Circulating MicroRNAs in Cord Blood to Predict Attention-Deficit/Hyperactivity Disorder Diagnosis

Background
There are large knowledge gaps in the etiology of attention-deficit/hyperactivity disorder (ADHD), and although it is a prevalent and highly heritable neurodevelopmental disorder, diagnosis can be challenging. We aimed to assess the association of circulating blood plasma microRNAs (miRNAs) at birth with ADHD for use as biomarker candidates and build an miRNA-based prediction model.

Methods
Our study population consisted of 206 children with ADHD (33.0% female), 207 control children (33.8% female), and their parents from the MoBa (Norwegian Mother, Father, and Child Cohort Study). Expression levels of 51 selected miRNAs in plasma from children’s cord blood at birth and from both parents during early pregnancy were quantified by quantitative polymerase chain reaction and tested for association with children’s ADHD diagnosis and ADHD symptom scores based on ratings by parents.

Results
Seven miRNAs were differentially expressed at birth in children with ADHD and control children (false discovery rate < .05), and 31 had a statistically significant linear relationship with parent-rated ADHD symptom score at 8 years. A 19-miRNA ADHD prediction model achieved good discrimination in the test population (area under the receiver operating curve = 0.959, accuracy = 0.893). Functional analysis for the 19-miRNA prediction set revealed involvement in several highly relevant pathways, e.g., dopaminergic synapse, circadian rhythm, and axon guidance. We also found that parental miRNA expression levels significantly associated with children’s ADHD diagnoses and/or ADHD symptoms scores. Conclusions We showed that expression levels of circulating miRNAs at birth may be used to predict increased risk of ADHD diagnosis, and our 19-miRNA set should be included in future efforts to develop a biomarker panel.