The recent explosion in the identification of genetic risk factors for autism spectrum disorder (ASD) has revealed many genes that are likely to be involved in these debilitating disorders. These efforts have resulted in exciting glimpses of molecular pathways emerging from the data (e.g., chromatin remodeling and synaptic transmission). Such examples illustrate how genes linked to ASD interact at the level of proteins to form networks involved in diverse areas of neurobiology. However, most of the identified genes do not fall into any well-defined cellular pathway, and it is now clear that the biology also includes largely uncharted and incomplete networks that are probably unique to the human brain. This is a key bottleneck for biological insight and therapeutic intervention.
Kasper Lage proposes to overcome these challenges through an integrative approach that leverages recent genetic discoveries with large-scale proteomics experiments to derive a human brain network of physically interacting proteins perturbed by ASD risk genes. This network will serve as an accelerator of functional insight from current and future psychiatric genetics data, and sits at the infliction point of transformative technology and data that have just become mature.
To create this network, Lage’s laboratory, together with collaborators like Kevin Eggan in the Stanley Center, will capitalize on new, unbiased genetic data to choose corresponding ‘index’ proteins as the starting point of network analysis. Lage’s team will then exploit new proteomics technologies to map the tissue-specific quantitative interactions of these index proteins at high resolution. Lage believes that this ASD-risk protein network will be important to interpret current and future studies in psychiatric genetics, and it will immediately contribute to guiding therapeutic insight and intervention. The proteomics experiments will be further validated in induced pluripotent stem-cell-derived human neurons so that the interactions of index proteins are placed within a biologically meaningful cellular (and human) context. Lage’s team will experimentally follow up on discoveries from these analyses using reductionist neurobiological assays.
This project will establish a robust statistical methodology, which is currently lacking, for integrative analyses of experimental proteomics networks and genetic data. It will also provide a model for others to use in any area of genetics in the future. Overall, the goal of this project is to leverage the genetic analyses to map, validate and follow up on the brain-specific cellular networks perturbed by genetics in ASD. This will catalyze biological insight and inform future therapeutic opportunities.