 0.001 for women, P = 0.001 for men). CONCLUSIONS: A difference in the usual diet exists between individuals with alcohol use disorders and the remaining participants on a population level. No consistent difference in both genders between those with depressive or anxiety disorders and the remaining was found.
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Alcoholismo/psicología , Trastornos de Ansiedad/psicología , Trastorno Depresivo/psicología , Dieta/estadística & datos numéricos , Conducta Alimentaria/psicología , Adulto , Anciano , Ingestión de Energía , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración PsiquiátricaRESUMEN
In supervision, a doctor examines in interaction with the supervisor her/his work, work role and collaborative relationships with the aim to develop herself/himself and the associated work community. In clinical supervision, a doctor's way of acting in interactive relationships with the patients is examined through patient cases, based on the doctor's own experience. Supervision can be used to strengthen the physician identity, clarify the work role, assimilate and delve into clinical work, support professional development and working career, manage one's own work and coping at work, develop collaboration and team work, and support the work of medical directors.
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Competencia Clínica , Conducta Cooperativa , Administración de Personal , Relaciones Médico-Paciente , Administración de la Práctica Médica , Humanos , Relaciones InterprofesionalesRESUMEN
Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Esquizofrenia/genética , Factores de Transcripción/genética , Alelos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Riesgo , Factor de Transcripción 4RESUMEN
OBJECTIVE: We investigated mortality and its determinants in people with psychotic disorder. METHODS: A nationally representative two-stage cluster sample of 8028 persons aged 30 years or older from Finland was selected for a comprehensive health survey conducted from 2000 to 2001. Participants were screened for psychotic disorder, and screen-positive persons were invited for a Structured Clinical Interview for DSM-IV. The diagnostic assessment of DSM-IV psychotic disorders was based on the Structured Clinical Interview for DSM-IV, case records from mental health treatments, or both. Mortality was followed up until September 2009 and analyzed using Cox proportional hazards model. RESULTS: People with schizophrenia (hazard ratio [HR] = 3.03; 95% confidence interval [CI] = 1.93-4.77) and other nonaffective psychoses (HR = 1.84; 95% CI = 1.17-2.91) had elevated mortality risk, whereas people with affective psychoses did not (HR = 0.61; 95% CI = 0.24-1.55). Antipsychotic medication use was associated with increased mortality (HR = 2.34; 95% CI = 1.86-2.96). There was an interaction between antipsychotic medication use and the presence of a psychotic disorder: antipsychotic medication use was only associated with elevated mortality in persons who were using antipsychotics and did not have primary psychotic disorder. In persons with psychotic disorder, mortality was predicted by smoking and Type 2 diabetes at baseline survey. CONCLUSIONS: Schizophrenia and nonaffective psychoses are associated with increased mortality risk, whereas affective psychoses are not. Antipsychotic medication use increases mortality risk in older people without primary psychotic disorder, but not in individuals with schizophrenia. Smoking and Type 2 diabetes are important predictors of elevated mortality risk in persons with psychotic disorder.
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Trastornos Psicóticos Afectivos/mortalidad , Trastornos Psicóticos/mortalidad , Esquizofrenia/mortalidad , Adulto , Trastornos Psicóticos Afectivos/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Estudios de Cohortes , Diabetes Mellitus Tipo 2/mortalidad , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Trastornos Psicóticos/tratamiento farmacológico , Factores de Riesgo , Esquizofrenia/tratamiento farmacológico , Fumar/mortalidadRESUMEN
Background: Substance 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. Study Design: 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). Results: 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% CI: 1.49 to 2.16, P < .001), current smoking (short sleep duration OR = 1.28, 95% CI: 1.08 to 1.52, P = .005), and lifetime benzodiazepine misuse (difficulties initiating sleep OR = 2.00, 95% CI: 1.55 to 2.48, P < .001) were associated with sleep problems. Conclusions: 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.
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PURPOSE: SUPER-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. PARTICIPANTS: 10 474 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 DATE: 5757 (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 PLANS: Compare 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.
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Trastorno Bipolar , Trastornos Psicóticos , Esquizofrenia , Humanos , Finlandia/epidemiología , Variaciones en el Número de Copia de ADN , Trastornos Psicóticos/epidemiología , Esquizofrenia/epidemiología , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Trastorno Bipolar/diagnósticoRESUMEN
The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.
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Proteínas Adaptadoras Transductoras de Señales/genética , Esquizofrenia/genética , Proteínas Adaptadoras del Transporte Vesicular , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Población Blanca/genéticaRESUMEN
BACKGROUND: Bipolar I disorder is a highly heritable psychiatric illness with undetermined predisposing genetic and environmental risk factors. We examined familial contributions to hippocampal morphology in bipolar disorder, using a population-based twin cohort design. METHODS: We acquired high-resolution brain MRI scans from 18 adult patients with bipolar I disorder [BPI; mean age 45.6 ± 8.69 (SD); 10 lithium-treated], 14 non-bipolar co-twins, and 32 demographically matched healthy comparison twins. We used three-dimensional radial distance mapping techniques to visualize hippocampal shape differences between groups. RESULTS: Lithium-treated BPI patients had significantly larger global hippocampal volume compared to both healthy controls (9%) and non-bipolar co-twins (12%), and trend-level larger volumes relative to non-lithium-treated BPI patients (8%). In contrast, hippocampal volumes in non-lithium-treated BPI patients did not differ from those of non-bipolar co-twins and control twins. 3D surface maps revealed thicker hippocampi in lithium-treated BPI probands compared with control twins across the entire anterior-to-posterior extent of the cornu ammonis (CA1 and 2) regions, and the anterior part of the subiculum. Unexpectedly, co-twins also showed significantly thicker hippocampi compared with control twins in regions that partially overlapped those showing effects in the lithium treated BPI probands. CONCLUSIONS: These findings suggest that regionally thickened hippocampi in bipolar I disorder may be partly due to familial factors and partly due to lithium-induced neurotrophy, neurogenesis, or neuroprotection. Unlike schizophrenia, hippocampal alterations in co-twins of bipolar I disorder probands are likely to manifest as subtle volume excess rather than deficit, perhaps indicating protective rather than risk effects.
Asunto(s)
Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Compuestos de Litio/uso terapéutico , Adulto , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Mental disorders are associated with increased mortality, but population-based surveys with reliable diagnostic procedures controlling for somatic health status are scarce. AIMS: To assess excess mortality associated with depressive, anxiety and alcohol use disorders and the principal causes of death. METHOD: In a nationally representative sample of Finns aged 30-70 years, psychiatric disorders were diagnosed with the Composite International Diagnostic Interview. After an 8-year follow-up period, vital status and cause of death of each participant was obtained from national registers. RESULTS: After adjusting for sociodemographic factors, health status and smoking, depressive (hazard ratio (HR) = 1.97) and alcohol use disorders (HR = 1.72) were statistically significantly associated with mortality. Risk of unnatural death was increased among individuals diagnosed with anxiety disorders or alcohol dependence. CONCLUSIONS: Individuals with depressive and alcohol use disorders have an increased mortality risk comparable with many chronic somatic conditions, that is only partly attributable to differences in sociodemographic, somatic health status and hazardous health behaviour.
Asunto(s)
Trastornos Relacionados con Alcohol/mortalidad , Trastornos de Ansiedad/mortalidad , Trastorno Depresivo/mortalidad , Vigilancia de la Población , Adulto , Anciano , Anciano de 80 o más Años , Causas de Muerte , Femenino , Finlandia/epidemiología , Conductas Relacionadas con la Salud , Estado de Salud , Humanos , Entrevista Psicológica , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores SocioeconómicosRESUMEN
CONTEXT: The consumption of statins (HMG-CoA reductase inhibitors) in most Western countries has increased to the extent that it may affect all-cause and disease-specific mortality. OBJECTIVE: To analyze the association of statin use with all-cause and disease-specific mortality utilizing nationwide databases in a record linkage study in Finland. METHODS: The study population included all statin users in Finland who had purchased at least one prescription between 1997 and 2005. A control population matched for age, sex, and place of residence and without statin usage was selected. The study population consisted of 336, 618 pairs of individuals, and the mean length of follow-up was 4.4 years. All-cause mortality and mortality caused by coronary heart disease (CHD), stroke, other circulatory causes, cancer, unnatural causes, and suicide were analyzed. Persistence to treatment was calculated by varying adherence criteria between 20 and 80%. RESULTS: We observed association between all-cause, non-CHD and CHD and treatment with statins in statin user group. For CHD mortality, we observed a relationship between the persistence to statin treatment and a decreasing CHD mortality. For each 10% increase in adherence criteria, a 5% (2-8%) decrease in CHD mortality was observed within the range of 20% (RR 0.81, 95%CI 0.32-2.02) to 80% (RR 0.54, 95%CI 0.46-0.64). CONCLUSION: In this nationwide study, long-term use of statins is associated with the reduction in CHD mortality.