Long-term physical health conditions and youth anxiety and depression: Is there a causal link?

Background: The prevalence of youth anxiety and depression has increased globally, with limited causal explanations. Long-term physical health conditions (LTCs) affect 20-40% of youth, with rates also rising. LTCs are associated with higher rates of youth depression and anxiety; however, it is uncertain whether observed associations are causal or explained by unmeasured confounding or reverse causation.

Methods: Using data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and Norwegian National Patient Registry, we investigated phenotypic associations between childhood LTCs, and depression and anxiety diagnoses in youth (<19 years), defined using ICD-10 diagnoses and self-rated measures. We then conducted two-sample Mendelian Randomization (MR) analyses using SNPs associated with childhood LTCs from existing genome-wide association studies (GWAS) as instrumental variables. Outcomes were: (i) diagnoses of major depressive disorder (MDD) and anxiety disorders or elevated symptoms in MoBa, and (ii) youth-onset MDD using summary statistics from a GWAS in iPSYCH2015 cohort.

Results: Having any childhood LTC phenotype was associated with elevated youth MDD (OR = 1.48 [95% CIs 1.19, 1.85], p = 4.2×10^-4) and anxiety disorder risk (OR = 1.44 [1.20, 1.73], p = 7.9×10^-5). Observational and MR analyses in MoBa were consistent with a causal relationship between migraine and depression (IVW OR = 1.38 [1.19, 1.60], p_FDR = 1.8x10^-4). MR analyses using iPSYCH2015 did not support a causal link between LTC genetic liabilities and youth-onset depression or in the reverse direction.

Conclusions: Childhood LTCs are associated with depression and anxiety in youth, however, little evidence of causation between LTCs genetic liability and youth depression/anxiety was identified from MR analyses, except for migraine.