Psychiatric disorders such as depression and schizophrenia, and neurodevelopmental conditions such as ADHD are strongly influenced by genetics. At the same time, brain scans consistently show that these conditions affect specific brain regions rather than the brain as a whole.
What has remained unclear is how these two facts connect. In particular, researchers and clinicians are interested to find out if genetic risks actually help explain where in the brain these disorders leave their mark?
Genetic maps and real brain changes
In a recent study, published in Molecular Psychiatry, we explored this question by linking genetic risk data with maps of gene expression across the human brain, using a new approach called Gene Expression-based Disorder-Associated Risk (GEDAR).
The idea behind GEDAR is simple. Instead of asking how genetic risk affects individuals, we asked how it is distributed across the brain. In this study we started with large genetic studies of seven major mental health conditions — Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Obsessive Compulsive Disorder, Anorexia Nervosa, ADHD and Autism Spectrum Disorder.
From this we identified the genes whose activity is predicted to change for each disorder We then projected those genes onto detailed maps of where they are normally expressed in the brain, derived from the Allen Human Brain Atlas. This allowed us to create brain-wide maps showing predictions for the location of genetically driven changes in the gene expression.
The crucial question was whether these genetic maps resemble real brain changes observed in patients. To answer this, we compared GEDAR maps with thousands of MRI scans analysed by the ENIGMA Consortium, which has identified reliable patterns of brain structure differences across mental health conditions.
Different genetic risk maps for different conditions
The results were strikingly selective. For major depressive disorder, genetic risk mapped strongly onto both cortical and subcortical brain changes. In other words, the brain regions where genetic data predicted there would be the most altered gene expression are also the regions most affected in depression. Many of these genes are involved in immune and inflammatory processes, adding spatial evidence to the growing link between depression, inflammation, and brain structure.
For ADHD and schizophrenia, the alignment appeared mainly in deeper, subcortical brain regions such as the striatum or the hippocampus. In ADHD, the implicated genes were tied to brain development and connectivity, while in schizophrenia they were largely immune-related. Other conditions, such as autism, anorexia nervosa, and obsessive-compulsive disorder, showed little correspondence between genetic maps and adult brain structure.
Importantly, this doesn’t mean genetics are less important in those conditions. Instead, it is likely that it reflects timing. Some disorders may be shaped by genetic effects early in development, long before adult brain structure can be measured with MRI. Our approach captures where genetic risk is expressed in the adult brain (from donors toughly between 24 and 57 years old), and not when it exerts its strongest influence which is likely to be earlier in life.