Researchers uncover complex genetic ties between ADHD and morning cortisol

A new study suggests the connection between Attention-Deficit/Hyperactivity Disorder (ADHD) and the body’s primary stress hormone, cortisol, is not one of direct cause and effect. Instead, the two appear to share a complex genetic foundation, pointing toward common biological pathways that regulate arousal and behavior. The research, published in the journal Psychoneuroendocrinology, helps refine scientific understanding of the physiological underpinnings of ADHD.

Attention-Deficit/Hyperactivity Disorder is a common neurodevelopmental condition characterized by persistent patterns of inattention, impulsivity, and hyperactivity. For some time, researchers have investigated its relationship with the body’s stress response system, formally known as the hypothalamic-pituitary-adrenal axis. This system’s main product is cortisol, a hormone that follows a natural daily rhythm, typically peaking in the morning to promote wakefulness and declining throughout the day.

Because this system also governs general arousal levels, which are thought to be regulated differently in individuals with ADHD, scientists have explored whether cortisol levels might be linked to the condition. Some previous analyses of multiple studies indicated that people with ADHD, particularly youths, tend to have lower baseline levels of morning cortisol.

However, results across individual studies have been inconsistent, leaving the nature of this relationship ambiguous. It was not clear if cortisol differences contributed to ADHD, if ADHD itself altered cortisol regulation, or if another factor linked them both.

To investigate this question, a team of researchers from institutions in Brazil and Denmark turned to genetics. Led by scientists at the University of São Paulo and the Federal University of Rio Grande do Sul, the group used large-scale genetic data to dissect the biological connection between ADHD and morning cortisol levels. Their approach was designed to move beyond simple correlation and test for causal links and shared genetic architecture.

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The researchers first employed a powerful statistical method known as Mendelian Randomization. This technique uses genetic variants as a proxy for an exposure, in this case, morning cortisol levels. Because a person’s genes are randomly assigned at conception and generally remain fixed, this method can help determine if an exposure causes an outcome without the confounding influence of environmental or lifestyle factors. The analysis drew on genetic data from two massive datasets: one for ADHD that included over 225,000 people and one for morning cortisol levels from over 25,000 people.

After applying seven different Mendelian Randomization models, the team found no evidence of a causal relationship in either direction. Genetically predicted morning cortisol levels did not appear to increase the likelihood of having ADHD. Similarly, a genetic predisposition for ADHD did not seem to cause alterations in morning cortisol levels. This result suggested that a simple, direct causal link was unlikely and that a more complex connection might exist.

Next, the team searched for evidence of pleiotropy, a phenomenon where the same genes influence multiple, seemingly unrelated traits. They started by conducting a global genetic correlation analysis, which scans the entire genome to see if the genetic factors for ADHD and cortisol overlap on a broad scale. This analysis did not find a significant overall correlation, indicating that on a genome-wide level, the two traits do not share substantial genetic influences.

The investigation then shifted to a more fine-grained approach. Using a technique called Local Analysis of Variant Association, the researchers zoomed in on 2,495 specific segments of the genome to search for localized regions of genetic overlap. Here, they made a key discovery. They identified two distinct genomic regions, one on chromosome 5 and another on chromosome 22, where the genetics of ADHD and morning cortisol were significantly linked.

The nature of these links was bidirectional. The region on chromosome 5 showed a negative correlation, meaning that genetic variants associated with a higher likelihood of ADHD were also associated with lower morning cortisol levels.

In contrast, the region on chromosome 22 showed a positive correlation, where genetic variants linked to a higher likelihood of ADHD were tied to higher morning cortisol levels. This mixture of positive and negative associations in different parts of the genome helps explain why the global analysis found no overall effect.

The genes located within these two regions, such as RASGRF2 and TRIOBP, have previously been implicated in a range of psychiatric conditions, cognitive functions, and risk-taking behaviors. An additional analysis designed to pinpoint single genetic markers associated with both traits identified one variant located within a gene called ZNF652-AS1. This marker has also been connected in other research to behaviors related to impulsivity.

To see how these genetic predispositions play out in people, the researchers conducted a final analysis in an independent group of 1,660 Brazilian adults, some with ADHD and some without. For each person, they calculated a polygenic score, which summarizes an individual’s genetic tendency toward higher or lower morning cortisol. The team then tested if this score was associated with having an ADHD diagnosis or other co-occurring psychiatric conditions.

The cortisol polygenic score was not directly associated with having an ADHD diagnosis on its own. It was, however, associated with the presence of other conditions known as externalizing disorders. A higher genetic predisposition for morning cortisol was linked to a greater likelihood of having a substance use disorder, oppositional defiant disorder, or antisocial personality disorder.

When the researchers statistically accounted for the presence of these co-occurring conditions, a new pattern emerged: a lower cortisol polygenic score was then associated with ADHD. This finding suggests the link between cortisol genetics and ADHD may be partly masked or mediated by related behavioral conditions.

Taken together, the study’s results argue against a direct causal pathway between cortisol and ADHD. Instead, they support a model of localized pleiotropy, where specific sets of genes influence both the body’s arousal systems and the behaviors characteristic of ADHD. The researchers propose that these findings align with an “inverted U-shaped” model of physiological regulation.

In this view, optimal functioning occurs at a moderate level of arousal, and deviations in either direction, resulting in either too low or too high cortisol, could be associated with ADHD-related traits. This perspective reframes ADHD not just as a disorder of attention, but as a condition involving broader systemic dysregulation.

The study has some limitations. The large genetic datasets used for the initial analyses were drawn predominantly from individuals of European ancestry, which may limit the generalizability of the findings to other populations. The polygenic score analysis in the Brazilian sample highlighted this, as the associations were primarily detected in the subgroup of participants with greater European ancestry. The clinical sample for the polygenic score analysis was also modest in size.

Future research could build on these findings by examining these genetic links in larger and more diverse populations. Integrating genetic data with direct, repeated measurements of cortisol levels in individuals over time would also help to clarify how these shared genetic factors influence the body’s hormonal dynamics from day to day. Such work would continue to illuminate the complex biological interplay that contributes to ADHD.

The study, “Shared biological pathways linking ADHD and cortisol variability are related to externalizing behaviors,” was authored by João K.N. Ramos, Eugenio H. Grevet, Iago Junger-Santos, Nicolas P. Ciochetti, Cibele E. Bandeira, Maria E. de Araujo Tavares, Victor F. de Oliveira, Eduardo S. Vitola, Luis A. Rohde, Rodrigo Grassi-Oliveira, Bruna S. da Silva, Claiton H. Dotto Bau, and Diego L. Rovaris.