Dissecting the causal relationships between childhood-onset asthma and major mental disorders: a univariable and multivariable Mendelian randomization study

BackgroundAsthma with a childhood-onset is found to be associated with increased risk of severe mental illnesses in later life. However, the causal relationships between childhood-onset asthma and major mental disorders remained unclear. MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of childhood-onset asthma (n=327,670) on six major mental illnesses, including major depressive disorders (n=143,265), bipolar disorder (n=353,899), schizophrenia (n=130,644), anxiety (n=10,240), autism (n=46,350), and ADHD (n=225,534) using summary statistics of genome-wide association studies (GWAS). The inverse variance weighted (IVW) method, along with weighted median and MR-Egger were employed for the causal estimates. Multiple sensitivity analyses were conducted to examine the robustness of the estimates. Moreover, the direct effects of childhood-onset asthma on mental disorders after accounting for the effects of adult-onset asthma were evaluated through the multivariable MR (MVMR) analysis. ResultsWe found that genetically determined childhood-onset asthma significantly increased the risk of depression (IVW OR=1.059, 95%CI:1.025-1.095, p=5.72e-04) and bipolar disorder (IVW OR=1,065, 95%CI:1.027-1.105, p=6.75e-04), but not associated with other mental disorders. Further MVMR analysis indicated that the causal relationships remained significant with the adjustment of adult-onset asthma. Interestingly, we found that childhood-and adult-onset asthma exerted distinct causal effects on depression and bipolar disorders. No significant heterogeneity and horizontal pleiotropy were found to influence the causal estimates. ConclusionsMR analysis indicated a significant causal relationship between genetically determined childhood-onset asthma and increased risk of depression and bipolar disorder in later life. The causal effects of childhood-onset asthma were distinct to the adult-onset asthma. Further studies were warranted to investigate the mechanisms underlying the causal relationships.