A new study conducted by researchers at the Lieber Institute for Brain Development (LIBD), with colleagues in Italy, shows that reduced, or inhibited, expression of two specific genes in isolation improves cognition but, paradoxically, reduced expression of both genes at the same time has the opposite effect. This suggests that researchers should consider such gene-to-gene interactions when investigating cognition or other complex brain functions, write Francesco Papaleo, Ph.D.; Daniel R. Weinberger, M.D.; and colleagues in a paper published March, 2014 in the journal Molecular Psychiatry. The findings could help explain some of the difficulties in identifying genetic “causes” of psychiatric illnesses and other complex behavioral conditions, as single-gene studies would miss such interactions.
In this study, the genes analyzed have been linked to schizophrenia, and more specifically to higher order cognitive functions such as working memory, which keeps data and information at the ready for planning and decision-making. Both the genes—catechol-O-methyl transferase (COMT) and dystrobrevin-binding protein 1 (DTNBP1)—are involved in sending dopamine signals to the prefrontal cortex (PFC) region of the brain. Dopamine modulates working memory, and both too much and too little dopamine signaling have been shown to disrupt working memory.
This suggests that researchers should consider such gene-to-gene interactions when investigating cognition or other complex brain functions ... The findings could help explain some of the difficulties in identifying genetic “causes” of psychiatric illnesses and other complex behavioral conditions, as single-gene studies would miss such interactions.
Previous studies have shown that COMT enzymes de-activate dopamine. That means that when COMT activity decreases, dopamine signals increase and working memory improves. The reverse also holds true, which means there are beneficial and deleterious COMT variations. Similarly, decreases in DTNBP1 leads to improvements in working memory, although the mode of action differs from COMT in that less DTNBP1 increases receptors on the cell surface that allow more dopamine to act.
Counter-intuitively, though, when Papaleo and the research team looked at activity in both those genes in mice and humans, they found that decreasing activity in both hurt, rather than helped, performance on working memory tasks. They found this in both genetically-modified mouse models and in a human neuroimaging working memory test on 176 volunteers with genetic variations in COMT and DTNBP1. The results were strikingly similar with decreased activity in both genes leading to poorer performance on the task.