Systems genetics analyses reveals key genes related to behavioral traits in the striatum of CFW mice

The striatum plays a central role in directing many complex behaviors ranging from motor control to action choice and reward learning. In our study, we used 55 CFW mice with rapid decay linkage disequilibrium to systematically mine the striatum-related behavioral functional genes by analyzing their striatal transcriptomes and 79 measured behavioral phenotypic data. By constructing a gene co-expression network, we clustered the genes into 13 modules, with most of them being positively correlated with motor traits. Based on functional annotations as well as Fisher's exact and hypergeometric distribution tests, brown and magenta modules were identified as core modules. They were significantly enriched for striatal-related functional genes. Subsequent Mendelian randomization analysis verified the causal relationship between the core modules and dyskinesia. Through the intra-modular gene connectivity analysis, Adcy5 and Kcnma1 were identified as brown and magenta module hub genes, respectively. Knockouts of both Adcy5 and Kcnma1 lead to motor dysfunction in mice, and KCNMA1 acts as a risk gene for schizophrenia and smoking addiction in humans. We also evaluated the cellular composition of each module and identified oligodendrocytes in the striatum to have a positive role in motor regulation. Significance Statement The striatum plays a central role in guiding many complex behaviours from motor control to action selection and reward learning. Clinically, striatal dysfunction contributes to a variety of neurodegenerative diseases, including the well-known Alzheimer's disease and Huntington's disease. In our study, we systematically mined striatum-associated behavioural function genes using 55 CFW mice. And we validated our findings in multiple ways. We found that Adcy5 and Kcnma1 knockouts in mice lead to motor dysfunction in mice and that Kcnma1 is associated with schizophrenia, a finding that holds true in humans. Finally, we also assessed the role of different cells in the regulation of striatal behaviour and found that oligodendrocytes in the striatum play an active role in movement regulation.