Psychiatric diagnoses are notoriously imprecise. Patients with the same diagnosis typically differ from one another in many respects, including in their particular symptoms as well as in measurements made with brain imaging approaches. This variability is a tough challenge for scientists trying to develop novel, more personalized treatments.
In schizophrenia, results from genetic studies have promised to explain some of these differences in terms of genetic predispositions. However, genetic associations also differ between individuals affected with schizophrenia. One approach to characterize individual differences in genetic risk is the so-called polygenic risk score. These scores sum up many genetic variants to generate a number to quantify the individual risk of developing schizophrenia.
While this measure can differentiate patients from unaffected individuals at the population level, it is not helpful in determining the illness status of individuals and does not show strong associations with measures in the brain that are thought to underly the disorder.
Now, a team of scientists at the Lieber Institute for Brain Development, including senior author and Lieber Institute Investigator Giulio Pergola, lead author Leonardo Sportelli, and collaborators from the National Institutes of Health, the University of Bari in Italy, and King’s College and Cardiff University in the UK, have developed a new type of genetic score that is both associated with risk for illness and also biologically interpretable and potentially individually meaningful. Their research, entitled “Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo,” was published April 30 in the journal Nature Communications. Read the paper.
Using measures of gene expression in postmortem brains, the scientists identified a set of genes enriched for dopamine neurotransmission, a neurochemical process long thought to be important in psychosis and in the current treatment of psychosis. The investigators showed that this dopamine genetic score predicts neuroimaging measures of dopamine in vivo in five independent studies. In contrast, the rest of the genes that are thought to be schizophrenia risk genes did not show significant associations with these dopamine measures.
The results suggest that some of the diversity of patients with schizophrenia can be parsed into groups of patients who have a prominent dopamine component to their illness and others who do not.
The research may represent the first division of schizophrenia into subtypes with specific mechanisms that can be targeted for personalized treatment. Future studies will look into other gene sets not related to dopamine that could help explain other brain and clinical measures in patients with schizophrenia, and further slice through the cloud of heterogeneity.