Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity.
While highly heritable, the heterogeneity of clinical presentation suggests complex interactions between genetic and environmental risk factors.
A new study suggests that it may be possible to diagnose ADHD or detect ADHD susceptibility risk in children by analyzing microRNA in the blood.
- 29 microRNAs were associated with ADHD hyperactivity trait and 15 had been previously linked to ADHD.
- MicroRNAs associated with hyperactivity are involved in pathways related to neurodevelopment and function.
- MicroRNAs could enable earlier and minimally invasive diagnosis of ADHD.
Source: BMC Psychiatry (2023)
Challenges in ADHD Diagnosis
Despite being one of the most commonly diagnosed childhood psychiatric conditions, there are large gaps in knowledge regarding the etiology and pathology underlying ADHD.
Diagnosis is clinically challenging, relying on subjective evaluation of behavioral symptoms that lack biomarker correlates.
This often delays diagnosis, which is problematic as earlier intervention is associated with better prognosis.
Once diagnosed, finding an effective treatment regimen can involve months of trial-and-error.
There is also no way to predict which patients will experience symptom persistence into adulthood.
Potential for Blood-Based Biomarkers in Diagnosis
Objective biomarkers that enable earlier diagnosis and personalized treatment of ADHD are greatly needed.
One emerging option is microRNAs (miRNAs) – small non-coding RNAs that regulate gene expression.
As key regulators of neurodevelopment, miRNAs show promise as biomarkers reflective of ADHD-associated neurological abnormalities.
Crucially, miRNAs can be assayed from accessible sample types like blood.
Demonstrating associations between circulating miRNA levels and ADHD traits would underscore their biomarker potential.
Blood miRNAs in ADHD (Study): 1,000+ Children
A 2023 study published in BMC Psychiatry analyzed miRNA expression in relation to ADHD traits in over 1,000 children from six European cohort studies.
This large-scale analysis identified specific miRNAs associated with ADHD hyperactivity that warrant further investigation as biomarker candidates.
Design & ADHD Trait Measures
The study population consisted of 1126 children (aged 5-12 years) enrolled in the Human Early Life Exposome (HELIX) project spanning six ongoing European birth cohort studies in the UK, France, Spain, Lithuania, Norway and Greece.
ADHD traits were evaluated using two common rating scales completed by parents – Conners 3rd Edition Rating Scales and Child Behavior Checklist.
These provide index scores for ADHD symptoms as well as differentiated hyperactivity and inattention subscales.
Two computer-based neuropsychological tests of executive functioning were also administered.
Genome-wide miRNA expression profiling of whole blood samples was performed using microarray analysis.
Results: miRNAs Linked to Hyperactivity
Linear regression modeling identified 29 miRNAs significantly associated with Conners hyperactivity score.
All 29 were downregulated in relation to more severe parent-rated hyperactivity.
Fifteen of these miRNAs overlapped with those previously implicated in ADHD pathology.
An additional 3 miRNAs were associated with the Conners inattention score.
No miRNAs were significantly associated with computer-based test measures of executive functioning.
Findings Consistent with Prior ADHD-miRNA Studies
Several miRNAs identified as downregulated in relation to hyperactivity scores have been similarly reported as downregulated in ADHD cases versus controls in previous studies, including miR-106b-5p, miR-107, miR-24-3p and miR-148b-3p.
miR-142-3p was also previously found downregulated in ADHD cases with a family history of psychiatric disorders.
Involvement in Neurodevelopmental Pathways
Functional enrichment analysis of genes targeted by the 29 hyperactivity-related miRNAs highlighted involvement in pathways important for brain development and function – like neurotrophin signaling, sphingolipid metabolism, axon guidance, and insulin signaling.
Related Neuropsychiatric Conditions
Nearly all 32 ADHD trait-related miRNAs have also been linked to other neurodevelopmental and psychiatric conditions that frequently co-occur with ADHD, like autism spectrum disorder and schizophrenia.
This suggests key roles in developmental processes that underpin such disorders.
Evidence miRNA Linked to ADHD Traits
This large-scale analysis provides important confirmatory evidence that specific circulating miRNAs relate to ADHD traits.
The substantial overlap with miRNAs implicated in previous ADHD research is compelling and nominates a set warranting further validation as minimally invasive biomarker candidates.
Trait-Specific Differences & ADHD Heterogeneity
An intriguing aspect of this study was the specific association between miRNAs and parent-reported hyperactivity scores versus inattention or test measures of executive functioning.
This likely reflects the heightened observability and early emergence of hyperactive/impulsive symptoms that drive initial clinical referral.
It may also relate to the developmental lag in impaired attention becoming evident.
Such findings further underscore the heterogeneity of ADHD and importance of incorporating symptom dimension data.
Relevance for Early ADHD Diagnosis
The capacity to gauge ADHD risk from an accessible biosample like blood holds promise for enabling earlier and more efficient diagnosis.
Future studies should investigate whether these miRNA signatures are apparent during the preschool years when symptoms often first arise.
Detecting aberrant miRNA expression early in life could facilitate prompt intervention at a critical window for improving developmental trajectories.
Potential Limitations of this Study
As this study utilized a general population cohort, findings may not extend directly to clinically diagnosed ADHD cases.
Replication in a clinical sample would strengthen the results.
Small sample sizes limited sensitivity analyses stratified by cohort or sex.
While the cohorts were diverse geographically, differences in data collection protocols could have impacted consistency of results across sites.
Nonetheless, the extensive concordance with prior miRNA studies supports the validity of these hyperactivity-associated candidates as putative ADHD biomarkers.
Conclusions: miRNA Biomarkers for ADHD Diagnosis
This study nominated a set of blood-based miRNAs associated with ADHD hyperactivity traits, many overlapping with miRNAs previously linked to ADHD pathology.
These warrant further evaluation and validation as minimally invasive biomarker candidates that could enable earlier diagnosis and personalized treatment of ADHD.
Future research should investigate whether miRNA signatures can:
- Distinguish clinical ADHD cases from neurotypical controls
- Identify susceptibility early in life prior to onset of impairing symptoms
- Predict persistence of symptoms into adulthood
- Monitor treatment response and remission status
Isolating blood-based biomarkers that capture ADHD’s neurodevelopmental underpinnings could transform how this prevalent and impairing condition is recognized, understood, and managed across the lifespan.
The miRNA candidates identified here demonstrate promising clinical utility that merits continued investigation.
- Paper: Blood miRNA levels associated with ADHD traits in children across six European birth cohorts (2023)
- Authors: Lene B. Dypas et al.