Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features.

Alice W Yu,J David Peery,Hyejung Won

doi:10.3390/genes12071062

Alice W Yu, J David Peery + Show 1 more

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https://doi.org/10.3390/genes12071062

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Journal: Genes	Publication Date: Jul 12, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: University of North Carolina at Chapel Hill

Abstract

Schizophrenia is a polygenic disorder with many genomic regions contributing to schizophrenia risk. The majority of genetic variants associated with schizophrenia lie in the non-coding genome and are thought to contribute to transcriptional regulation. Extensive transcriptomic dysregulation has been detected from postmortem brain samples of schizophrenia-affected individuals. However, the relationship between schizophrenia genetic risk factors and transcriptomic features has yet to be explored. Herein, we examined whether varying gene expression features, including differentially expressed genes (DEGs), co-expression networks, and central hubness of genes, contribute to the heritability of schizophrenia. We leveraged quantitative trait loci and chromatin interaction profiles to identify schizophrenia risk variants assigned to the genes that represent different transcriptomic features. We then performed stratified linkage disequilibrium score regression analysis on these variants to estimate schizophrenia heritability enrichment for different gene expression features. Notably, DEGs and co-expression networks showed nominal heritability enrichment. This nominal association can be partly explained by cellular heterogeneity, as DEGs were associated with the genetic risk of schizophrenia in a cell type-specific manner. Moreover, DEGs were enriched for target genes of schizophrenia-associated transcription factors, suggesting that the transcriptomic signatures of schizophrenia are the result of transcriptional regulatory cascades elicited by genetic risk factors.

Highlights

Genomic regions associated with schizophrenic risk have been identified through genome-wide association studies (GWASs) [1,2]
These categories include differentially expressed genes (DEGs; PsychENCODE consortium (PEC)), differentially expressed transcripts (DETs; PEC), gene co-expression modules (PEC and CommonMind consortium (CMC)), isoform-level co-expression modules (PEC), and the two measures of central hubness of genes within a module: kME, which captures the centrality of a gene in a given module (PEC), and kTotal, which captures the overall connectivity between pairs of genes (CMC)
We obtained DEGs from Gandal et al [11] and partitioned them into sets of up- and downregulated genes. These gene sets were subsequently converted to a list of SNPs on the basis of SNP–gene relationships defined by eQTL and Hi-C datasets of the dorsolateral prefrontal cortex (DLPFC) [13]

Summary

Introduction

Genomic regions associated with schizophrenic risk have been identified through genome-wide association studies (GWASs) [1,2]. Schizophrenia risk genes include several transcriptional regulators [7,8,9,10], suggesting potential transcriptional dysregulation in schizophrenia. In line with these findings, there has been a series of studies measuring the expression signatures of postmortem brain tissue from schizophrenia-affected individuals. While the association between schizophrenia-associated genetic risk factors and transcriptomic signatures has been consistently reported [8,11,13], the effect size of the observed association was small, suggesting that the contribution of genetic risk factors to transcriptomic dysregulation may be nominal These results warrant systematic investigation of the relationship between schizophrenia genetic risk factors and transcriptomic features.

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