Are rare variants important in ADHD genetics? 

Yes, recent genetic research makes clear that ADHD, rare variants (mutations which are uncommon in the general population), play a meaningful role in ADHD risk, alongside more common variants uncovered by GWAS. Rare mutations such as de novo damaging variants, rare inherited protein‑truncating variants, and copy number variants (CNVs) add depth to our understanding of how ADHD develops, especially in children. 

Rare variants often have larger individual effects compared to common SNPs, and they can uncover risk genes that might be missed entirely when focusing just on common variation. Studies using exome sequencing and whole‑genome sequencing are starting to show how many genes contribute via these rare variants. 

What We have Learned about Rare Variants in ADHD 

Here are some of the key findings from recent research that show why rare variants matter: 

Enrichment of de novo damaging variants 

A recent study sequencing children with ADHD and their parents (“trios”) found that ADHD cases are significantly more likely to carry rare or ultra‑rare de novo mutations that damage genes, especially protein‑truncating variants (PTVs) and deleterious missense variants. One high‑confidence gene identified is KDM5B, among others, demonstrating that even rare variants in constrained genes (genes more intolerant to damaging variation) are implicated in ADHD risk. 

Contribution to heritability and “missing heritability” 

GWAS of common SNPs explain only part of ADHD’s heritability. Rare variants account for some of that gap. For example, studies report a higher burden of rare protein‑truncating variants in ADHD cases compared to controls, particularly in genes already flagged in common‑variant analyses.  

Overlap with other neurodevelopmental and psychiatric disorders 

Many of the rare genes implicated in ADHD also show up in autism, developmental delay, and other neuropsychiatric conditions. This suggests pleiotropy; some rare variants affect basic neurodevelopmental biology that manifests in different but related disorders.  

Challenges & early stage  

The studies into rare variants are still quite new, often with small sample sizes, which limits statistical power and the ability to detect specific risk genes reliably. As well, rare variant studies are expensive and more complex in analysis. Larger and more diverse sequencing cohorts are needed.  

Implications for Gene Discovery and Treatment 

• Rare variants give us new candidate genes to study, which may lead to better understanding of the biological mechanisms of ADHD. 

• Knowledge of rare variant risk could contribute, in future, to personalised medicine: knowing if someone carries a rare damaging variant might influence which treatments are more likely to help. 

• Gene discovery via rare variants also helps illuminate the developmental pathways involved (for instance early brain development, synaptic function, chromatin regulation) which may be potential therapeutic targets. 

For personal guidance or assessment, visit providers like ADHD Certify who may help interpret genetic findings.

For a deeper dive into the science, diagnosis, and full treatment landscape, read our complete guide to Genetic studies and biomarkers.