Early-life internalizing behavioral trajectories and childhood-onset asthma: An epigenetic link.

BACKGROUND: Behavioral problems and asthma in childhood are considered related despite the debatable causal relationship and unknown mechanisms. We investigated whether early-life behavioral problem trajectories affect the risk of childhood asthma and ascertained potential DNA-methylation mechanisms. METHODS: Based on two independent birth cohorts, this study included 1041 and 1647 children aged 6-10 and 6-7 years in the Cohort for Childhood Origin of Asthma and Allergic Diseases (COCOA) study and Panel Study on Korean Children (PSKC), wherein asthma was defined by a physician's diagnosis and parental questionnaire, respectively. The Korean version of the Child Behavior Checklist (CBCL) was administered at ages 2-6 years. The CBCL trajectories were identified using a latent generalized mixture model. Blood samples from 7-year-old participants were used for DNA-methylation profiling and quantifying metabolites and proteins. RESULTS: Trajectories with high internalizing behavioral problem scores in preschool age were significantly associated with childhood-onset asthma. Increased CBCL anxiety/depression scores at age 2 (COCOA) and somatization scores at ages 4 and 6 (COCOA and PSKC) significantly increased the risk of asthma symptoms and current asthma. In an exploratory sub-study, DNA-methylation analysis suggested hypomethylation of HAL and MAD1L1 in children with co-occurring asthma and behavioral problems, accompanied by higher HAL protein and lower circulating histidine. CONCLUSION: Early-life internalizing behavioral problem trajectories precede childhood asthma, which may be mediated by methylation, especially of HAL and MAD1L1.