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Background: A family history of specific disorders (e.g., autism, depression, epilepsy) has been linked to risk for autism spectrum disorder (ASD). This study examines whether family history data could be used for ASD risk prediction., Methods: We followed all Danish live births, from 1980 to 2012, of Denmark-born parents for an ASD diagnosis through April 10, 2017 ( N  = 1,697,231 births; 26,840 ASD cases). Linking each birth to three-generation family members, we identified 438 morbidity indicators, comprising 73 disorders reported prospectively for each family member. We tested various models using a machine learning approach. From the best-performing model, we calculated a family history risk score and estimated odds ratios and 95% confidence intervals for the risk of ASD., Results: The best-performing model comprised 41 indicators: eight mental conditions (e.g., ASD, attention-deficit/hyperactivity disorder, neurotic/stress disorders) and nine nonmental conditions (e.g., obesity, hypertension, asthma) across six family member types; model performance was similar in training and test subsamples. The highest risk score group had 17.0% ASD prevalence and a 15.3-fold (95% confidence interval, 14.0-17.1) increased ASD risk compared with the lowest score group, which had 0.6% ASD prevalence. In contrast, individuals with a full sibling with ASD had 9.5% ASD prevalence and a 6.1-fold (95% confidence interval, 5.9-6.4) higher risk than individuals without an affected sibling., Conclusions: Family history of multiple mental and nonmental conditions can identify more individuals at highest risk for ASD than only considering the immediate family history of ASD. A comprehensive family history may be critical for a clinically relevant ASD risk prediction framework in the future., (© 2021 The Authors.)

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., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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.

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

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 discovery  = 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.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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.

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.

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 × 10 8 ). 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.

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., (© 2020 World Psychiatric Association.)

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 2 ). 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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 females  = 1.59, 95% CI: 1.19-2.12, OR males  = 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., (© 2019 Society for the Study of Addiction.)

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., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Ambient air pollution affects neurological function, but its association with schizophrenia risk is unclear. We investigated exposure to nitrogen oxides (NO X ) as a whole and nitrogen dioxide (NO 2 ) specifically, as well as PM 10 , and PM 2·5 , 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 (NO 2 , NO X , PM 10 , and PM 2·5 ) 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 NO 2 and NO X exposure during childhood were associated with subsequent elevated schizophrenia risk. People exposed to daily mean concentrations of more than 26·5 μg/m 3 NO 2 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 3 . 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 3 NO 2 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 3 , 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 2·5 or PM 10 and schizophrenia risk were less consistent., Interpretation: If the association between air pollution and schizophrenia is causal, reducing ambient air pollution including NO 2 and NO X 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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

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 -208 , 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 -17 ) 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 -5 ) 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.

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.

Background: Mood disorders are known to be associated with poor socioeconomic outcomes, but no study has examined these associations across the entire worklife course. Our goal was to estimate the associations between bipolar disorder and depression in early adulthood and subsequent employment, income, and educational attainment., Methods: We conducted a nationwide prospective cohort study including all individuals (n = 2,390,127; 49% female) born in Denmark between 1955 and 1990. Hospital-based diagnoses of depression and bipolar disorder before age 25 were obtained from the Danish psychiatric register. Yearly employment, earnings, and education status from ages 25 to 61 were obtained from the Danish labor market and education registers. We estimated both absolute and relative proportions., Results: Population rates of hospital-diagnosed depression and bipolar between ages 15-25 were 1% and 0.12%, respectively. Compared to individuals without mood disorders, those with depression and particularly bipolar disorder had consistently poor socioeconomic outcomes across the entire work-life span. For example, at age 30, 62% of bipolar and 53% of depression cases were outside the workforce compared to 19% of the general population, and 52% of bipolar and 42% of depression cases had no higher education compared to 27% of the general population. Overall, individuals with bipolar disorder or depression earned around 36% and 51%, respectively, of the income earned by individuals without mood disorders. All associations were smaller for individuals not rehospitalized after age 25., Conclusions: Severe mood disorders with onset before age 25, particularly bipolar disorder, are associated with persistent poor socioeconomic outcomes across the entire work-life course., (© 2019 Wiley Periodicals, Inc.)

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

Childhood infection has been proposed as an important etiologic factor for schizophrenia. However, it is unclear to what extent the association between childhood infection and schizophrenia is confounded by parental socioeconomic status and mental illness, and childhood adversity, and whether the association is explained by familial liability for infections. We used a historical, population-based cohort design, selecting all singletons born in Denmark between 1981 and 1998 (n = 882,813). We identified exposure to infection as having been hospitalized with an infection in the Danish national registers. Data from a range of population-based registers were used to construct a childhood adversity index. The index included the following adversities: family disruption, parental incarceration, parental chronic somatic disease, death of a parent, parent permanently outside of workforce, childhood abuse and placement in out-of-home care. We also assessed parental socioeconomic status and mental illness. Multiple admissions with infections during childhood increased the risk of schizophrenia with an Incidence Rate Ratio (IRR) of 1.28 (95% CI: 1.19-1.38) for 1 infection to an IRR of 1.43 (95% CI: 1.30-1.58) for 2-3 infections and an IRR of 1.95 (95% CI: 1.66-2.29) for ≥4 infections. Parental socioeconomic status and mental illness, and childhood adversities increased the odds of acquiring childhood infections and was associated with schizophrenia, but did not explain the results. Similarly did familial liability for infection increase the risk of schizophrenia, but did not explain the association between infection and schizophrenia. Parental mental health modified the association between childhood infection and schizophrenia (p-value 0.02), and we found no significant effect of childhood infection in those with propensity for psychotic disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10 -12 ) that replicates in an independent population (P replication  = 3.27 × 10 -3 , P meta-analysis  = 9.09 × 10 -12 ). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.

We sought to investigate the risk of incident major depressive disorder (MDD) attributable to a range of sleep disorders in the Danish population. Data were obtained by linking longitudinal Danish population-based registers. A total of 65,739 individuals who had first onset of depression between 1995 and 2013 were selected as cases. For each case, a set of 20 controls of the same sex, birth month and year and who had not had depression by the date that the case was diagnosed were selected at random form the population (N = 1,307,580 in total). We examined whether there was an increased rate of prior sleep disorders in MDD cases compared to controls using conditional logistic regression. An increased risk of incident depression in cases was found for all sleep disorders analyzed. Highest incidence rate ratios (IRRs) were found for circadian rhythm disorders (IRR = 7.06 [2.78-17.91]) and insomnia of inorganic origin (IRR = 6.76 [4.37-10.46]). The lowest estimated IRR was for narcolepsy (IRR = 2.00 [1.26-3.17]). Those diagnosed with a sleep disorder in the last 6 months were at highest risk of developing depression compared to those with at least 1 year since diagnosis (3.10 vs. 2.36). Our results suggest that having any sleep disorder is a risk factor for incident depression. Depression screening should be considered for patients with sleep disorders, and where possible, long-term follow-up for mental health problems is advisable.

Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored., Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis., Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018., Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium., Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency)., Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002)., Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 -4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 -8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Background: Childhood and adolescent mortality accounts for a substantial proportion of years lost prematurely. Reducing childhood and adolescent mortality relies on knowing characteristics of those at elevated risk of dying young. We therefore aimed to identify such characteristics; our main hypothesis is that psychosocial adversity in infancy is linked to increased mortality rates in childhood and adolescence., Methods: We conducted a register-based cohort study involving all 1,549,581 children born to Danish-born parents in Denmark between 1 January 1981 and 31 December 2010. For each infant, we extracted data relevant to Rutter's indicators of adversity (low social class, parents not cohabiting, large family size, paternal criminality, maternal mental disorder, and placement in out-of-home care). Follow-up began on the cohort member's first birthday. We estimated the association between adversity score (the number of Rutter's indicators of adversity present in infancy) and death via. Cox regression., Results: During follow-up (18,874,589 person-years), 2,081 boys and 1,420 girls died before or on their 18th birthday. The hazard ratios for death were 2.3 (95% CI = 1.9, 2.9) and 2.1 (95% CI = 1.6, 2.7) for boys and girls with adversity scores of 3-6 compared with those with a score of 0. These associations were driven by causes of death with known links to psychosocial adversity., Conclusion: While absolute mortality rates were low, infants with adversity scores of 3-6 were approximately twice as likely to die prematurely compared with infants with adversity scores of 0. Whether these associations generalize to other countries should be subjected to further study.

Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity., Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice., Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018., Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated., Results: A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years)., Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12-1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.

Background: Studies have suggested that poor school achievement is associated with increased risk of schizophrenia; however, the possible genetic contribution to this association is unknown. We investigated the possible effect of the polygenic risk score (PRS) for schizophrenia (PRS SCZ ) and for educational attainment (PRS EDU ) on the association between school performance and later schizophrenia., Methods: We conducted a case-cohort study on a Danish population-based sample born from 1987 to 1995 comprising 1470 individuals with schizophrenia and 7318 subcohort noncases. Genome-wide data, school performance, and family psychiatric and socioeconomic background information were obtained from national registers and neonatal biobanks. PRS SCZ and PRS EDU were calculated using discovery effect size estimates from a meta-analysis of 34,600 cases and 45,968 controls and 293,723 individuals., Results: Higher PRS SCZ increased the risk (incidence rate ratio [IRR]: 1.28; 95% confidence interval [CI], 1.19-1.36), whereas higher PRS EDU decreased the risk of schizophrenia (IRR, 0.87; 95% CI, 0.82-0.92) per standard deviation. Not completing primary school and receiving low school marks were associated with increased risk of schizophrenia (IRR, 2.92; 95% CI, 2.37-3.60; and IRR, 1.58; 95% CI, 1.27-1.97, respectively), which was not confounded by PRS SCZ or PRS EDU . Adjusting for social factors and parental psychiatric history, effects of not completing primary school and receiving low school marks were attenuated by up to 25% (IRR, 2.19; 95% CI, 1.75-2.73; and IRR, 1.39; 95% CI, 1.11-1.75, respectively). Increasing PRS EDU correlated with better school performance (p < .01; R 2  = 7.6%). PRS SCZ and PRS EDU was significantly negatively correlated (r = -.31, p < .01)., Conclusions: The current PRS did not account for the observed association between primary school performance and risk of schizophrenia., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Otitis media infections and antibiotic treatment have been linked to the risk of developing autism spectrum disorder. Broad-spectrum antibiotics may alter the composition of the gut flora microbiota, which is hypothesized to be involved in the regulation of the immune system. This study examines the interplay among otitis media, antibiotics, and the subsequent risk of developing autism. Based on the entire Danish population, 780,547 children were followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012. We calculated adjusted hazard ratios and absolute risks of autism with 95% confidence intervals (CIs) related to previous otitis media diagnoses and antibiotic prescriptions redeemed at Danish pharmacies. The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males). Similarly, we found an increased hazard ratio of autism associated with otitis media (1.83 95% CI 1.71-1.95) and antibiotics usage (1.29 95% CI 1.17-1.43). A history of both otitis media and antibiotic treatment did not further increase the risk of autism. Although the risk of autism was associated with otitis media and treatment with antibiotics, we found little evidence of a synergistic effect between otitis media infections and treatment with antibiotics. Autism Res 2018, 11: 1432-1440. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We investigated whether otitis media ear infections and antibiotic treatment were associated with autism spectrum disorder. Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics. Given the observational nature of our data, our study cannot be used to conclude that otitis media or use of antibiotics cause autism, as our findings may be subject to unobserved confounding., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Background: Schizophrenia (SZ) and bipolar disorder (BP) are causes of severe disability worldwide and parents' severe mental illness (SMI) is associated with childhood adversity, and socio-emotional and cognitive problems in children. Yet, how parental BP and SZ affect educational attainment in offspring is still unclear., Method: We included all children (N = 684.248) born and living in Denmark between 1986 and 1996 and their parents. Our follow-up lasted from 1986 until children's graduation in 2014. The main outcome variable was their school grades following their primary education. School outcomes were divided into four categories: not graduated, low-grade point average (GPA), medium GPA and high GPA. We then performed a multiple logistic regression with medium GPA as the reference category, with the children of parents without SZ or BP as the reference group., Results: Children of parents with SZ faced higher odds than their peers of not graduating primary education (OR 2.6), along with low GPA (odds ratios (OR) 1.6) and lower odds for a high GPA (OR 0.7). Moreover, it was the children of mothers rather than fathers with BP who had higher odds of not graduating primary education (OR 1.6). Lastly, child placement was associated with lower grades and lower graduation rates, and outcomes for children of parents with SMI were favorable compared with other children placed in care., Conclusion: For children, parental SZ is associated with lower grades and lower chances for graduating primary education. In contrast, the children of parents with BP were indistinguishable from the reference group regarding school grades. This signifies that specificity of parental severe mental illness is important in relation to educational achievement of children.

Importance: The repercussions of abortion for mental health have been used to justify state policies that limit access to abortion in the United States. Much earlier research has relied on self-report of abortion or mental health conditions or on convenience samples. This study uses data that rely on neither., Objective: To examine whether first-trimester first abortion or first childbirth is associated with an increase in women's initiation of a first-time prescription for an antidepressant., Design, Setting, and Participants: This study linked data and identified a cohort of women from Danish population registries who were born in Denmark between January 1, 1980, and December 30, 1994. Overall, 396 397 women were included in this study; of these women, 30 834 had a first-trimester first abortion and 85 592 had a first childbirth., Main Outcomes and Measure: First-time antidepressant prescription redemptions were determined and used as indication of an episode of depression or anxiety, and incident rate ratios (IRRs) were calculated comparing women who had an abortion vs women who did not have an abortion and women who had a childbirth vs women who did not have a childbirth., Results: Of 396 397 women whose data were analyzed, 17 294 (4.4%) had a record of at least 1 first-trimester abortion and no children, 72 052 (18.2%) had at least 1 childbirth and no abortions, 13 540 (3.4%) had at least 1 abortion and 1 childbirth, and 293 511 (74.1%) had neither an abortion nor a childbirth. A total of 59 465 (15.0%) had a record of first antidepressant use. In the basic and fully adjusted models, relative to women who had not had an abortion, women who had a first abortion had a higher risk of first-time antidepressant use. However, the fully adjusted IRRs that compared women who had an abortion with women who did not have an abortion were not statistically different in the year before the abortion (IRR, 1.46; 95% CI, 1.38-1.54) and the year after the abortion (IRR, 1.54; 95% CI, 1.45-1.62) (P = .10) and decreased as time from the abortion increased (1-5 years: IRR, 1.24; 95% CI, 1.19-1.29; >5 years: IRR, 1.12; 95% CI, 1.05-1.18). The fully adjusted IRRs that compared women who gave birth with women who did not give birth were lower in the year before childbirth (IRR, 0.47; 95% CI, 0.43-0.50) compared with the year after childbirth (IRR, 0.93; 95% CI, 0.88-0.98) (P < .001) and increased as time from the childbirth increased (1-5 years: IRR, 1.52; 95% CI, 1.47-1.56; >5 years: IRR, 1.99; 95% CI, 1.91-2.09). Across all women in the sample, the strongest risk factors associated with antidepressant use in the fully adjusted model were having a previous psychiatric contact (IRR, 3.70; 95% CI, 3.62-3.78), having previously obtained an antianxiety medication (IRR, 3.03; 95% CI, 2.99-3.10), and having previously obtained antipsychotic medication (IRR, 1.88; 95% CI, 1.81-1.96)., Conclusions and Relevance: Women who have abortions are more likely to use antidepressants compared with women who do not have abortions. However, additional aforementioned findings from this study support the conclusion that increased use of antidepressants is not attributable to having had an abortion but to differences in risk factors for depression. Thus, policies based on the notion that abortion harms women's mental health may be misinformed.

Background: Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort., Methods: This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders., Findings: Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012-0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040-0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy., Interpretation: The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry., Funding: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: People with mental illness are more likely to have contact with the criminal justice system, but research to date has focused on risk of offense perpetration, while less is known about risk of being subjected to crime and violence., Objectives: To establish the incidence of being subjected to all types of criminal offenses, and by violent crimes separately, after onset of mental illness across the full diagnostic spectrum compared with those in the population without mental illness., Design, Setting, and Participants: This investigation was a longitudinal national cohort study using register data in Denmark. Participants were a cohort of more than 2 million persons born between 1965 and 1998 and followed up from 2001 or from their 15th birthday until December 31, 2013. Analysis was undertaken from November 2016 until February 2018., Exposures: Cohort members were followed up for onset of mental illness, recorded as first contact with outpatient or inpatient mental health services. Diagnoses across the full spectrum of psychiatric diagnoses were considered separately for men and women., Main Outcomes and Measures: Incidence rate ratios (IRRs) were estimated for first subjection to crime event (any crime and violent crime) reported to police after onset of mental illness. The IRRs were adjusted for cohort member's own criminal offending, in addition to several sociodemographic factors., Results: In a total cohort of 2 058 063 (48.7% male; 51.3% female), the adjusted IRRs for being subjected to crime associated with any mental disorder were 1.49 (95% CI, 1.46-1.51) for men and 1.64 (95% CI, 1.61-1.66) for women. The IRRs were higher for being subjected to violent crime at 1.76 (95% CI, 1.72-1.80) for men and 2.72 (95% CI, 2.65-2.79) for women. The strongest associations were for persons diagnosed as having substance use disorders and personality disorders, but significant risk elevations were found across almost all diagnostic groups examined., Conclusions and Relevance: Onset of mental illness is associated with increased risk of exposure to crime, and violent crime in particular. Elevated risk is not confined to specific diagnostic groups. Women with mental illness are especially vulnerable to being subjected to crime. Individual's own offending accounts for some but not all of the increased vulnerability to being subjected to crime.

Background: The postpartum period is well-known risk period for the first onset of autoimmune thyroid disorders (AITDs) as well as first onset of psychiatric disorders. These two disorders are some of the most prevalent medical conditions postpartum, often misdiagnosed and disabling if left untreated. Our study was designed to explore the possible bidirectional association between AITDs and psychiatric disorders during the postpartum period., Methods: A population-based cohort study through linkage of Danish national registers, which comprised 312 779 women who gave birth to their first child during 1997-2010. We conducted Poisson regression analysis to estimate the incidence rate ratio (IRR) of psychiatric disorders among women with first-onset AITDs, the IRR of AITDs among women with first-onset psychiatric disorders as well as the overlap between these disorders using a comorbidity index., Results: Women with first-onset AITDs postpartum were more likely to have first-onset psychiatric disorders than women who did not have postpartum AITDs (IRR = 1.88, 95% confidence interval (CI): 1.25-2.81). Women with first-onset postpartum psychiatric disorders had a higher risk of AITDs than women with no psychiatric disorders (IRR = 2.16, 95% CI: 1.45-3.20). The comorbidity index 2 years after delivery was 2.26 (95% CI: 1.61-2.90), indicating a comorbidity between first-onset AITDs and psychiatric disorders., Conclusions: First-onset AITDs and psychiatric disorders co-occur in the postpartum period, which has relevance to further studies on the etiologies of these disorders and why childbirth in particular triggers the onset.

Background: For different migrant groups living in an area with few people from the same ethnic background is associated with increased psychosis incidence (the ethnic density effect). We set out to answer the question: are there generational differences in this effect?, Methods: Analysis of a population based cohort (2.2 million) comprising all those born 1st January 1965, or later, living in Denmark on their 15th birthday. This included 90,476 migrants from Africa, Europe (excluding Scandinavia) and the Middle East, with 55% first generation and the rest second-generation migrants. Neighbourhood co-ethnic density was determined at age 15 and we adjusted for age, gender, calendar period, parental psychiatric history and parental income., Results: For first-generation migrants from Africa, there was no statistically significant difference (p=0.30) in psychosis rates when comparing lowest with highest ethnic density quintiles, whereas the second generation showed a 3.87-fold (95% CI 1.77-8.48) increase. Similarly, for migrants from the Middle East, the first generation showed no evidence of an ethnic density effect (p=0.94) while the second showed a clear increase in psychosis when comparing lowest with highest quintiles, incidence rate ratio (IRR) 2.43 (95% CI, 1.18-5.00). For European migrants, there was some limited evidence of an effect in the first generation, (IRR) 1.69 (95% CI, 1.19-2.40), with this slightly raised in the second: IRR 1.80 (95% CI, 1.27-2.56)., Conclusions: We found strong evidence for an ethnic density effect on psychosis incidence for second-generation migrants but this was either weak or absent for the first generation., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Background: There is increasing interest in the possible link between maternal hypothyroidism in the perinatal period and childhood asthma risk. We explored this in this study while accounting for the timing of hypothyroidism diagnosis. Further, we evaluated whether the risk was moderated by thyroid hormone treatment during pregnancy., Methods: We conducted a population-based cohort study using Danish national registers. All live-born singletons in Denmark from 1998 to 2007 were identified. Maternal hypothyroidism and asthma in the children were defined by data from the Patient Register and Prescription Registry. We estimated incidence rate ratios (IRRs) of asthma among children born to hypothyroid mothers versus children born to mothers with no recorded thyroid dysfunction using Poisson regression models., Results: Of 595 669 children, 3524 children were born to mothers with hypothyroidism diagnosed before delivery and 4664 diagnosed after delivery. Overall, 48 990 children received treatment for asthma. The IRRs of asthma was 1.16 (95% confidence interval (CI): 1.03-1.30) and 1.12 (95% CI: 1.02-1.24) for children born to mothers with hypothyroidism diagnosed before and after delivery, compared to children born to mothers with no thyroid dysfunction. The highest risk was observed among children born to mothers with hypothyroidism diagnosed before delivery who did not receive thyroid hormone treatment during pregnancy (IRR=1.37, 95% CI: 1.04-1.80)., Conclusion: Our findings suggest that maternal hypothyroidism, especially when it is untreated, increases childhood asthma risk. Early detection and appropriate treatment of hypothyroidism in pregnant women may be an area for possible prevention of childhood asthma., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)