Blood miRNA levels associated with ADHD traits in children across six European birth cohorts

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable neurodevelopmental disorder of major societal concern. Diagnosis can be challenging and there are large knowledge gaps regarding its etiology, though studies suggest an interplay of genetic and environmental factors involving epigenetic mechanisms. MicroRNAs (miRNAs) show promise as biomarkers of human pathology and novel therapies, and here we aimed to identify blood miRNAs associated with traits of ADHD as possible biomarker candidates and further explore their biological relevance. Methods Our study population consisted of 1126 children (aged 5–12 years, 46% female) from the Human Early Life Exposome study, a study spanning six ongoing population-based European birth cohorts. Expression profiles of miRNAs in whole blood samples were quantified by microarray and tested for association with ADHD-related measures of behavior and neuropsychological functions from questionnaires (Conner’s Rating Scale and Child Behavior Checklist) and computer-based tests (the N-back task and Attention Network Test). Results We identified 29 miRNAs significantly associated (false discovery rate < .05) with the Conner’s questionnaire-rated trait hyperactivity, 15 of which have been linked to ADHD in previous studies. Investigation into their biological relevance revealed involvement in several pathways related to neurodevelopment and function, as well as being linked with other neurodevelopmental or psychiatric disorders known to overlap with ADHD both in symptomology, genetic risk, and co-occurrence, such as autism spectrum disorder or schizophrenia. An additional three miRNAs were significantly associated with Conner’s-rated inattention. No associations were found with questionnaire-rated total ADHD index or with computer-based tests. Conclusions The large overlap of our hyperactivity-associated miRNAs with previous studies on ADHD is intriguing and warrant further investigation. Though this study should be considered explorative and preliminary, these findings contribute towards identifying a set of miRNAs for use as blood-based biomarkers to aid in earlier and easier ADHD diagnosis

Additional file 3 of Blood miRNA levels associated with ADHD traits in children across six European birth cohorts

Additional file 3: Table S1. Change in number of miRNAs significantly differentially expressed after sensitivity analyses. Table S2. miRNAs linked to ADHD in previous literature. Table S3. Functional enrichment analysis of 29 miRNAs significantly associated with hyperactivity. Table S4. Functional enrichment analysis of 15 miRNAs associated with hyperactivity/ADHD in this and previous studies. Table S5. MiRNAs statistically significant for Conner’s hyperactivity or inattention score, and their previous associations with neurodevelopmental or psychiatric phenotypes

Additional file 1 of Blood miRNA levels associated with ADHD traits in children across six European birth cohorts

Additional file 1. Additional details of methods

Additional file 2 of Blood miRNA levels associated with ADHD traits in children across six European birth cohorts

Additional file 2: Fig. S1. PCA (principal component analysis) before and after SVA (surrogate variable analysis). Fig. S2. Correlation matrix for bivariate association between measures of behavior and neuropsychological functions and child’s age. Fig. S3. Behavioral and neuropsychological scores by sex