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1.
JAMA Psychiatry ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33439215

RESUMO

Importance: Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk. Objective: To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression. Design, Setting, and Participants: This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs. Exposures: The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses). Main Outcomes and Measures: Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings. Results: Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders. Conclusions and Relevance: This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33453761

RESUMO

BACKGROUND: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. METHODS: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. FINDINGS: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10-8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10-11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10-8). All associated variants in the chromosome 6 locus were replicated (p<8 × 10-3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. INTERPRETATION: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. FUNDING: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

3.
Nat Commun ; 11(1): 6398, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328473

RESUMO

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11-1.25), Pdiscovery = 2.6 × 10-9) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Asma/genética , Epistasia Genética , Fucosiltransferases/genética , Infecções Pneumocócicas/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Streptococcus pneumoniae/patogenicidade
4.
Nat Hum Behav ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168953

RESUMO

Although the genetic influence on voter turnout is substantial (typically 40-50%), the underlying mechanisms remain unclear. Across the social sciences, research suggests that 'resources for politics' (as indexed notably by educational attainment and intelligence test performance) constitute a central cluster of factors that predict electoral participation. Educational attainment and intelligence test performance are heritable. This suggests that the genotypes that enhance these phenotypes could positively predict turnout. To test this, we conduct a genome-wide complex trait analysis of individual-level turnout. We use two samples from the Danish iPSYCH case-cohort study, including a nationally representative sample as well as a sample of individuals who are particularly vulnerable to political alienation due to psychiatric conditions (n = 13,884 and n = 33,062, respectively). Using validated individual-level turnout data from the administrative records at the polling station, genetic correlations and Mendelian randomization, we show that there is a substantial genetic overlap between voter turnout and both educational attainment and intelligence test performance.

5.
BMC Med ; 18(1): 323, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33190641

RESUMO

BACKGROUND: Links between parental socioeconomic position during childhood and subsequent risks of developing mental disorders have rarely been examined across the diagnostic spectrum. We conducted a comprehensive analysis of parental income level, including income mobility, during childhood and risks for developing mental disorders diagnosed in secondary care in young adulthood. METHODS: National cohort study of persons born in Denmark 1980-2000 (N = 1,051,265). Parental income was measured during birth year and at ages 5, 10 and 15. Follow-up began from 15th birthday until mental disorder diagnosis or 31 December 2016, whichever occurred first. Hazard ratios and cumulative incidence were estimated. RESULTS: A quarter (25.2%; 95% CI 24.8-25.6%) of children born in the lowest income quintile families will have a secondary care-diagnosed mental disorder by age 37, versus 13.5% (13.2-13.9%) of those born in the highest income quintile. Longer time spent living in low-income families was associated with higher risks of developing mental disorders. Associations were strongest for substance misuse and personality disorders and weaker for mood disorders and anxiety/somatoform disorders. An exception was eating disorders, with low parental income being associated with attenuated risk. For all diagnostic categories examined except for eating disorders, downward socioeconomic mobility was linked with higher subsequent risk and upward socioeconomic mobility with lower subsequent risk of developing mental disorders. CONCLUSIONS: Except for eating disorders, low parental income during childhood is associated with subsequent increased risk of mental disorders diagnosed in secondary care across the diagnostic spectrum. Early interventions to mitigate the disadvantages linked with low income, and better opportunities for upward socioeconomic mobility could reduce social and mental health inequalities.

6.
Transl Psychiatry ; 10(1): 335, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009369

RESUMO

The objective of the present study was to investigate whether the polygenic liability for attention-deficit/hyperactivity disorder (ADHD) and the psychosocial environment impact the risk of ADHD in interaction or independently of each other. We conducted a register- and biobank-based cohort study of 13,725 individuals with ADHD and 20,147 randomly drawn population-based controls. These 33,872 cohort members were genotyped on the Infinium PsychChip v1.0 array (Illumina). Subsequently, we calculated the polygenic risk score (PRS) for ADHD and extracted register data regarding the following risk factors pertaining to the psychosocial environment for each cohort member at the time of birth: maternal/paternal history of mental disorders, maternal/paternal education, maternal/paternal work status, and maternal/paternal income. We used logistic regression analyses to assess the main effects of the PRS for ADHD and the psychosocial environment on the risk of ADHD. Subsequently, we evaluated whether the effect of the PRS and the psychosocial environment act independently or in interaction upon the risk of ADHD. We found that ADHD was strongly associated with the PRS (odds ratio: 6.03, 95%CI: 4.74-7.70 for highest vs. lowest 2% liability). All risk factors pertaining to the psychosocial environment were associated with an increased risk of ADHD. These associations were only slightly attenuated after mutual adjustments. We found no statistically significant interaction between the polygenic liability and the psychosocial environment upon the risk of ADHD. In conclusion, we found main effects of both polygenic liability and risk factors pertaining to the psychosocial environment on the risk of ADHD-in the expected direction.

7.
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.

8.
Brain Behav Immun ; 89: 433-439, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735934

RESUMO

OBJECTIVE: Major depression and asthma frequently co-occur, suggesting shared genetic vulnerability between these two disorders. We aimed to determine whether a higher genetic liability to major depression was associated with increased childhood asthma risk, and if so, whether such an association differed by sex of the child. METHODS: We conducted a population-based cohort study comprising 16,687 singletons born between 1991 and 2005 in Denmark. We calculated the polygenic risk score (PRS) for major depression as a measure of genetic liability based on the summary statistics from the Major Depressive Disorder Psychiatric Genomics Consortium collaboration. The outcome was incident asthma from age 5 to 15 years, identified from the Danish National Patient Registry and the Danish National Prescription Registry. Stratified Cox regression was used to analyze the data. RESULTS: Greater genetic liability to major depression was associated with an increased asthma risk with a hazard ratio (HR) of 1.06 (95% CI: 1.01-1.10) per standard deviation increase in PRS. Children in the highest major depression PRS quartile had a HR for asthma of 1.20 (95% CI: 1.06-1.36), compared with children in the lowest quartile. However, major depression PRS explained only 0.03% of asthma variance (Pseudo-R2). The HRs of asthma by major depression PRS did not differ between boys and girls. CONCLUSION: Our results suggest a shared genetic contribution to major depression and childhood asthma, and there is no evidence of a sex-specific difference in the association.

9.
Am J Psychiatry ; 177(10): 936-943, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32660297

RESUMO

OBJECTIVE: The authors investigated the associations between polygenic liability and progression to bipolar disorder or psychotic disorders among individuals diagnosed with unipolar depression in early life. METHODS: A cohort comprising 16,949 individuals (69% female, 10-35 years old at the first depression diagnosis) from the iPSYCH Danish case-cohort study (iPSYCH2012) who were diagnosed with depression in Danish psychiatric hospitals from 1994 to 2016 was examined. Polygenic risk scores (PRSs) for major depression, bipolar disorder, and schizophrenia were generated using the most recent results from the Psychiatric Genomics Consortium. Hazard ratios for each disorder-specific PRS were estimated using Cox regressions with adjustment for the other two PRSs. Absolute risk of progression was estimated using the cumulative hazard. RESULTS: Patients were followed for up to 21 years (median=7 years, interquartile range, 5-10 years). The absolute risks of progression to bipolar disorder and psychotic disorders were 7.3% and 13.8%, respectively. After mutual adjustment for the other PRSs, only the PRS for bipolar disorder predicted progression to bipolar disorder (adjusted hazard ratio for a one-standard-deviation increase in PRS=1.11, 95% CI=1.03, 1.21), and only the PRS for schizophrenia predicted progression to psychotic disorders (adjusted hazard ratio=1.10, 95% CI=1.04, 1.16). After adjusting for PRSs, parental history still strongly predicted progression to bipolar disorder (adjusted hazard ratio=5.02, 95% CI=3.53, 7.14) and psychotic disorders (adjusted hazard ratio=1.63, 95% CI=1.30, 2.06). CONCLUSIONS: PRSs for bipolar disorder and schizophrenia are associated with risk for progression to bipolar disorder or psychotic disorders, respectively, among individuals diagnosed with depression; however, the effects are small compared with parental history, particularly for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo/genética , Herança Multifatorial/genética , Transtornos Psicóticos/genética , Adolescente , Adulto , Criança , Dinamarca , Progressão da Doença , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Fatores de Risco , Esquizofrenia/genética , Adulto Jovem
10.
Schizophr Bull ; 46(6): 1629-1637, 2020 Dec 01.
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.

11.
N Engl J Med ; 382(18): 1721-1731, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32348643

RESUMO

BACKGROUND: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions. METHODS: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses. RESULTS: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder. CONCLUSIONS: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).


Assuntos
Doença/etiologia , Transtornos Mentais/complicações , Adulto , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Doenças Urogenitais Femininas/etiologia , Humanos , Masculino , Doenças Urogenitais Masculinas/etiologia , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/etiologia , Neoplasias/etiologia , Risco , Esquizofrenia/complicações , Fatores Sexuais
12.
Neurol Genet ; 6(2): e398, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32211514

RESUMO

Objective: To investigate the genetic contribution to amyotrophic lateral sclerosis (ALS) and the phenotypic and genetic associations between ALS and psychiatric and cardiovascular disorders (CVD) we used the national registry data from Denmark linked to first-degree relatives to estimate heritability and cross-trait parameters. Methods: ALS cases and 100 sex and birth-matched controls per case from the Danish Civil Registration System were linked to their records in the Danish National Patient Registry. Cases and controls were compared for (1) risk of ALS in first-degree relatives, used to estimate heritability, (2) comorbidity with psychiatric disorders and CVD, and (3) risk of psychiatric disorders and CVD in first-degree relatives. Results: 5,808 ALS cases and 580,800 controls were identified. Fifteen percent of cases and controls could be linked to both parents and full siblings, whereas 70% could be linked to children. (1) We estimated the heritability of ALS to be 0.43 (95% CI, 0.34-0.53). (2) We found increased rates of diagnosis of mental disorders (risk ratio = 1.18; 95% CI, 1.09-1.29) and CVD in those later diagnosed with ALS. (3) In first-degree relatives of those with ALS, we found increased rate of schizophrenia (1.17; 95% CI, 0.96-1.42), but no evidence for increased risk CVD. Conclusions: Heritability of ALS is lower than commonly reported. There is likely a genetic relationship between ALS and schizophrenia, and a nongenetic relationship between ALS and CVD.

13.
Lancet Planet Health ; 4(2): e64-e73, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32112749

RESUMO

BACKGROUND: Ambient air pollution affects neurological function, but its association with schizophrenia risk is unclear. We investigated exposure to nitrogen oxides (NOX) as a whole and nitrogen dioxide (NO2) specifically, as well as PM10, and PM2·5, during childhood and subsequent schizophrenia risk. METHODS: People born in Denmark from 1980 to 1984 (N=230 844), who were residing in the country on their tenth birthday, and who had two Danish-born parents were followed-up from their tenth birthday until schizophrenia diagnosis or Dec 31, 2016. Mean daily exposure to each pollutant (NO2, NOX, PM10, and PM2·5) at all of an individual's residential addresses from birth to their tenth birthday was modelled. Incidence rate ratios, cumulative incidence, and population attributable risks were calculated using survival analysis techniques. FINDINGS: We analysed data between Aug 1, 2018, and Nov 15, 2019. Of 230 844 individuals included, 2189 cohort members were diagnosed with schizophrenia during follow-up. Higher concentrations of residential NO2 and NOX exposure during childhood were associated with subsequent elevated schizophrenia risk. People exposed to daily mean concentrations of more than 26·5 µg/m3 NO2 had a 1·62 (95% CI 1·41-1·87) times increased risk compared with people exposed to a mean daily concentration of less than 14·5 µg/m3. The absolute risks of developing schizophrenia by the age of 37 years when exposed to daily mean concentrations of more than 26·5 µg/m3 NO2 between birth and 10 years were 1·45% (95% CI 1·30-1·62%) for men and 1·03% (0·90-1·17) for women, whereas when exposed to a mean daily concentration of less than 14·5 µg/m3, the risk was 0·80% (95% CI 0·69-0·92%) for men and 0·67% (0·57-0·79) for women. Associations between exposure to PM2·5 or PM10 and schizophrenia risk were less consistent. INTERPRETATION: If the association between air pollution and schizophrenia is causal, reducing ambient air pollution including NO2 and NOX could have a potentially considerable effect on lowering schizophrenia incidence at the population level. Further investigations are necessary to establish a causal relationship. FUNDING: Lundbeck Foundation, Stanley Medical Research Institute, European Research Council, NordForsk, Novo Nordisk Foundation, National Health and Medical Research Council, Danish National Research Foundation.

14.
Br J Psychiatry ; 217(1): 390-396, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32024557

RESUMO

BACKGROUND: Residential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear. AIMS: We used a population-based case-cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10-14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder. METHOD: Information on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981-1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses. RESULTS: PRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00-1.16; and odds ratio 1.10, 95% CI 1.04-1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5-11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08-1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92-4.86; three or more moves and bipolar disorder). CONCLUSIONS: Associations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.

15.
JAMA Psychiatry ; 77(1): 17-24, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31642886

RESUMO

Importance: Evidence linking parental socioeconomic position and offspring's schizophrenia risk has been inconsistent, and how risk is associated with parental socioeconomic mobility has not been investigated. Objective: To elucidate the association between parental income level and income mobility during childhood and subsequent schizophrenia risk. Design, Setting, and Participants: National cohort study of all persons born in Denmark from January 1, 1980, to December 31, 2000, who were followed up from their 15th birthday until schizophrenia diagnosis, emigration, death, or December 31, 2016, whichever came first. Data analyses were from March 2018 to June 2019. Exposure: Parental income, measured at birth year and at child ages 5, 10, and 15 years. Main Outcomes and Measures: Hazard ratios (HRs) for schizophrenia were estimated using Cox proportional hazard regression. Cumulative incidence values (absolute risks) were also calculated. Results: The cohort included 1 051 033 participants, of whom 51.3% were male. Of the cohort members, 7544 (4124 [54.7%] male) were diagnosed with schizophrenia during 11.6 million person-years of follow-up. There was an inverse association between parental income level and subsequent schizophrenia risk, with children from lower income families having especially elevated risk. Estimates were attenuated, but risk gradients remained after adjustment for urbanization, parental mental disorders, parental educational levels, and number of changes in child-parent separation status. A dose-response association was observed with increasing amount of time spent in low-income conditions being linked with higher schizophrenia risk. Regardless of parental income level at birth, upward income mobility was associated with lower schizophrenia risk compared with downward mobility. For example, children who were born and remained in the lowest income quintile at age 15 years had a 4.12 (95% CI, 3.71-4.58) elevated risk compared with the reference group, those who were born in and remained in the most affluent quintile, but even a rise from the lowest income quintile at birth to second lowest at age 15 years appeared to lessen the risk elevation (HR, 2.80; 95% CI, 2.46-3.17). On the contrary, for those born in the most affluent quintile, downward income mobility between birth and age 15 years was associated with increased risks of developing schizophrenia. Conclusions and Relevance: This study's findings suggest that parental income level and income mobility during childhood may be linked with schizophrenia risk. Although both causation and selection mechanisms could be involved, enabling upward income mobility could influence schizophrenia incidence at the population level.

16.
Mol Psychiatry ; 25(10): 2410-2421, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-30116032

RESUMO

Family studies have shown an aggregation of suicidal behavior in families. Yet, molecular studies are needed to identify loci accounting for genetic heritability. We conducted a genome-wide association study and estimated single nucleotide polymorphisms (SNP) heritability for a suicide attempt. In a case-cohort study, national data on all individuals born in Denmark after 1981 and diagnosed with severe mental disorders prior to 2013 (n = 57,377) and individuals from the general population (n = 30,000) were obtained. After quality control, the sample consisted of 6024 cases with an incidence of suicide attempt and 44,240 controls with no record of a suicide attempt. Suggestive associations between SNPs, rs6880062 (p-value: 5.4 × 10-8) and rs6880461 (p-value: 9.5 × 10-8), and suicide attempt were identified when adjusting for socio-demographics. Adjusting for mental disorders, three significant associations, all on chromosome 20, were identified: rs4809706 (p-value: 2.8 × 10-8), rs4810824 (p-value: 3.5 × 10-8), and rs6019297 (p-value: 4.7 × 108). Sub-group analysis of cases with affective disorders revealed SNPs associated with suicide attempts when compared to the general population for gene PDE4B. All SNPs explained 4.6% [CI-95: 2.9-6.3%] of the variation in suicide attempt. Controlling for mental disorders reduced the heritability to 1.9% [CI-95: 0.3-3.5%]. Affective and autism spectrum disorders exhibited a SNP heritability of 5.6% [CI-95: 1.9-9.3%] and 9.6% [CI-95: 1.1-18.1%], respectively. Using the largest sample to date, we identified significant SNP associations with suicide attempts and support for a genetic transmission of suicide attempt, which might not solely be explained by mental disorders.

17.
Addiction ; 115(7): 1368-1377, 2020 07.
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.

18.
Lancet Psychiatry ; 6(12): 1031-1038, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31757590

RESUMO

BACKGROUND: Suicidal ideation due to abortion has been used to justify restrictive US abortion policies. Much research examining abortion and mental health has relied on self-report, has had low participation rates, and did not consider confounding factors. In the present study, we used data that do not rely on self-report and are not affected by low participation rates to examine the association between abortion and non-fatal suicide attempts, adjusting for confounding factors. METHODS: In this longitudinal cohort study of Danish population registries, we linked data on a cohort of women born in Denmark between Jan 1, 1980, and Dec 30, 1998, who did not die or emigrate from Denmark before their 18th birthday or before study entry. Follow-up started on the woman's 18th birthday or Jan 1, 2000, whichever came last. Follow-up ended at the date of first suicide attempt, date of emigration from Denmark, date of death, or Dec 31, 2016, whichever came first. Women were between the ages of 18 and 36 years during the study period. We used a survival analysis to examine the risk of first suicide attempts or self-harm associated with a first abortion compared with no abortion, in the complete study cohort. To examine incidence rate ratios (IRRs) associated with abortion, we used Poisson regression with the logarithm of woman-years at risk as an offset. We also examined whether the risk of suicide attempts changed before and after the abortion, adjusting for age, calendar year, socioeconomic status, and history of childbirth, mental health, parental mental health, and physical health. FINDINGS: Data on 523 280 women were included in this study. Of these, 48 990 (9·4%) women had a record of at least one first-trimester abortion, and 10 216 (2·0%) had a suicide attempt during the study period. Among 48 990 women who had an abortion, 1402 (2·9%) had a first suicide attempt after the first abortion. In our fully-adjusted model which adjusted for all covariates, the risk of first-time non-fatal suicide attempts was similar in the year before an abortion (IRR 2·46 [95% CI 2·22-2·72]) and the year after an abortion (IRR 2·54 [2·29-2·81], p=0·509) compared with women who had not had an abortion, and decreased with increasing time since the abortion (1-5 years IRR 1·90 [1·75-2·06]; ≥5 years IRR 1·73 [1·53-1·96]). INTERPRETATION: We found that women who had abortions had a higher risk of non-fatal suicide attempts compared with women who did not have an abortion. However, because the increased risk was the same both the year before and after the abortion, it is not attributable to the abortion. Thus, policies based on the notion that abortion increases women's risk of suicide attempts are misinformed. FUNDING: Society of Family Planning, American Foundation for Suicide Prevention, and The Lundbeck Foundation Initiative for Integrative Psychiatric Research.


Assuntos
Aborto Legal/estatística & dados numéricos , Tentativa de Suicídio/estatística & dados numéricos , Aborto Legal/psicologia , Adolescente , Adulto , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Transtornos Mentais/psicologia , Gravidez , Sistema de Registros , Fatores de Risco , Tentativa de Suicídio/psicologia , Adulto Jovem
19.
JAMA Netw Open ; 2(11): e1914401, 2019 11 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.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental/efeitos adversos , Dióxido de Nitrogênio/toxicidade , Esquizofrenia/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Sistema de Registros , Medição de Risco , Adulto Jovem
20.
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
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