bims-agalsp 2023-03-12 papers

Issue of 2023–03–12
three papers selected by
Dongmeng Wang, King’s College

Elife. 2023 Mar 09. pii: e81097. [Epub ahead of print]12

Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations.

Chiara Auwerx, Marie C Sadler, Tristan Woh, Alexandre Reymond, Zoltán Kutalik, Eleonora Porcu.

Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 216 transcript-metabolite-trait causal triplets involving 26 medically relevant phenotypes. Among these associations, 58% were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. This allowed the identification of biologically relevant pathways, such as between ANKH and calcium levels mediated by citrate levels and SLC6A12 and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found, thanks to the increase in power conferred by integrating multiple omics layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.

Keywords: Mediation; Mendelian Randomization; gene expression; genetics; genomics; human; metabolomics

DOI: https://doi.org/10.7554/eLife.81097

Sci Rep. 2023 Mar 09. 13(1): 3950

Genome- and transcriptome-wide splicing associations with alcohol use disorder.

Spencer B Huggett, Ami S Ikeda, Qingyue Yuan, Chelsie E Benca-Bachman, Rohan H C Palmer.

Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study utilized RNA-sequencing data on alcohol use disorder (AUD) in four brain regions (n = 56; ages 40-73; 100% 'Caucasian'; PFC, NAc, BLA and CEA) and genome-wide association data on AUD (n = 435,563, ages 22-90; 100% European-American). Polygenic scores of AUD were associated with AUD-related alternative mRNA splicing in the brain. We identified 714 differentially spliced genes between AUD vs controls, which included both putative addiction genes and novel gene targets. We found 6463 splicing quantitative trait loci (sQTLs) that linked to the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of AUD was enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of AUD and other drug use traits that unveiled specific genes for follow-up and splicing correlations across SUDs. Finally, we showed that differentially spliced genes between AUD vs control were also associated with primate models of chronic alcohol consumption in similar brain regions. Our study found substantial genetic contributions of alternative mRNA splicing in AUD.

DOI: https://doi.org/10.1038/s41598-023-30926-z

Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Mar 03. pii: S1388-1981(23)00017-3. [Epub ahead of print] 159293

STAU1 promotes adipogenesis by regulating the alternative splicing of Pparγ2 mRNA.

Shuo Jiang, Xuanyu Meng, Hao Gu, Jialei Sun, Siyuan Chen, Zhe Chen, Dihui Liu, Xiaodi Liang.

During adipocyte differentiation, specific genes such as peroxisome proliferator-activated receptor γ (PPARγ) are transcribed and post-transcriptional pre-mRNA is processed into mature mRNA. Since Pparγ2 pre-mRNAs contain putative binding sites for STAUFEN1 (STAU1), which can affect the alternative splicing of pre-mRNA, we hypothesized that STAU1 might regulate the alternative splicing of Pparγ2 pre-mRNA. In this study, we found that STAU1 affects the differentiation of 3 T3-L1 pre-adipocytes. Through RNA-seq analysis, we confirmed that STAU1 can regulate alternative splicing events during adipocyte differentiation, mainly through exon skipping, which suggests that STAU1 is mainly involved in exon splicing. In addition, gene annotation and cluster analysis revealed that the genes affected by alternative splicing were enriched in lipid metabolism pathways. We further demonstrated that STAU1 can regulate the alternative splicing of Pparγ2 pre-mRNA and affect the splicing of exon E1 through RNA immuno-precipitation, photoactivatable ribonucleotide enhanced crosslinking and immunoprecipitation, and sucrose density gradient centrifugation assays. Finally, we confirmed that STAU1 can regulate the alternative splicing of Pparγ2 pre-mRNA in stromal vascular fraction cells. In summary, this study improves our understanding of the function of STAU1 in adipocyte differentiation and the regulatory network of adipocyte differentiation-related gene expression.

Keywords: Adipogenesis; Alternative splicing; Peroxisome proliferator-activated receptor gamma; RNA sequencing; Staufen1

DOI: https://doi.org/10.1016/j.bbalip.2023.159293