Imaging genomics of functional brain networks

During rest, brain activity is intrinsically synchronized between different brain regions, forming networks of coherent activity. These functional networks (FNs), consisting of multiple regions widely distributed across lobes and hemispheres, appear to be a fundamental theme of neural organization in mammalian brains.

Despite hundreds of studies detailing this phenomenon, the genetic and molecular mechanisms supporting these functional networks remain undefined. Previous work has mostly focused on polymorphisms in candidate genes, or used a twin study approach to demonstrate heritability of aspects of resting-state connectivity. The recent availability of high spatial resolution post-mortem brain gene expression datasets, together with several large-scale imaging genetics datasets, which contain joint in-vivo functional brain imaging data and genotype data for several hundred subjects, opens intriguing data analysis avenues.

Using novel cross-modal graph-based statistics, we show that functional brain networks defined with resting-state fMRI can be recapitulated using measures of correlated gene expression, and that the relationship is not driven by gross tissue types. The set of genes we identify is significantly enriched for certain types of ion channels and synapse-related genes. We validate results by showing that polymorphisms in this set significantly correlate with alterations of in-vivo resting-state functional connectivity in a group of 259 adolescents. We further validate results on another species by showing that our list of genes is significantly associated with neuronal connectivity in the mouse brain.  These results provide convergent, multimodal evidence that resting-state functional networks emerge from the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function.

Functional brain networks are also known to be perturbed in a variety of neurological and neuropsychological disorders, including Alzheimer's and schizophrenia. Given this link between disease and networks, and the fact that many brain disorders have genetic contributions, it seems that functional brain networks may be an interesting endophenotype for clinical use. We discuss the translational potential of the imaging genomics techniques we developed.