Mapping causal pathways from genetics to neuropsychiatric disorders using genome-wide imaging genetics: Current status and future directions.
Le BD., Stein JL.
Imaging genetics aims to identify genetic variants associated with the structure and function of the human brain. Recently, collaborative consortia have been successful in this goal, identifying and replicating common genetic variants influencing gross human brain structure as measured through magnetic resonance imaging. In this review, we contextualize imaging genetic associations as one important link in understanding the causal chain from genetic variant to increased risk for neuropsychiatric disorders. We provide examples in other fields of how identifying genetic variant associations to disease and multiple phenotypes along the causal chain has revealed a mechanistic understanding of disease risk, with implications for how imaging genetics can be similarly applied. We discuss current findings in the imaging genetics research domain, including that common genetic variants can have a slightly larger effect on brain structure than on risk for disorders like schizophrenia, indicating a somewhat simpler genetic architecture. Also, gross brain structure measurements share a genetic basis with some, but not all, neuropsychiatric disorders, invalidating the previously held belief that they are broad endophenotypes, yet pinpointing brain regions likely involved in the pathology of specific disorders. Finally, we suggest that in order to build a more detailed mechanistic understanding of the effects of genetic variants on the brain, future directions in imaging genetics research will require observations of cellular and synaptic structure in specific brain regions beyond the resolution of magnetic resonance imaging. We expect that integrating genetic associations at biological levels from synapse to sulcus will reveal specific causal pathways impacting risk for neuropsychiatric disorders.