Immune system may shape ADHD risk, new genetic study suggests

A new study published in the Journal of Affective Disorders has identified a two-way relationship between attention-deficit/hyperactivity disorder (ADHD) and the immune system. Using a genetic method known as Mendelian randomization, researchers found that ADHD is linked to increased levels of several immune cell traits. At the same time, they identified specific immune traits that appear to raise or reduce the likelihood of developing ADHD. The findings shed light on the biological complexity of ADHD and point to the immune system as a potential contributor to the disorder’s development.

ADHD is a neurodevelopmental condition marked by patterns of inattention, impulsivity, and hyperactivity. It often emerges in childhood and can persist into adulthood, affecting school performance, relationships, and occupational outcomes. Although it is widely recognized that brain differences play a role in ADHD, increasing evidence suggests that immune system activity may also be involved.

Previous studies have reported that people with ADHD tend to have higher levels of inflammation-related molecules in the blood, such as interleukin-6 and interferon-gamma, and lower levels of protective factors like interleukin-10. However, these observations do not clarify whether immune changes cause ADHD, result from it, or are related to other variables. The researchers behind the new study wanted to clarify the direction and strength of these relationships.

To explore whether ADHD and immune traits influence each other, researchers from the Affiliated Mental Health Center of Jiangnan University used a technique called bidirectional Mendelian randomization. This method relies on large genetic datasets and is often used to infer causal links between biological traits. The team used genome-wide association study data from two sources: immune cell trait data from 3,757 individuals in a Sardinian population, and ADHD data from a meta-analysis that included over 225,000 individuals across several cohorts.

The researchers examined 731 immune cell traits, ranging from absolute counts and proportions to markers of immune cell activation, across panels including B cells, monocytes, dendritic cells, and myeloid-derived suppressor cells. Using statistical models that help minimize bias and confounding, they assessed whether genetic markers associated with ADHD were also linked to changes in immune cell traits, and vice versa.

They found that ADHD was associated with increases in three immune cell traits. These included forward scatter measurements—a marker of cell size or complexity—on myeloid dendritic cells, monocytes, and granulocytes. These types of immune cells play a role in the body’s inflammatory response and can help regulate communication between the immune system and the brain. Previous studies have shown that children with neurodevelopmental disorders, including autism and Tourette syndrome, often have higher levels of these cell types.

The study also found that six immune traits appeared to influence the likelihood of developing ADHD. One immune trait, a B cell marker involving a surface protein called IgD, was associated with a slightly higher risk of ADHD. B cells are white blood cells that are central to the body’s adaptive immune response. They produce antibodies, release inflammatory signals, and interact with other immune cells. Some researchers believe that an overactive B cell response may contribute to psychiatric conditions through chronic low-level inflammation. The authors suggest that this heightened immune activity could also be relevant to ADHD.

In contrast, five other immune traits were associated with a lower likelihood of developing ADHD. These included features of CD14+ monocytes, basophils, and subsets of myeloid-derived suppressor cells. These cells are often involved in dampening immune responses or helping to maintain immune balance. For instance, myeloid-derived suppressor cells are known to regulate inflammation and have been found in greater numbers in people with mood disorders. Their suppressive effects may help prevent excessive immune activity that could otherwise interfere with brain function.

The researchers note that the immune system could interact with the brain in multiple ways. Under certain conditions, such as stress or illness, the protective barrier between the bloodstream and the brain can become more permeable. This allows immune cells and inflammatory molecules to enter brain tissue, where they may influence neural development or activity. During early life, when the brain is still forming, such immune activity could potentially disrupt circuits involved in attention, impulse control, or emotional regulation—key functions affected in ADHD.

These findings align with other evidence showing that immune changes, especially inflammation, may influence brain structure and function. For example, inflammation can interfere with the production of neurotransmitters like dopamine and serotonin, which are known to play a role in ADHD. It can also affect glial cells in the brain, which help regulate neural signaling and respond to injury.

While the study offers new insights into the biology of ADHD, the researchers caution that it has limitations. Because the genetic data came primarily from individuals of European ancestry, the findings may not apply to people from other backgrounds. The study also could not account for potential differences by sex or age, since those details were not available in the dataset. In addition, the threshold used for identifying some associations was relatively lenient, which could increase the chance of false positives.

Still, the use of Mendelian randomization helps strengthen confidence in the findings, since this method reduces the influence of environmental confounders and reverse causation. The results suggest that immune system activity is not just a side effect of ADHD, but may play an active role in shaping the disorder—or be shaped by it in turn.

Looking ahead, the researchers suggest that immune system markers could serve as early indicators of ADHD risk or guide the development of new treatments. Anti-inflammatory strategies or drugs that adjust immune cell activity could be explored as potential therapies. More work is needed to identify which patients might benefit most from such approaches and to understand how immune profiles relate to different types or severities of ADHD.

The study, “Exploring the complex relationship between attention deficit hyperactivity disorder and the immune system: A bidirectional Mendelian randomization analysis,” was authored by Jianbin Du, Lin Fang, Kunlun Dong, and Zhenhe Zhou.