Prioritization of schizophrenia risk genes from GWAS results by integrating multi-omics data

Abstract

Schizophrenia (SCZ) is a polygenic disease with a heritability approaching 80%. Over 100 SCZ-related loci have so far been identified by genome-wide association studies (GWAS). However, the risk genes associated with these loci often remain unknown. We present a new risk gene predictor, rGAT-omics, that integrates multi-omics data under a Bayesian framework by combining the Hotelling and Box–Cox transformations. The Bayesian framework was constructed using gene ontology, tissue-specific protein–protein networks, and multi-omics data including differentially expressed genes in SCZ and controls, distance from genes to the index single-nucleotide polymorphisms (SNPs), and de novo mutations. The application of rGAT-omics to the 108 loci identified by a recent GWAS study of SCZ predicted 103 high-risk genes (HRGs) that explain a high proportion of SCZ heritability (Enrichment = 43.44 and $$p = 9.30 \times 10^{ - 9}$$ p = 9.30 × 1 0 − 9 ). HRGs were shown to be significantly ($$p_{\mathrm{adj}} = 5.35 \times 10^{ - 7}$$ p adj = 5.35 × 1 0 − 7 ) enriched in genes associated with neurological activities, and more likely to be expressed in brain tissues and SCZ-associated cell types than background genes. The predicted HRGs included 16 novel genes not present in any existing databases of SCZ-associated genes or previously predicted to be SCZ risk genes by any other method. More importantly, 13 of these 16 genes were not the nearest to the index SNP markers, and them would have been difficult to identify as risk genes by conventional approaches while ten out of the 16 genes are associated with neurological functions that make them prime candidates for pathological involvement in SCZ. Therefore, rGAT-omics has revealed novel insights into the molecular mechanisms underlying SCZ and could provide potential clues to future therapies.

Regulation of neuronal circHomer1 biogenesis by PKA/CREB/ERK-mediated pathways and effects of glutamate and dopamine receptor blockade.

“…Further research is needed to understand how our results can be translated into clinical effective strategies with an unprecedented mechanism that targets circHomer1 rather than Glu receptors. Since there are many genes known to be associated with SCZ 100 , 101 , the possibility of other circRNAs derived from such SCZ GWAS-linked genes should be examined. Regarding the role of circHomer1 in the regulation of SCZ-GWAS genes, our lab has previously demonstrated that in vivo circRNA-specific knockdown of circHomer1 in mouse PFC, modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease, attributing an upstream role for the SCZ-GWAS differential expression.…”

Pharmacogenetics and Schizophrenia—Can Genomics Improve the Treatment with Second-Generation Antipsychotics?

“…The papers analyzed in this review allow to state unequivocally that there are multiple alleles of genes directly related to SGAs response treatment—both those linked to pharmacokinetics, as well as genes associated with pharmacodynamics such as those involved in dopaminergic and serotonergic neurotransmitter systems. What is more, although they have not been the focus of this paper, multiple genes unrelated to traditional theories of schizophrenia genesis have also shown significant correlation with antipsychotic response [ 89 ].…”

Bridging the Gap Between Environmental Adversity and Neuropsychiatric Disorders: The Role of Transposable Elements

“…Schizophrenia is a complex neurodevelopmental disorder that is characterized by the presence of symptoms like delusions, hallucinations, disorganized speech, and negative affect ( James et al, 2018 ; NIMH, 2020 ). While the mechanistic underpinnings of schizophrenia can be genetically derived ( He et al, 2021 ) another risk factor is early life adversity, where certain environmental stressors (e.g., physical or emotional abuse, maternal infection) contribute to permeant changes in brain physiology and behavior ( Bennouna-Greene et al, 2011 ; Kraan, et al, 2015 ; Rokita et al, 2020 ; Matheson et al, 2013 ). Stress in the prenatal environment can increase one’s risk for developing psychiatric disorders including schizophrenia.…”