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5-HTTLPR affects stress response in brain regions involved in ADHD

5-HTTLPR genotype appears to be involved in moderating the influence of stress on brain regions linked to social cognitive processing and cognitive control, which may play a role in attention-deficit/hyperactivity disorder severity, according to recent findings.

In the study, researchers evaluated 701 adolescents participating in the NeuroIMAGE study, a follow-up of the International Multicenter ADHD Genetics (IMAGE) study. The present study evaluated structural MRI data from 385 families; 291 participants from 233 of these families had diagnosed ADHD, while 78 participants had subthreshold ADHD. A comparison group of 332 participants without ADHD were also analyzed, and 154 of these participants were siblings of participants with ADHD. Participants were 55.8% male with an average age of 17 years.

Study participants/parents completed two questionnaires to evaluate the extent of exposure to psychosocial stress. The Long-Term Difficulties Inventory, which was completed by parents, utilized 13 items to evaluate children’s exposure to chronic stress such as a handicap, bullying, financial struggles or other ongoing stressors at home or school. Additionally, the participants themselves responded to the 11-item Stressful Life Events Screening Questionnaire, which addressed exposure to major stressful events within the previous 5 years. Such major stressors included death or illness of a loved one, physical or sexual abuse or a failure at an endeavor the child considered important. The researchers established a composite stress measure by converting the questionnaire scores to z values, and averaging them based on common aggregation practices.

ADHD symptom count was calculated using the Conners’ ADHD Rating Scales questionnaires. Parents, teachers, or the participant (if 18 years or older) completed these questionnaires, which assessed the presence or absence of each of the 18 ADHD symptoms outlined in the DSM-IV-TR. 

Participants also underwent two high-resolution MRI scans. The researchers conducted a whole-brain, voxel based morphometry mediation analysis, designating the interaction of genes/environment as a predictor, gray matter volume as a mediator, and ADHD symptom count as the outcome.

They found an association between exposure to stress and grey matter volume, moderated by 5-HTTLPR in the precentral gyrus, middle and superior frontal gyri, frontal pole, and cingulate gyrus. S-allele carriers had a more pronounced effect vs. participants homozygous for the L-allele. Gray matter volume in in the frontal pole and anterior cingulate were found to play a role in the association of this gene-environment interaction.

According to the researchers, the regions of the brain for which stress is moderated by 5-HTTLPR are those associated with social cognition, regulation of emotions, and other measures of cognitive control. They said these findings may be used to guide personalized medicine for ADHD patients.

 “Clinicians may eventually use information on the moderating effects of patients’ genotypes to shape their prevention and treatment strategies to individual patients’ needs; S-allele carriers may benefit more from preventing stressful experiences and treatments in order to better regulate their behavior, although more research is needed to confirm this,” the researchers wrote. – by Jennifer Byrne

Disclosure: Please see the full study for a list of relevant disclosures.