Gene and Environment Interactions in the Brain: A Pathway to ADHD?

Defining how interactions between an individual’s genotype andenvironment (“gene-byenvironment”) actupon thebrain to result in mental illness is a vital but challenging endeavor. The study by van derMeer et al. (1) in this issue of the Journal takes one of the most widely studied of all gene-by environment interactions into the brain in an effort tomap out neural pathways to attention deficit hyperactivity disorder (ADHD). The “gene” under study is a genetic variant, a variable number tandem repeat polymorphism, in the promoter region of the serotonin transporter referred to as 5-HTTLPR. It has a short (“S”-allele) and a long (“L”-allele) form, and the variation affects serotonergic signaling (2). The “environment” is an amalgam of chronic social stressors and major adverse life events. It has been reported that carriers of the short, S-allele are more vulnerable to depression when exposed to adverse events (3–6). Here, the authors find that the same gene-byenvironment interaction may extend to ADHD. They show that young adults with one or two copies of the S-allele when exposedtosocial stressorshavemoresymptomsofADHDthan thosewith two copies of the L-allele. They proceed to askwhy and look to the brain for an answer. The study’s sample is enriched for ADHD, with 291 young, affected adults, 78 individuals with subthreshold ADHD, and 332healthy comparison subjects;many of the participantswere siblings. All had magnetic resonance neuroanatomic scans to allow the definition of gray matter volume with an exquisite level of spatial resolution (around half-a-million voxels, or tiny “volumes”). The authors askwhether change in brain structure is the mechanism through which the 5-HTTLPR/stress interaction affects the severity of ADHD symptoms. Mediation analysesarewidelyused inmappingsuchpossiblecausalchains. The authors start by defining a term that reflects the interaction ofthegeneandstressfulenvironments.Theyshowthatthis term is significantly associated with the volume of several prefrontal cortical regions. Next, they find that some of these prefrontal regions are further associated with the severity of ADHD symptoms. Combined, this demonstrates that variation in prefrontal cortical structuremediates, or statistically accounts for, the stronger correlation seen in S-allele carriers between social stress and ADHD symptoms. Specifically, decreased volumes of the left frontal pole and right anterior cingulate cortex emerge as possible contributors to the increasedADHD symptom severity seen in S-allele carriers when exposed to stress. It has been intensely debated whether this interaction between 5-HTTLPR and social stress plays a role in altering risk for psychopathology. Most studies have examined vulnerability to depressionwithmeta-analytic evidence both for andagainst a link (4–6).Theproposal by vanderMeer et al. that this gene-by-environment interaction is also linked to ADHD is much less studied. One prior study of 110 adults with ADHD found that the L-allele (but not the S-allele) interacted with childhood stressors in altering ADHD severity (7, 8). A second study of 184 boys with conduct problems found that S-allele carriershadfewerADHDsymptomswhenunder lowstress,but not more symptoms when under high stress. Despite the differences, in combination with the van derMeer et al. study, the findingssuggest that it isworthwhile toexplore furtherwhether this gene-by-environment interaction affects ADHD. If replicated, this would add the 5-HTTLPR to the list of genes that alter the risk of a wide range of psychiatric disorders, either directly or through interaction with key environments. It also raises the question of whether this gene-by-environment interaction operates upon a behavioral dimension that might underpinmultipledisorders.Theauthorsreasonablysuggestthatthe regulation of attention and emotion could be such a dimension. While the gene-by-environmentfield has had its fair share of nonreplications, three features bolster confidence in the present study. Firstly, the sample size of 701 is very impressive by neuroimaging standards. It afforded the detection of a gene-byenvironment interaction that accounts for between 0.1% and 0.8% of the variance in key brain regions. For a phenotype as complexasbrainmorphology,explainingthisamountofvariance is in line with expectations. To appreciate the scale, the largest genetic imaging study to date of brain structure examined 30,717 individuals and found that the most strongly associated single common genetic variant explained 0.52% of the variation in the size of the caudate (9). Secondly, the authors carefully consider potential confounding variables. They demonstrate that the pattern of results holds across the two magnetic resonance scanners used. Importantly, they show that age—which is Decreased volumes of the left frontal pole and right anterior cingulate cortex emerge as possible contributors to the increased ADHD symptom severity seen in S-allele carriers when exposed to stress.