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1.
World Psychiatry ; 19(3): 339-349, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32931098

RESUMO

The nature and prevalence of combinations of mental disorders and their associations with premature mortality have never been reported in a comprehensive way. We describe the most common combinations of mental disorders and estimate excess mortality associated with these combinations. We designed a population-based cohort study including all 7,505,576 persons living in Denmark at some point between January 1, 1995 and December 31, 2016. Information on mental disorders and mortality was obtained from national registers. A total of 546,090 individuals (10.5%) living in Denmark on January 1, 1995 were diagnosed with at least one mental disorder during the 22-year follow-up period. The overall crude rate of diagnosis of mental disorders was 9.28 (95% CI: 9.26-9.30) per 1,000 person-years. The rate of diagnosis of additional mental disorders was 70.01 (95% CI: 69.80-70.26) per 1,000 person-years for individuals with one disorder already diagnosed. At the end of follow-up, two out of five individuals with mental disorders were diagnosed with two or more disorder types. The most prevalent were neurotic/stress-related/somatoform disorders (ICD-10 F40-F48) and mood disorders (ICD-10 F30-F39), which - alone or in combination with other disorders - were present in 64.8% of individuals diagnosed with any mental disorder. Mortality rates were higher for people with mental disorders compared to those without mental disorders. The highest mortality rate ratio was 5.97 (95% CI: 5.52-6.45) for the combination of schizophrenia (ICD-10 F20-F29), neurotic/stress-related/somatoform disorders and substance use disorders (ICD-10 F10-F19). Any combination of mental disorders was associated with a shorter life expectancy compared to the general Danish population, with differences in remaining life expectancy ranging from 5.06 years (95% CI: 5.01-5.11) to 17.46 years (95% CI: 16.86-18.03). The largest excess mortality was observed for combinations that included substance use disorders. This study reports novel estimates related to the "force of comorbidity" and provides new insights into the contribution of substance use disorders to premature mortality in those with comorbid mental disorders.

2.
Hum Mol Genet ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32959868

RESUMO

Many medical treatments, from oncology to psychiatry, can lower white blood cell counts and thus access to these treatments can be restricted to individuals with normal levels of white blood cells, principally in order to minimise risk of serious infection. This adversely affects individuals of African or Middle Eastern ancestries who have on average a reduced number of circulating white blood cells, due to the Duffy-null (CC) genotype at rs2814778 in the ACKR1 gene. Here, we investigate whether the Duffy-null genotype is associated with the risk of infection using the UK Biobank sample and the iPSYCH Danish case-cohort study, two population-based samples from different countries and age ranges. We found that a high proportion of those with the Duffy-null genotype (21%) had a neutrophil count below the threshold often used as a cut-off for access to relevant treatments, compared to 1% of those with the TC/TT genotype. In addition we found that despite its strong association with lower average neutrophil counts, the Duffy-null genotype was not associated with an increased risk of infection, viral or bacterial. These results have widespread implications for the clinical treatment of individuals of African ancestry and indicate that that neutrophil thresholds to access treatments could be lowered in individuals with the Duffy-null genotype without an increased risk of infection.

3.
Pediatr Res ; 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32942288

RESUMO

BACKGROUND: Prematurity is a severe pathophysiological condition, however, little is known about the gestational age-dependent development of the neonatal metabolome. METHODS: Using an untargeted liquid chromatography-tandem mass spectrometry metabolomics protocol, we measured over 9000 metabolites in 298 neonatal residual heel prick dried blood spots retrieved from the Danish Neonatal Screening Biobank. By combining multiple state-of-the-art metabolome mining tools, we retrieved chemical structural information at a broad level for over 5000 (60%) metabolites and assessed their relation to gestational age. RESULTS: A total of 1459 (~16%) metabolites were significantly correlated with gestational age (false discovery rate-adjusted P < 0.05), whereas 83 metabolites explained on average 48% of the variance in gestational age. Using a custom algorithm based on hypergeometric testing, we identified compound classes (617 metabolites) overrepresented with metabolites correlating with gestational age (P < 0.05). Metabolites significantly related to gestational age included bile acids, carnitines, polyamines, amino acid-derived compounds, nucleotides, phosphatidylcholines and dipeptides, as well as treatment-related metabolites, such as antibiotics and caffeine. CONCLUSIONS: Our findings elucidate the gestational age-dependent development of the neonatal blood metabolome and suggest that the application of metabolomics tools has great potential to reveal novel biochemical underpinnings of disease and improve our understanding of complex pathophysiological mechanisms underlying prematurity-associated disorders. IMPACT: A large variation in the neonatal dried blood spot metabolome from residual heel pricks stored at the Danish Neonatal Screening Biobank can be explained by gestational age. While previous studies have assessed the relation of selected metabolic markers to gestational age, this study assesses metabolome-wide changes related to prematurity. Using a combination of recently developed metabolome mining tools, we assess the relation of over 9000 metabolic features to gestational age. The ability to assess metabolome-wide changes related to prematurity in neonates could pave the way to finding novel biochemical underpinnings of health complications related to preterm birth.

5.
Environ Res ; 188: 109788, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562949

RESUMO

Natural environments have been associated with mental health benefits worldwide. However, how different elements and types of natural environments associate with mental health is still largely unknown. In this study, we perform a detailed analysis on a large, nation-wide data set of mental health records (908 553 individuals) for Denmark combined with remotely-sensed land cover and vegetation density data. We explore associations between growing up surrounded by different environments and rates of a spectrum of 18 psychiatric disorders. Childhood land cover exposure for urban, agricultural, near-natural green space, and blue space was determined around the residence of each individual. Vegetation density and air pollution were evaluated as potential pathways. Cox proportional hazards models were used to estimate rates as hazard ratios and then adjusted for potential confounding from other known risk factors. For 12 of 18 disorders, rates were lower for children growing up in environments with more natural elements (near-natural green space, blue space, and agriculture) compared to children growing up in urban environments. High vegetation density was associated with lower rates for most disorders within all the examined environments, whereas mitigation of air pollution by natural environments seemed a less important potential pathway. Rates were not notably changed by adjustment for urbanization, parental and municipal socioeconomic status, family history of mental illness, and parents' age. In conclusion, we found that growing up surrounded by a range of natural environments such as near-natural green space, blue space, and agriculture may lower rates of psychiatric disorders. Our results show the importance of ensuring access to natural environments from as nature-based solutions for improved public health and sustainable, livable cities.

6.
Schizophr Bull ; 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32415773

RESUMO

Childhood exposure to green space has previously been associated with lower risk of developing schizophrenia later in life. It is unclear whether this association is mediated by genetic liability or whether the 2 risk factors work additively. Here, we investigate possible gene-environment associations with the hazard ratio (HR) of schizophrenia by combining (1) an estimate of childhood exposure to residential-level green space based on the normalized difference vegetation index (NDVI) from Landsat satellite images, with (2) genetic liability estimates based on polygenic risk scores for 19 746 genotyped individuals from the Danish iPSYCH sample. We used information from the Danish registers of health, residential address, and socioeconomic status to adjust HR estimates for established confounders, ie, parents' socioeconomic status, and family history of mental illness. The adjusted HRs show that growing up surrounded by the highest compared to the lowest decile of NDVI was associated with a 0.52-fold (95% confidence interval [CI]: 0.40 to 0.66) lower schizophrenia risk, and children with the highest polygenic risk score had a 1.24-fold (95% CI: 1.18 to 1.30) higher schizophrenia risk. We found that NDVI explained 1.45% (95% CI: 1.07 to 1.90) of the variance on the liability scale, while polygenic risk score for schizophrenia explained 1.01% (95% CI: 0.77 to 1.46). Together they explained 2.40% (95% CI: 1.99 to 3.07) with no indication of a gene-environment interaction (P = .29). Our results suggest that risk of schizophrenia is associated additively with green space exposure and genetic liability, and provide no support for an environment-gene interaction between NDVI and schizophrenia.

7.
Hum Genet ; 139(5): 593-604, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32152699

RESUMO

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10-25). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10-8), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine.


Assuntos
Gastroenteropatias/epidemiologia , Marcadores Genéticos , Predisposição Genética para Doença , Transtornos Mentais/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Gastroenteropatias/genética , Gastroenteropatias/microbiologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Incidência , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
8.
JAMA Psychiatry ; 77(8): 797-805, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32211833

RESUMO

Importance: Onset of mental disorders during childhood or adolescence has been associated with underperformance in school and impairment in social and occupational life in adulthood, which has important implications for the affected individuals and society. Objective: To compare the educational achievements at the final examination of compulsory schooling in Denmark between individuals with and those without a mental disorder. Design, Setting, and Participants: This population-based cohort study was conducted in Denmark and obtained data from the Danish Civil Registration System and other nationwide registers. The 2 cohorts studied were (1) all children who were born in Denmark between January 1, 1988, and July 1, 1999, and were alive at age 17 years (n = 629 622) and (2) all children who took the final examination at the end of ninth grade in both Danish and mathematics subjects between January 1, 2002, and December 31, 2016 (n = 542 500). Data analysis was conducted from March 1, 2018, to March 1, 2019. Exposures: Clinical diagnosis by a psychiatrist of any mental disorder or 1 of 29 specific mental disorders before age 16 years. Main Outcomes and Measures: Taking the final examination at the end of ninth grade and mean examination grades standardized as z scores with differences measured in SDs (standardized mean grade difference). Results: Of the total study population (n = 629 622; 306 209 female and 323 413 male), 523 312 individuals (83%) took the final examination before 17 years of age and 38 001 (6%) had a mental disorder before that age. Among the 542 500 individuals (274 332 female and 268 168 male), the mean (SD) age was 16.1 (0.33) years for the females and 16.2 (0.34) years for the males. Among the 15 843 female and 22 158 male students with a mental disorder, a lower proportion took the final examination (0.52; 95% CI, 0.52-0.53) compared with individuals without a mental disorder (0.88; 95% CI, 0.88-0.88). Mental disorders affected the grades of male individuals (standardized mean grade difference, -0.30; 95% CI, -0.32 to -0.28) more than the grades of their female peers (standardized mean grade difference, -0.24; 95% CI, -0.25 to -0.22) when compared with same-sex individuals without mental disorders. Most specific mental disorders were associated with statistically significantly lower mean grades, with intellectual disability associated with the lowest grade in female and male students (standardized mean grade difference, -1.07 [95% CI, -1.23 to -0.91] and -1.03 [95% CI, -1.17 to -0.89]; P = .76 for sex differences in the mean grades). Female and male students with anorexia nervosa achieved statistically significantly higher grades on the final examination (standardized mean grade difference, 0.38 [95% CI, 0.32-0.44] and 0.31 [95% CI, 0.11-0.52]; P = .54 for sex differences in the mean grades) compared with their peers without this disorder. For those with anxiety, attachment, attention-deficit/hyperactivity, and other developmental disorders, female individuals attained relatively lower standardized mean grades compared with their male counterparts. Conclusions and Relevance: Results of this study suggest that, in Denmark, almost all mental disorders in childhood or adolescence may be associated with a lower likelihood of taking the final examination at the end of ninth grade; those with specific disorders tended to achieve lower mean grades on the examination; and female, compared with male, individuals with certain mental disorders appeared to have relatively more impairment. These findings appear to emphasize the need to provide educational support to young people with mental disorders.

9.
Schizophr Res ; 216: 488-495, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31699630

RESUMO

High exposure to green space and natural environments has previously been associated with lower schizophrenia rates possibly through low air pollution and improved psychological restoration. Exposure to natural environments could explain the negative urban-rural gradient of schizophrenia, but it is unclear if all natural environments are associated with schizophrenia rates. We investigated the association between schizophrenia and growing up surrounded by environments classified as mainly urban, agricultural, near-natural green space, and blue space. Vegetation density and air pollution were assessed as potential pathways. We used the Danish population (943 027 people) and remotely-sensed environmental data to determine land cover exposure and vegetation density around each individual's residence. Effect sizes were estimated using Cox regression and adjusted for air pollution, socioeconomic status, and urbanization. Our results show that growing up surrounded by non-urban environments is associated with lower schizophrenia rates. Firstly, growing up surrounded by non-built-up areas (agricultural areas, near-natural green and blue space) is associated with lower schizophrenia rates compared to urban areas. Secondly, rates decrease with vegetation density in a dose-response relationship for urban and agricultural areas. Air pollution mitigation more strongly explained the protective association in near-natural green spaces, implying that restorative pathways together with air pollution mitigation may explain lower rates in natural environments. This study suggests that ensuring access to natural environments during childhood may be important for schizophrenia prevention, whilst being the first study to show that natural environments may influence schizophrenia rates through multiple pathways.

10.
Addiction ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31803957

RESUMO

AIMS: 1) To investigate whether genetic liability to attention-deficit/hyperactivity disorder (ADHD), indexed by polygenic risk scores for ADHD (PRS-ADHD), is associated with substance use disorders (SUD) in individuals with ADHD. 2) To investigate whether other individual- or family-related risk factors for SUD could mediate or confound this association. DESIGN: Population-based cohort study SETTING AND PARTICIPANTS: ADHD cases in the iPSYCH sample (a Danish case-cohort sample of genotyped cases with specific mental disorders), born in Denmark between 1981 and 2003 (N = 13 116). Register-based information on hospital diagnoses of SUD was available until December 31, 2016. MEASUREMENTS: We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for any SUD as well as for different SUD types (alcohol, cannabis, and other illicit drugs) and severities (use, abuse, and addiction), with effect sizes corresponding to a comparison of the highest PRS-ADHD decile to the lowest. FINDINGS: PRS-ADHD were associated with any SUD (OR = 1.30, 95% CI: 1.11-1.51). Estimates were similar across different types and severity levels of SUD. Other risk factors for SUD (male sex, age at ADHD diagnosis, comorbid conduct problems, and parental factors including SUD, mental disorders, and socio-economic status) were independently associated with increased risk of SUD. PRS-ADHD explained a minor proportion of the variance in SUD (0.2% on the liability scale) compared to the other risk factors. The association between PRS-ADHD and any SUD was slightly attenuated (OR = 1.21, 95% CI: 1.03-1.41) after adjusting for the other risk factors for SUD. Furthermore, associations were nominally higher in females than in males (ORfemales  = 1.59, 95% CI: 1.19-2.12, ORmales  = 1.18, 95% CI: 0.98-1.42). CONCLUSIONS: A higher genetic liability to attention-deficit/hyperactivity disorder appears to be associated with higher risks of substance use disorders in individuals with attention-deficit/hyperactivity disorder.

11.
Transl Psychiatry ; 9(1): 288, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712652

RESUMO

Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 (n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery (n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02-1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81-1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19-1.74) and without (OR, 1.88; 95% CI: 1.26-2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.

12.
JAMA Psychiatry ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746968

RESUMO

Importance: Knowledge about the epidemiology of mental disorders in children and adolescents is essential for research and planning of health services. Surveys can provide prevalence rates, whereas population-based registers are instrumental to obtain precise estimates of incidence rates and risks. Objective: To estimate age- and sex-specific incidence rates and risks of being diagnosed with any mental disorder during childhood and adolescence. Design: This cohort study included all individuals born in Denmark from January 1, 1995, through December 31, 2016 (1.3 million), and followed up from birth until December 31, 2016, or the date of death, emigration, disappearance, or diagnosis of 1 of the mental disorders examined (14.4 million person-years of follow-up). Data were analyzed from September 14, 2018, through June 11, 2019. Exposures: Age and sex. Main Outcomes and Measures: Incidence rates and cumulative incidences of all mental disorders according to the ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, diagnosed before 18 years of age during the study period. Results: A total of 99 926 individuals (15.01%; 95% CI, 14.98%-15.17%), including 41 350 girls (14.63%; 95% CI, 14.48%-14.77%) and 58 576 boys (15.51%; 95% CI, 15.18%-15.84%), were diagnosed with a mental disorder before 18 years of age. Anxiety disorder was the most common diagnosis in girls (7.85%; 95% CI, 7.74%-7.97%); attention-deficit/hyperactivity disorder (ADHD) was the most common in boys (5.90%; 95% CI, 5.76%-6.03%). Girls had a higher risk than boys of schizophrenia (0.76% [95% CI, 0.72%-0.80%] vs 0.48% [95% CI, 0.39%-0.59%]), obsessive-compulsive disorder (0.96% [95% CI, 0.92%-1.00%] vs 0.63% [95% CI, 0.56%-0.72%]), and mood disorders (2.54% [95% CI, 2.47%-2.61%] vs 1.10% [95% CI, 0.84%-1.21%]). Incidence peaked earlier in boys than girls in ADHD (8 vs 17 years of age), intellectual disability (5 vs 14 years of age), and other developmental disorders (5 vs 16 years of age). The overall risk of being diagnosed with a mental disorder before 6 years of age was 2.13% (95% CI, 2.11%-2.16%) and was higher in boys (2.78% [95% CI, 2.44%-3.15%]) than in girls (1.45% [95% CI, 1.42%-1.49%]). Conclusions and Relevance: This nationwide population-based cohort study provides a first comprehensive assessment of the incidence and risks of mental disorders in childhood and adolescence. By 18 years of age, 15.01% of children and adolescents in this study were diagnosed with a mental disorder. The incidence of several neurodevelopmental disorders peaked in late adolescence in girls, suggesting possible delayed detection. The distinct signatures of the different mental disorders with respect to sex and age may have important implications for service planning and etiological research.

13.
JAMA Netw Open ; 2(11): e1914401, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675084

RESUMO

Importance: Schizophrenia is a highly heritable psychiatric disorder, and recent studies have suggested that exposure to nitrogen dioxide (NO2) during childhood is associated with an elevated risk of subsequently developing schizophrenia. However, it is not known whether the increased risk associated with NO2 exposure is owing to a greater genetic liability among those exposed to highest NO2 levels. Objective: To examine the associations between childhood NO2 exposure and genetic liability for schizophrenia (as measured by a polygenic risk score), and risk of developing schizophrenia. Design, Setting, and Participants: Population-based cohort study including individuals with schizophrenia (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code F20) and a randomly selected subcohort. Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia, emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019. Exposures: Individual exposure to NO2 during childhood estimated as mean daily exposure to NO2 at residential addresses from birth to the 10th birthday. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file. Main Outcomes and Measures: The main outcome was schizophrenia. Weighted Cox proportional hazards regression models were fitted to estimate adjusted hazard ratios (AHRs) for schizophrenia with 95% CIs according to the exposures. Results: Of a total of 23 355 individuals, 11 976 (51.3%) were male and all had Danish-born parents. During the period of the study, 3531 were diagnosed with schizophrenia. Higher polygenic risk scores were correlated with higher childhood NO2 exposure (ρ = 0.0782; 95% CI, 0.065-0.091; P < .001). A 10-µg/m3 increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15-1.32) and a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23-1.35) were independently associated with increased schizophrenia risk. Conclusions and Relevance: These findings suggest that the apparent association between NO2 exposure and schizophrenia is only slightly confounded by a higher polygenic risk score for schizophrenia among individuals living in areas with greater NO2. The findings demonstrate the utility of including polygenic risk scores in epidemiologic studies.

14.
Lancet ; 394(10211): 1827-1835, 2019 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-31668728

RESUMO

BACKGROUND: Systematic reviews have consistently shown that individuals with mental disorders have an increased risk of premature mortality. Traditionally, this evidence has been based on relative risks or crude estimates of reduced life expectancy. The aim of this study was to compile a comprehensive analysis of mortality-related health metrics associated with mental disorders, including sex-specific and age-specific mortality rate ratios (MRRs) and life-years lost (LYLs), a measure that takes into account age of onset of the disorder. METHODS: In this population-based cohort study, we included all people younger than 95 years of age who lived in Denmark at some point between Jan 1, 1995, and Dec 31, 2015. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and the date and cause of death was obtained from the Danish Register of Causes of Death. We classified mental disorders into ten groups and causes of death into 11 groups, which were further categorised into natural causes (deaths from diseases and medical conditions) and external causes (suicide, homicide, and accidents). For each specific mental disorder, we estimated MRRs using Poisson regression models, adjusting for sex, age, and calendar time, and excess LYLs (ie, difference in LYLs between people with a mental disorder and the general population) for all-cause mortality and for each specific cause of death. FINDINGS: 7 369 926 people were included in our analysis. We found that mortality rates were higher for people with a diagnosis of a mental disorder than for the general Danish population (28·70 deaths [95% CI 28·57-28·82] vs 12·95 deaths [12·93-12·98] per 1000 person-years). Additionally, all types of disorders were associated with higher mortality rates, with MRRs ranging from 1·92 (95% CI 1·91-1·94) for mood disorders to 3·91 (3·87-3·94) for substance use disorders. All types of mental disorders were associated with shorter life expectancies, with excess LYLs ranging from 5·42 years (95% CI 5·36-5·48) for organic disorders in females to 14·84 years (14·70-14·99) for substance use disorders in males. When we examined specific causes of death, we found that males with any type of mental disorder lost fewer years due to neoplasm-related deaths compared with the general population, although their cancer mortality rates were higher. INTERPRETATION: Mental disorders are associated with premature mortality. We provide a comprehensive analysis of mortality by different types of disorders, presenting both MRRs and premature mortality based on LYLs, displayed by age, sex, and cause of death. By providing accurate estimates of premature mortality, we reveal previously underappreciated features related to competing risks and specific causes of death. FUNDING: Danish National Research Foundation.


Assuntos
Transtornos Mentais/mortalidade , Indicadores de Qualidade em Assistência à Saúde , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/mortalidade , Mortalidade Prematura , Sistema de Registros , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Suicídio/estatística & dados numéricos , Adulto Jovem
15.
Transl Psychiatry ; 9(1): 252, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591381

RESUMO

Mental disorders have for the majority of cases an unknown etiology, but several studies indicate that neurodevelopmental changes happen in utero or early after birth. We performed a nested case-control study of the relation between blood levels of neuro-developmental (S100B, BDNF, and VEGF-A) and inflammatory (MCP-1, TARC, IL-8, IL-18, CRP, and IgA) biomarkers in newborns, and later development of autism spectrum disorders (ASD, N = 751), attention deficit hyperactivity disorders (ADHD, N = 801), schizophrenia (N = 1969), affective (N = 641) or bipolar disorders (N = 641). Samples and controls were obtained as part of the iPSYCH Danish Case-Cohort Study using dried blood spot samples collected between 1981 and 2004, and stored frozen at the Danish National Biobank. In newborns lower blood level of BDNF was significantly associated with increased odds (OR 1.15) of developing ASD (p = 0.001). This difference could not be explained by genetic variation in the BDNF coding gene region. A tendency of decreased levels of all the neurotrophic markers and increased levels of all inflammatory markers was noted. The low newborn blood levels of BDNF in children developing ASD is an important finding, suggesting that lower BDNF levels in newborns contributes to the etiology of ASD and indicates new directions for further research. It may also help identifying a long-sought marker for high-ASD risk in, e.g., younger siblings of ASD children.

16.
Mol Psychiatry ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492941

RESUMO

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

17.
Nat Commun ; 10(1): 3927, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.


Assuntos
Cromossomos Humanos Par 2/genética , Citocinas/genética , Feto/metabolismo , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/genética
18.
Soc Psychiatry Psychiatr Epidemiol ; 54(11): 1343-1351, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456027

RESUMO

PURPOSE: Individuals with schizophrenia have been reported to have low employment rates. We examined the associations of schizophrenia with employment, income, and status of cohabitation from a work life course perspective. METHODS: Nationwide cohort study including all individuals (n = 2,390,127) born in Denmark between 1955 and 1991, who were alive at their 25th birthday. Diagnosis of schizophrenia (yes/no) between ages 15 and 25 was used as an exposure. Employment status, annual wage or self-employment earnings, level of education, and cohabitant status from the age of 25-61 (years 1980-2016) were used as outcomes. RESULTS: Schizophrenia diagnosis between ages 15 and 25 (n = 9448) was associated with higher odds of not being employed (at the age of 30: OR 39.4, 95% CI 36.5-42.6), having no secondary or higher education (7.4, 7.0-7.8), and living alone (7.6, 7.2-8.1). These odds ratios were two-to-three times lower and decreasing over time for those individuals who did not receive treatment in a psychiatric inpatient or outpatient clinic for schizophrenia after the age of 25. Between ages 25-61, individuals with schizophrenia have cumulative earning of $224,000, which is 14% of the amount that the individuals who have not been diagnosed with schizophrenia earn. CONCLUSIONS: Individuals with schizophrenia are at high risk of being outside the labour market and living alone throughout their entire life, resulting in an enormous societal loss in earnings. Individuals with less chronic course of schizophrenia had a gradual but substantial improvement throughout their work life.


Assuntos
Escolaridade , Emprego/estatística & dados numéricos , Renda/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Esquizofrenia/epidemiologia , Adolescente , Adulto , Estudos de Coortes , Dinamarca/epidemiologia , Emprego/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Psychoneuroendocrinology ; 108: 150-154, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31284079

RESUMO

Increasing evidence shows that latent infections and inflammation is associated with cognitive and behavioral changes in humans. This case-control study investigates the association between Herpes Simplex Virus Type 1 (HSV-1) infection and C-reactive Protein (CRP) levels, and psychiatric disorders and suicidal behavior. Public health register data from 81,912 participants in the Danish Blood Donor Study, were reviewed to identify individuals registered with an ICD-10 code of any psychiatric diagnosis, or who had attempted or committed suicide. We found 1,504 psychiatric cases and 353 suicidal cases; for all cases, controls were frequency-matched by age and sex, resulting in 5,336 participants. Plasma samples were analyzed for IgG-class antibodies against HSV-1 and CRP. HSV-1 infection was associated with suicidal behavior (odds-ratio, 1.40; 95% confidence interval [CI] 1.11-1.77). Accounting for temporality, HSV-1 infection was associated with having first psychiatric disorder after the date of blood collection (incidence rate ration, 1.44; 95% CI, 1.05-1.95). No association between CRP and psychiatric disorders or suicidal behavior was found. The finding that HSV-1 was associated with suicidal behavior and first psychiatric disorder indicates that infection may play a role in the etiology and pathogenesis of suicidal behavior and development of psychiatric disorders.

20.
Nat Commun ; 10(1): 3043, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292440

RESUMO

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.


Assuntos
Testes Genéticos , Modelos Genéticos , Idade Paterna , Adulto , Fatores Etários , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Criança , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Incidência , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prevalência , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Sequenciamento Completo do Exoma
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