Genetic and psychosocial influence on the association between early childhood infections and later psychiatric disorders.

OBJECTIVE: To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders METHODS: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case-cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio-economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression RESULTS: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19-1.41), ASD (HR 1.28, 95% CI: 1.18-1.40), MDD (HR 1.23, 95% CI: 1.14-1.33), and SCZ (HR 1.21, 95% CI: 1.07-1.36), but not for BIP (HR1.17, 95% CI: 0.96-1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene-environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk CONCLUSION: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene-environment correlation, it had minor impact on the results.

Incidence Rates and Cumulative Incidences of the Full Spectrum of Diagnosed Mental Disorders in Childhood and Adolescence.

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