Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia
Schizophrenia is characterized by severe impairments in cognition and brain function for which the underlying neural mechanisms are essentially unknown. This lack of knowledge is a critical barrier to progress in developing more effective treatments and early interventions to improve patient outcome. Recently, the schizophrenia genetics field has been ignited by the conclusive identification of genetic variants contributing to schizophrenia susceptibility from the consensus of large-scale genome-wide association studies (GWAS). The next logical and necessary step is to translate these findings into a better understanding of the neural processes that are impaired in schizophrenia, which is critical for the development of more effective therapeutics.
The GENUS Consortium proposes to take advantage of this long-awaited advancement in the schizophrenia genetics field to elucidate the underlying neurobiology of schizophrenia. Specifically, we will leverage the colossal efforts of large schizophrenia consortia such as the Psychiatric Genomics Consortium (PGC) that identified genetic loci and polygenic variation associated with schizophrenia risk. The weight of evidence for these independent and polygenic risk variants across many schizophrenia samples far exceeds that of previously implicated candidate genes, and warrants comprehensive investigations to determine their causal function in schizophrenia.
The central hypothesis of the GENUS Consortium is that genetic variation that contributes to schizophrenia susceptibility also contributes to impaired brain function. Our objective is to examine the genetic risk variants identified by prior large-scale GWAS and other studies for association with variation in brain-based phenotypes that are abnormal in schizophrenia.
In recent years, a number of research groups around the world have begun conducting cognitive and neuroimaging studies of schizophrenia patients, persons at risk for developing schizophrenia, and healthy individuals, in addition to obtaining GWAS data. By combining cognitive and neuroimaging data from these groups we can achieve the large samples of thousands of individuals, which are necessary to detect the modest gene effect sizes that are common for complex traits.
The expected outcome of this research is a clearer definition of the function of existing schizophrenia risk variants in contributing to neural aberrations that are directly causal in the disease. The results will have a significant impact on the schizophrenia research and clinical fields by linking the genetic etiology of schizophrenia with specific neural mechanisms, which will implicate new leads for the development of better prediction, intervention, and treatment approaches.
- Examine existing schizophrenia and phenotype GWAS genes for association with brain function as indexed by cognitive and neuroimaging phenotypes. Single Nucleotide Polymorphisms (SNPs) will be selected based on prior GWAS evidence for association with schizophrenia, cognition, or neuroanatomical traits surpassing the genome-wide significance threshold.
- Clarify the role of polygenic variation in impaired brain function in schizophrenia as indexed by cognitive and neuroimaging phenotypes. Starting with a polygenic set of SNPs identified by the Psychiatric Genomics Consortium (PGC) that in aggregate significantly contribute to schizophrenia risk, subsets of biologically-related genetic variants will be selected and their association with cognitive and neuroimaging phenotypes will be examined.
- Identify phenotypic profiles associated with schizophrenia risk variants. Genetic variation may have pleiotropic effects on brain-based phenotypes due to modulation of a common neural mechanism that underlies the phenotypes. Multivariate analysis across neuropsychological and imaging domains will be used to identify clusters of traits associated with independent genetic variants and polygenic variants that may point to overlapping genetic relationships between different brain functions that are impaired in schizophrenia.