Publications by authors named "Esben Agerbo"

144 Publications

Exposure to ambient air pollution during childhood and subsequent risk of self-harm: A national cohort study.

Prev Med 2021 Nov 16;152(Pt 1):106502. Epub 2021 Sep 16.

Centre for Mental Health and Safety, Division of Psychology and Mental Health, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK; NIHR Greater Manchester Patient Safety Translational Research Centre, Manchester, UK.

A growing body of evidence indicates that exposure to air pollution not only impacts on physical health but is also linked with a deterioration in mental health. We conducted the first study to investigate exposure to ambient particulate matter with an aerodynamic diameter of less than 2.5 μm (PM) and nitrogen dioxide (NO) during childhood and subsequent self-harm risk. The study cohort included persons born in Denmark between January 1, 1979 and December 31, 2006 (N = 1,424,670), with information on daily exposures to PM and NO at residence from birth to 10th birthday. Follow-up began from 10th birthday until first hospital-presenting self-harm episode, death, or December 31, 2016, whichever came first. Incidence rate ratios estimated by Poisson regression models revealed a dose relationship between increasing PM exposure and rising self-harm risk. Exposure to 17-19 μg/m of PM on average per day from birth to 10th birthday was associated with a 1.45 fold (95% CI 1.37-1.53) subsequently elevated self-harm risk compared with a mean daily exposure of <13 μg/m, whilst those exposed to 19 μg/m or above on average per day had a 1.59 times (1.45-1.75) elevated risk. Higher mean daily exposure to NO during childhood was also linked with increased self-harm risk, but the dose-response relationship observed was less evident than for PM. Covariate adjustment attenuated the associations, but risk remained independently elevated. Although causality cannot be assumed, these novel findings indicate a potential etiological involvement of ambient air pollution in the development of mental ill health.
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http://dx.doi.org/10.1016/j.ypmed.2021.106502DOI Listing
November 2021

School performance of children whose parents suffered torture and war-a register-based study in Denmark.

Eur J Public Health 2021 Oct;31(4):749-755

Department of Economics and Business Economics, NCRR, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.

Background: Young refugees and descendants of refugees have different preconditions for learning than their peers without refugee background. Children growing up in families where parents have suffered torture and war trauma may represent a particularly vulnerable group. This study investigates whether children of torture survivors living in Denmark achieved different test scores throughout primary and secondary school compared to children of non-traumatized parents.

Methods: Using data from a national school test programme, tests from Grades 2-8 were compared for children whose parents had been treated for torture and war trauma as to their peers. Referral to specialized rehabilitation clinics was used to identify the traumatized parent group. The mean score difference was estimated using multilevel linear regression, and outcomes were measured within groups of parental region of origin to allow for region-specific effects. The odds of missing a test were also estimated with multilevel logistic regression.

Results: The study included 854 467 children [median age (interquartile range) =12 (3.3)] of which 7809 were children of the trauma-exposed parents. The analysis revealed that children of torture survivors achieved test scores between -6% (95% CI: -0.13, 0.00) and -38% (95% CI: -0.44, -0.32) of a standard deviation compared to children of non-traumatized parents, adjusted for the main effect of region of origin. They were also more likely to miss a test [OR=4.95 (95% CI: 4.30, 5.71)].

Conclusions: The findings indicate that risk factors for poorer school performance cluster in children of traumatized refugee parents, and reveal the possible adverse educational effects of trauma across generations.
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http://dx.doi.org/10.1093/eurpub/ckab108DOI Listing
October 2021

Genetic, Clinical, and Sociodemographic Factors Associated With Stimulant Treatment Outcomes in ADHD.

Am J Psychiatry 2021 09 22;178(9):854-864. Epub 2021 Jun 22.

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen and Aarhus, Denmark (Brikell, Wimberley, Albiñana, Pedersen, Vilhjálmsson, Agerbo, Demontis, Børglum, Schork, LaBianca, Werge, Mors, Hougaard, Mortensen, Dalsgaard); National Center for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark (Brikell, Wimberley, Albiñana, Pedersen, Vilhjálmsson, Agerbo, Mortensen, Dalsgaard); Center for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark (Wimberley, Agerbo, Mortensen, Dalsgaard); Department of Biomedicine and Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Børglum); Center for Genomics and Personalized Medicine, Central Region Denmark and Aarhus University, Aarhus, Denmark (Demontis, Børglum); Neurogenomics Division, Translational Genomics Research Institute, Phoenix (Schork); Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen (Schork, LaBianca, Werge); Department of Clinical Medicine and Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen (Werge); Psychosis Research Unit, Aarhus University Hospital, Psychiatry, Aarhus, Denmark (Mors); Department for Congenital Disorders, Statens Serum Institut, Copenhagen (Hougaard); Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Child and Adolescent Psychiatry, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, U.K. (Thapar).

Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.

Methods: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h).

Results: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05-1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27-2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84-0.88) and increased rates of discontinuation (hazard ratio range, 1.19-1.45) and switch (hazard ratio range, 1.40-2.08). h estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.

Conclusions: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study's limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.
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http://dx.doi.org/10.1176/appi.ajp.2020.20121686DOI Listing
September 2021

Lack of fit with the neighbourhood social environment as a risk factor for psychosis - a national cohort study.

Psychol Med 2021 Jun 18:1-9. Epub 2021 Jun 18.

National Centre for Register-Based Research (NCCR), Aarhus University, Aarhus, Denmark.

Background: Many studies report an ethnic density effect whereby psychosis incidence among ethnic minority groups is higher in low co-ethnic density areas. It is unclear whether an equivalent density effect applies with other types of socioeconomic disadvantages.

Methods: We followed a population cohort of 2 million native Danes comprising all those born on 1st January 1965, or later, living in Denmark on their 15th birthday. Socioeconomic disadvantage, based on parents' circumstances at age 15 (low income, manual occupation, single parent and unemployed), was measured alongside neighbourhood prevalence of these indices.

Results: Each indicator was associated with a higher incidence of non-affective psychosis which remained the same, or was slightly reduced, if neighbourhood levels of disadvantage were lower. For example, for individuals from a low-income background there was no difference in incidence for those living in areas where a low-income was least common [incidence rate ratio (IRR) 1.01; 95% confidence interval (CI) 0.93-1.10 v. those in the quintile where a low income was most common. Typically, differences associated with area-level disadvantage were the same whether or not cohort members had a disadvantaged background; for instance, for those from a manual occupation background, incidence was lower in the quintile where this was least v. most common (IRR 0.83; 95% CI 0.71-0.97), as it was for those from a non-manual background (IRR 0.77; 95% CI 0.67-0.87).

Conclusion: We found little evidence for group density effects in contrast to previous ethnic density studies. Further research is needed with equivalent investigations in other countries to see if similar patterns are observed.
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http://dx.doi.org/10.1017/S0033291721002233DOI Listing
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Leveraging both individual-level genetic data and GWAS summary statistics increases polygenic prediction.

Am J Hum Genet 2021 06 7;108(6):1001-1011. Epub 2021 May 7.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus V, Denmark; National Centre for Register-Based Research, Aarhus University, 8210 Aarhus V, Denmark; Bioinformatics Research Centre, Aarhus University, 8000 Aarhus C, Denmark. Electronic address:

The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such as the UK Biobank data. To the best of our knowledge, it has not yet been explored how best to combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. The most widely used approach to combine data is the meta-analysis of GWAS summary statistics (meta-GWAS), but we show that it does not always provide the most accurate PRS. Through simulations and using 12 real case-control and quantitative traits from both iPSYCH and UK Biobank along with external GWAS summary statistics, we compare meta-GWAS with two alternative data-combining approaches, stacked clumping and thresholding (SCT) and meta-PRS. We find that, when large individual-level data are available, the linear combination of PRSs (meta-PRS) is both a simple alternative to meta-GWAS and often more accurate.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206385PMC
June 2021

Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

Psychol Med 2021 May 5:1-10. Epub 2021 May 5.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

Background: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark.

Methods: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions.

Results: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (β = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15.

Conclusions: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.
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http://dx.doi.org/10.1017/S0033291721001410DOI Listing
May 2021

Register-based metrics of years lived with disability associated with mental and substance use disorders: a register-based cohort study in Denmark.

Lancet Psychiatry 2021 04;8(4):310-319

National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.

Background: Mental disorders account for a substantial proportion of the years lived with disability (YLDs) globally. These estimates have generally been calculated top down based on summary statistics. The aim for this study was to calculate YLDs and a novel related measure, Health Loss Proportion (HeLP), for 18 mental and substance use disorders, based on person-level register data (bottom up).

Methods: A cohort of 6 989 627 Danish residents (5·9% had a diagnosis of a mental or substance use disorder registered in the Danish Psychiatric Central Research Register) was investigated. YLDs (the duration of disease multiplied by a disability weight) were calculated for the disorder of interest and for comorbid mental and substance use disorders. HeLPs were estimated as YLDs associated with an index disorder and comorbid mental and substance use disorders divided by person-years at risk in persons with the index disorder. All analyses were adjusted for mental and substance use comorbidity using a multiplicative model of disability weights.

Findings: Major depressive disorder was the most prevalent disorder, although schizophrenia was the leading cause of YLDs in both sexes combined (YLDs 273·3 [95 % CI 232·3-313·6] per 100 000 person-years). People diagnosed with schizophrenia lost the equivalent of 73% (63-83%) of healthy life per year due to mental and substance use disorders, the largest HeLP of all mental and substance use disorders. Comorbidity of mental and substance use disorders accounted for 69-83% of HeLPs in people with either cannabis use disorders, other drug use disorder and ADHD. By contrast, comorbidity explained 11-23% of the HeLPs in people with autism spectrum disorders, conduct disorder, and schizophrenia.

Interpretation: Substantial variation in disability was observed across age, sex, and disorders. The new HeLP metric provides novel details of the contribution of comorbidity to the disability associated with mental and substance use disorders.

Funding: The Danish National Research Foundation, Queensland Government Department of Health, European Union's Horizon 2020, Lundbeck Foundation, Stanley Medical Research Institute.

Translation: For the Danish translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2215-0366(21)00029-8DOI Listing
April 2021

Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study.

Lancet Child Adolesc Health 2021 03 15;5(3):201-209. Epub 2021 Jan 15.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; Centre for Genomics and Personalized Medicine (CGPM), Aarhus University, Aarhus, Denmark. Electronic address:

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). 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), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10). All associated variants in the chromosome 6 locus were replicated (p<8 × 10) 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.
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http://dx.doi.org/10.1016/S2352-4642(20)30350-3DOI Listing
March 2021

Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status.

JAMA Psychiatry 2021 Apr;78(4):387-397

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

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.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.4172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807393PMC
April 2021

FUT2-ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses.

Nat Commun 2020 12 16;11(1):6398. Epub 2020 Dec 16.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

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), P = 2.6 × 10) 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.
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http://dx.doi.org/10.1038/s41467-020-19814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744576PMC
December 2020

Parental income as a marker for socioeconomic position during childhood and later risk of developing a secondary care-diagnosed mental disorder examined across the full diagnostic spectrum: a national cohort study.

BMC Med 2020 11 16;18(1):323. Epub 2020 Nov 16.

Centre for Mental Health and Safety, Division of Psychology and Mental Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1186/s12916-020-01794-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667856PMC
November 2020

Genetic predictors of educational attainment and intelligence test performance predict voter turnout.

Nat Hum Behav 2021 02 9;5(2):281-291. Epub 2020 Nov 9.

Department of Political Science, Aarhus University, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1038/s41562-020-00952-2DOI Listing
February 2021

Polygenic risk score, psychosocial environment and the risk of attention-deficit/hyperactivity disorder.

Transl Psychiatry 2020 10 2;10(1):335. Epub 2020 Oct 2.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

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.
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http://dx.doi.org/10.1038/s41398-020-01019-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532146PMC
October 2020

Nature and prevalence of combinations of mental disorders and their association with excess mortality in a population-based cohort study.

World Psychiatry 2020 Oct;19(3):339-349

National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1002/wps.20802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491620PMC
October 2020

Genetic liability to major depression and risk of childhood asthma.

Brain Behav Immun 2020 10 28;89:433-439. Epub 2020 Jul 28.

NCRR-The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; iPSYCH-Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; CIRRAU-Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.

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-R). 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.
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http://dx.doi.org/10.1016/j.bbi.2020.07.030DOI Listing
October 2020

Polygenic Risk and Progression to Bipolar or Psychotic Disorders Among Individuals Diagnosed With Unipolar Depression in Early Life.

Am J Psychiatry 2020 10 14;177(10):936-943. Epub 2020 Jul 14.

Department of Economics and Business Economics, National Center for Register-Based Research, Aarhus University, Aarhus, Denmark (Musliner, Albiñana, Vilhjalmsson, Agerbo, Mortensen); Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark (Musliner, Krebs, Albiñana, Hougaard, Vilhjalmsson, Agerbo, Nordentoft, Børglum, Werge, Mortensen, Østergaard); Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services, Roskilde, Denmark (Krebs, Werge); Center for Integrated Register-Based Research, Aarhus University, Aarhus (Agerbo, Mortensen); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Zandi); Department for Congenital Disorders, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen (Hougaard); Department of Clinical Medicine, Copenhagen Research Center for Mental Health, Copenhagen University Hospital, Copenhagen (Nordentoft); Center for Genomics and Personalized Medicine, Aarhus (Børglum); Department of Biomedicine and the Center for Integrative Sequencing (Børglum), and Department of Clinical Medicine (Østergaard), Aarhus University, Aarhus; and Department of Affective Disorders, Aarhus University Hospital-Psychiatry, Aarhus (Østergaard).

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.
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http://dx.doi.org/10.1176/appi.ajp.2020.19111195DOI Listing
October 2020

Association Between Childhood Green Space, Genetic Liability, and the Incidence of Schizophrenia.

Schizophr Bull 2020 12;46(6):1629-1637

Big Data Centre for Environment and Health, Aarhus University, 8210 Aarhus V, Denmark.

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.
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http://dx.doi.org/10.1093/schbul/sbaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496913PMC
December 2020

Association between Mental Disorders and Subsequent Medical Conditions.

N Engl J Med 2020 04;382(18):1721-1731

From the National Center for Register-based Research (N.C.M., O.P.-R., E.A., M.K.C., S.D., J.-C.P.G.D., T.M.L., P.B.M., K.L.M., C.B.P., L.V.P., B.V., N.W., J.J.M.), Center for Integrated Register-based Research (E.A., P.B.M., C.B.P.), the Departments of Biomedicine-Human Genetics (A.D.B.) and Public Health (M.K.C., M.F.-G., K.M.I., M.V., A.P.), the Center for Integrative Sequencing (A.D.B.), and the Big Data Center for Environment and Health (C.B.P.), Aarhus University, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (E.A., A.D.B., S.D., O.M., P.B.M., K.L.M., M.N., C.B.P., L.V.P., A.J.S., B.V., T.W.), the Center for Genomics and Personalized Medicine (A.D.B.), the Department of Neurology (J.-C.P.G.D.), and the Research Unit, Department of Psychosis (O.M.), Aarhus University Hospital, and the Research Unit for General Practice (M.F.-G., A.R.R., M.V., A.P.), Aarhus, the Copenhagen Research Center for Mental Health, Mental Health Center Copenhagen, Copenhagen University Hospital (M.E.B., M.N., H.J.S.), Psychiatric Center Copenhagen (L.V.K.), Faculty of Health and Medical Sciences (L.V.K.), the Department of Clinical Medicine (T.W.), and the Lundbeck Foundation GeoGenetics Center, GLOBE Institute (T.W.), University of Copenhagen, Copenhagen, and the Institute of Biological Psychiatry, Mental Health Center Sankt Hans, Mental Health Services Capital Region, Roskilde (A.J.S., T.W.) - all in Denmark; the National Drug and Alcohol Research Centre, University of New South Wales, Sydney (L.D.), the Department of General Practice, Melbourne Medical School, University of Melbourne, Melbourne, VIC (J.M.G.), and the Queensland Brain Institute (C.C.W.L., S.S., J.J.M.), Queensland Centre for Mental Health Research, the Park Centre for Mental Health (C.C.W.L., S.S., T.J.S., H.A.W., J.J.M.), and the School of Public Health, Faculty of Medicine (H.A.W.), University of Queensland, Brisbane - all in Australia; the Departments of Psychology (P.J.) and Developmental Psychology (A.M.R.), Heymans Institute, and the Interdisciplinary Center, Psychopathology and Emotion Regulation (P.J., A.M.R.), University of Groningen, Groningen, the Netherlands; the Department of Health Care Policy, Harvard Medical School, Boston (R.C.K.); the Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ (A.J.S.); the Department of Psychological Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand (K.M.S.); Sievert Consulting, Minneapolis (C.S.); and the Institute for Health Metrics and Evaluation, University of Washington, Seattle (H.A.W.).

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.).
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http://dx.doi.org/10.1056/NEJMoa1915784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261506PMC
April 2020

ALS in Danish Registries: Heritability and links to psychiatric and cardiovascular disorders.

Neurol Genet 2020 Apr 20;6(2):e398. Epub 2020 Feb 20.

National Centre for Register-Based Research NCRR (B.B.T., P.B.M., E.A.), Aarhus University; Centre for Integrated Register-Based Research CIRRAU (B.B.T., P.B.M., E.A.), Aarhus University; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (B.B.T., P.B.M., E.A.), iPSYCH, Denmark; Institute for Molecular Bioscience (F.C.G., N.R.W.), University of Queensland, Brisbane, Australia; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; Department of Medical Epidemiology and Biostatistics (F.F.), Karolinska Institutet, Stockholm, Sweden; Centre for Clinical Research (R.D.H.), The University of Queensland, Brisbane; Queensland Brain Institute (R.D.H., N.R.W.), University of Queensland, Brisbane; Department of Neurology (R.D.H.), Royal Brisbane and Women's Hospital, Australia.

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.
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http://dx.doi.org/10.1212/NXG.0000000000000398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073454PMC
April 2020

Exposure to air pollution during childhood and risk of developing schizophrenia: a national cohort study.

Lancet Planet Health 2020 02 26;4(2):e64-e73. Epub 2020 Feb 26.

National Centre for Register-Based Research, Aarhus Business and Social Sciences, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark; Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.

Background: Ambient air pollution affects neurological function, but its association with schizophrenia risk is unclear. We investigated exposure to nitrogen oxides (NO) as a whole and nitrogen dioxide (NO) specifically, as well as PM, and PM, 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 (NO, NO, PM, and PM) 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 NO and NO exposure during childhood were associated with subsequent elevated schizophrenia risk. People exposed to daily mean concentrations of more than 26·5 μg/m NO 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/m. The absolute risks of developing schizophrenia by the age of 37 years when exposed to daily mean concentrations of more than 26·5 μg/m NO 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/m, 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 PM or PM and schizophrenia risk were less consistent.

Interpretation: If the association between air pollution and schizophrenia is causal, reducing ambient air pollution including NO and NO 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.
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http://dx.doi.org/10.1016/S2542-5196(20)30004-8DOI Listing
February 2020

Adolescent residential mobility, genetic liability and risk of schizophrenia, bipolar disorder and major depression.

Br J Psychiatry 2020 07;217(1):390-396

National Center for Register-Based Research, Business and Social Sciences, Aarhus University; and The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark.

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.
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http://dx.doi.org/10.1192/bjp.2020.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130005PMC
July 2020

Genetic liability to ADHD and substance use disorders in individuals with ADHD.

Addiction 2020 07 8;115(7):1368-1377. Epub 2020 Jan 8.

iPSYCH - The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen and Aarhus, Denmark.

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 (OR  = 1.59, 95% CI: 1.19-2.12, OR  = 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.
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http://dx.doi.org/10.1111/add.14910DOI Listing
July 2020

Genetic liability to ADHD and substance use disorders in individuals with ADHD.

Addiction 2020 07 8;115(7):1368-1377. Epub 2020 Jan 8.

iPSYCH - The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen and Aarhus, Denmark.

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 (OR  = 1.59, 95% CI: 1.19-2.12, OR  = 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.
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http://dx.doi.org/10.1111/add.14910DOI Listing
July 2020

Genetic risk scores for major psychiatric disorders and the risk of postpartum psychiatric disorders.

Transl Psychiatry 2019 11 11;9(1):288. Epub 2019 Nov 11.

Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

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.
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http://dx.doi.org/10.1038/s41398-019-0629-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848186PMC
November 2019

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population.

Transl Psychiatry 2019 11 11;9(1):283. Epub 2019 Nov 11.

iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus V, Denmark.

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10, OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.
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http://dx.doi.org/10.1038/s41398-019-0622-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848113PMC
November 2019

Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia.

JAMA Netw Open 2019 11 1;2(11):e1914401. Epub 2019 Nov 1.

Department of Economics and Business Economics, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.14401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827271PMC
November 2019

A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study.

Lancet 2019 11 24;394(10211):1827-1835. Epub 2019 Oct 24.

National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

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.
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http://dx.doi.org/10.1016/S0140-6736(19)32316-5DOI Listing
November 2019

Association Between Parental Income During Childhood and Risk of Schizophrenia Later in Life.

JAMA Psychiatry 2020 01;77(1):17-24

Centre for Mental Health and Safety, Division of Psychology and Mental Health, University of Manchester, Manchester, United Kingdom.

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.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.2299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813592PMC
January 2020
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