Functional genomic investigation of complement signaling in the human brain

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Large-scale genome-wide association studies (GWAS) have successfully identified hundreds of genetic risk factors associated with common but complex neuropsychiatric disorders. Increased expression of complement component 4A (C4A) is one such factor that has been implicated in schizophrenia (SCZ) pathophysiology. However, the exact biological mechanisms in the human brain through which C4A—and the broader complement system—confer risk for SCZ remains unclear, due to its modest effect size and the lack of an appropriate experimental system adequately recapitulating disease-relevant context. Furthermore, whereas recent work has revealed substantial genetic overlap across neuropsychiatric disorders, little is known about the extent to which the complement system contributes to other disorders with shared genetic influences. Here, we propose a comprehensive set of functional genomic analyses to investigate the dysregulation of the complement system in the human brain and its relation to risk for autism spectrum disorder (ASD), SCZ, bipolar disorder (BD), and major depressive disorder (MDD). Given the strength of the C4A association with SCZ and the significant genetic correlations among these disorders, we hypothesize that the complement system will be broadly involved in the pathophysiology of neuropsychiatric disorders. To test this hypothesis, we will build upon our recent work with PsychENCODE to compile a large-scale genotype array and RNA-seq dataset of ~3,000 adult human brain samples, including several hundred individuals with ASD, SCZ, BD, and MDD. Leveraging this dataset, we will assess case-control differential expression of the complement system across these four disorders (Aim 1). Next, we will identify genetic regulators of complement system gene expression and determine their relation to established neuropsychiatric genetic risk factors (Aim 2). Finally, to begin to elucidate the functional role of the complement system during human brain development, we will examine how complement system gene expression is related to variability in brain structure and behavior in the Adolescent Brain Cognitive Development (ABCD) study and how these relationships are moderated by sex and environmental factors (Aim 3). Taken together, these aims will systematically characterize the overall contribution of the complement system to a broad range of genetically related neuropsychiatric disorders, which is in line with the NIMH mission to elucidate the neurobiological mechanisms underlying mental illnesses. These studies will be conducted by Minsoo Kim, a MD- PhD student at UCLA, and will provide comprehensive training in psychiatric genetics and genomics. Mentorship will be provided by Drs. Michael J. Gandal and Daniel H. Geschwind, experts in the fields of cross-disorder genomics and neurobehavioral genetics.