NEW research shows how rare genetic variants increase the risk of ADHD, offering new insight into the biology behind this common neurodevelopmental condition. Researchers identified three genes whose disruption may significantly alter early brain development.
Genetic Architecture Behind the Risk of ADHD
Attention deficit hyperactivity disorder affects around 5 percent of children and 2.5 percent of adults, yet the role of rare variants in shaping the risk of ADHD has remained unclear. Although common variants have been linked to the disorder, this study used exome sequencing to examine 8,895 individuals with ADHD and 53,780 controls, revealing how uncommon genetic alterations exert outsized effects.
How Rare Variants Were Identified and What They Mean for Brain Function
By analysing rare coding variants, the team identified three significant genes, MAP1A, ANO8 and ANK2, with P < 3.07 × 10−6 and odds ratios ranging from 5.55 to 15.13. Their protein interaction networks were enriched for genes involved in synapse function, RNA processing and cytoskeleton organisation. Rare deleterious variants were linked to a 2.25 IQ point decrease per variant in a sample of 962 adults with ADHD, and individuals with ADHD and intellectual disability showed an increased overall variant load. Notably, nine of the top 20 associated genes have been implicated in autism or other neurodevelopmental disorders, and most showed high expression across pre and postnatal brain development. The results also confirmed that rare and common variants act additively, reinforcing a polygenic model of risk.
Implications for Clinical Practice and Future Research
These findings suggest that assessing rare variants could one day refine diagnostic pathways and help clinicians anticipate cognitive or developmental challenges associated with the risk of ADHD. As sequencing becomes more accessible, genetic profiling may support earlier intervention planning and tailored educational support. Future work aims to identify additional genes and clarify how variant patterns shape clinical outcomes, paving the way for more personalised approaches to neurodevelopmental care.
Reference
Demontis D et al. Rare genetic variants confer a high risk of ADHD and implicate neuronal biology. Nature. 2025;DOI:10.1038/s41586-025-09702-8.
