Schizophrenia (SZ) is a common, severe, highly heritable psychotic disorder. The vast majority of patients suffering from SZ remains ill after the initial episode, suffering from chronic and severely incapacitating symptoms, and is unable to work. Thus, there is a need for pathophysiologically based treatments that improved biological insights should enable. Genome-wide association studies (GWAS) have been successful in uncovering individual common susceptibility loci reproducibly associated with SZ, with the results suggesting a numerous and diverse set of possible etiological mechanisms. Identifying the underlying causal variants, risk genes, and etiological gene networks has proven difficult, like for most other complex disorders. Because many GWAS SNPs associated with SZ (as with other complex disorders) are either intergenic or otherwise uncorrelated with obvious candidate functional variation such as missense SNPs, it appears likely that many risk variants in these loci are regulatory in nature. These observations prompted us to examine transcriptomic signatures in our European ancestry (EA) Molecular Genetics of SZ (MGS) case-control sample (RC2MH90030), which converged with previous GWAS results in implicating the major histocompatibility (MHC) region, and also identified novel genes. We propose here to study the African-American (AA) MGS case-control sample. Much of the genetic research on SZ, including GWAS, has been biased towards EA samples, and the resulting findings, and their translational utility, may not fully extrapolate to other ancestral groups. Besides merely diversifying SZ research beyond EAs, there also are significant scientific advantages in studying an AA sample. We will generate expression signatures via RNAseq to seek transcripts associated with SZ, analyze the underlying regulatory DNA variants (i.e., expression quantitative trait nucleotides, eQTNs), and assess their association with SZ. We will then perform validation testing of lymphoblastoid cell line (LCL) findings in neuronal tissues, and will functionally characterize a set of most important eQTNs.
We aim at detecting SZ susceptibility genes specific to AA samples (i.e., undetectable in EA samples), and to inform our previous EA findings (for overlapping SZ susceptibility genes). The proposed study is expected to identify new loci influencing SZ risk, benefit from the reduced extent of linkage disequilibrium (LD) in Africans, reveal causal genes in already identified GWAS loci, and enable further study of the underlying etiological mechanisms. We will rapidly share our results and data with the scientific community through a dbGaP sponsored mechanism to maximize the return on this research investment not only in psychiatric genetics, but also due to general research interest since it wil provide the most detailed and precisely localized eQTNs map in an AA sample.
Schizophrenia is a disorder with largely unknown biology, and is also resilient to treatment. This project will identify gene expression characteristics associatd with schizophrenia in an understudied population, African Americans, from a large sample of cases and controls. The knowledge gathered from our proposed study will yield light into the pathophysiology of schizophrenia, and may offer novel leads to new or improved knowledge- based treatment strategies.
