Comprehensive and integrative analyses identify TYW5 as a schizophrenia risk gene

Abstract

Background Identifying the causal genes at the risk loci and elucidating their roles in schizophrenia (SCZ) pathogenesis remain significant challenges. To explore risk variants associated with gene expression in the human brain and to identify genes whose expression change may contribute to the susceptibility of SCZ, here we report a comprehensive integrative study on SCZ. Methods We systematically integrated the genetic associations from a large-scale SCZ GWAS (N = 56,418) and brain expression quantitative trait loci (eQTL) data (N = 175) using a Bayesian statistical framework (Sherlock) and Summary data-based Mendelian Randomization (SMR). We also measured brain structure of 86 first-episode antipsychotic-naive schizophrenia patients and 152 healthy controls with the structural MRI. Results Both Sherlock (P = 3. 38 × 10−6) and SMR (P = 1. 90 × 10−8) analyses showed that TYW5 mRNA expression was significantly associated with risk of SCZ. Brain-based studies also identified a significant association between TYW5 protein abundance and SCZ. The single-nucleotide polymorphism rs203772 showed significant association with SCZ and the risk allele is associated with higher transcriptional level of TYW5 in the prefrontal cortex. We further found that TYW5 was significantly upregulated in the brain tissues of SCZ cases compared with controls. In addition, TYW5 expression was also significantly higher in neurons induced from pluripotent stem cells of schizophrenia cases compared with controls. Finally, combining analysis of genotyping and MRI data showed that rs203772 was significantly associated with gray matter volume of the right middle frontal gyrus and left precuneus. Conclusions We confirmed that TYW5 is a risk gene for SCZ. Our results provide useful information toward a better understanding of the genetic mechanism of TYW5 in risk of SCZ.

Identification of Sex-Specific Genetic Variants Associated With Tau PET

“…TYW5 (tRNA-YW synthesizing protein 5) encodes protein TYW5, a tRNA hydroxylase that is involved in epigenetic modification in the brain, 40 and has been reported highly expressed in the dorsolateral prefrontal cortex in patients with schizophrenia as a risk gene of schizophrenia, which is related to a higher risk of AD. 41 In addition, a genome-wide association study study reported the associations between an SNP in TYW5 and sleep apnea. 42 Because sleep apnea has been reported to be related to tau aggregation in preclinical and prodromal stages of AD, 43 we hypothesize that the significant associations between TYW5 and tau pathology in women in this study might be related to sleep apnea, which suggests a potential avenue for future research.…”

To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families

“…TYW5 is involved in the carbon hydroxylation of wybutosine (yW), a hypermodified guanosine nucleoside that is essential for correct phenylalanine codon translation [41], into hydroxywybutosine (OHyW) in tRNA (Phe) [134]. While the regulatory functions of its action have not been dissected, TYW5 has been recently identified as a schizophrenia risk gene [135]. Again, the biological functions of this protein should be more deeply examined.…”

Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes

“…The eQTL SNPs can play critical roles in complex trait phenotypes. Indeed, studies of psychiatric disorders integrating GWAS and eQTLs have successfully identified novel genetic loci that were not detected with GWAS alone (e.g., major depressive disorder (MDD) and schizophrenia) [ 20 , 24 – 28 ]. Additionally, a recent study showed psychiatric disorders-related genetic variants are enriched at regulatory regions (e.g., histone modifications, DNA accessibility, and enhancer-promoter interaction regions affecting gene expression) [ 29 ] Although genomic studies integrating eQTLs in regulatory regions have been performed for several psychiatric disorders, to the best of our knowledge, this approach has not been taken for suicide death.…”