Meta-Analyses of splicing and expression quantitative trait loci identified susceptibility genes of glioma Journal Article
| Authors: | Patro, C. P. K.; Nousome, D.; The Glioma International Case Control Study (GICC); Lai, R. K. |
| Contributor: | Olson, S. H. |
| Article Title: | Meta-Analyses of splicing and expression quantitative trait loci identified susceptibility genes of glioma |
| Abstract: | Background: The functions of most glioma risk alleles are unknown. Very few studies had evaluated expression quantitative trait loci (eQTL), and insights of susceptibility genes were limited due to scarcity of available brain tissues. Moreover, no prior study had examined the effect of glioma risk alleles on alternative RNA splicing. Objective: This study explored splicing quantitative trait loci (sQTL) as molecular QTL and improved the power of QTL mapping through meta-analyses of both cis eQTL and sQTL. Methods: We first evaluated eQTLs and sQTLs of the CommonMind Consortium (CMC) and Genotype-Tissue Expression Project (GTEx) using genotyping, or whole-genome sequencing and RNA-seq data. Alternative splicing events were characterized using an annotation-free method that detected intron excision events. Then, we conducted meta-analyses by pooling the eQTL and sQTL results of CMC and GTEx using the inverse variance-weighted model. Afterward, we integrated QTL meta-analysis results (Q < 0.05) with the Glioma International Case Control Study (GICC) GWAS meta-analysis (case:12,496, control:18,190), using a summary statistics-based mendelian randomization (SMR) method. Results: Between CMC and GTEx, we combined the QTL data of 354 unique individuals of European ancestry. SMR analyses revealed 15 eQTLs in 11 loci and 32 sQTLs in 9 loci relevant to glioma risk. Two loci only harbored sQTLs (1q44 and 16p13.3). In seven loci, both eQTL and sQTL coexisted (2q33.3, 7p11.2, 11q23.3 15q24.2, 16p12.1, 20q13.33, and 22q13.1), but the target genes were different for five of these seven loci. Three eQTL loci (9p21.3, 20q13.33, and 22q13.1) and 4 sQTL loci (11q23.3, 16p13.3, 16q12.1, and 20q13.33) harbored multiple target genes. Eight target genes of sQTLs (C2orf80, SEC61G, TMEM25, PHLDB1, RP11-161M6.2, HEATR3, RTEL1-TNFRSF6B, and LIME1) had multiple alternatively spliced transcripts. Conclusion: Our study revealed that the regulation of transcriptome by glioma risk alleles is complex, with the potential for eQTL and sQTL jointly affecting gliomagenesis in risk loci. QTLs of many loci involved multiple target genes, some of which were specific to alternative splicing. Therefore, quantitative trait loci that evaluate only total gene expression will miss many important target genes. © Copyright © 2021 Patro, Nousome, The Glioma International Case Control Study (GICC) and Lai. |
| Keywords: | human tissue; unclassified drug; human cell; single nucleotide polymorphism; molecular genetics; glioma; gene expression; epidermal growth factor receptor; protein; gene locus; genotype; gene frequency; genome-wide association study; neural stem cell; gene mapping; messenger rna; genetic susceptibility; immunoprecipitation; telomerase reverse transcriptase; ribosome rna; meta analysis; quantitative trait loci; rna splicing; rna sequence; genetic database; meta-analysis; protein rna binding; cyclin dependent kinase inhibitor 2b; brain tissue; janus kinase 1; mendelian randomization analysis; gwas; human; article; whole genome sequencing; eqtl; rna sequencing; long untranslated rna; glioblastoma cell line; intron retention; expression quantitative trait locus; regulator of telomere elongation helicase 1; chromatin immunoprecipitation sequencing; h9 cell line; sqtl; summary data based mendelian randomization analyses; adp ribosylation factor related protein 1; akt serine threonine kinase 3; apobec1 complementation factor; archain 1; ccr4 not transcription complex subunit 4; cdkn2b antisense rna 1; chromosome 2 open reading frame 80; chromosome 22 open reading frame 23; ctd nuclear envelope phosphatase 1 regulatory subunit 1; dead box helicase 24; dead box helicase 6; decoy receptor 3; electron transfer flavoprotein subunit alpha; elongation factor tu gtp binding domain containing 2; fus rna binding protein; glucocorticoid modulatory element binding protein 2; heat repeat containing 3; heterogeneous nuclear ribonucleoproteins c1 c2; initiation factor 4b; iron regulatory protein 1; lck interacting transmembrane adaptor 1; lipase maturation factor 1; monocarboxylate transporter 3; peptidylprolyl isomerase g; pleckstrin homology like domain family b member 1; polypyrimidine tract binding protein 1; pre mrna processing factor 31; protein interacting with protein kinase c; pumilio rna binding family member 1; rna binding motif protein 22; rna binding motif protein 4b; rna binding protein 34; s phase cyclin a associated protein; sec61 translocon subunit gamma; serine arginine protein 55; serine arginine rich splicing factor 1; serine arginine rich splicing factor 4; splicing factor arginine serine rich 3; stathmin 3; sterile alpha motif domain containing 4a; transmembrane protein 25; u1 small nuclear ribonucleoprotein a; zinc finger protein 638; splicing quantitative trait loci |
| Journal Title: | Frontiers in Genetics |
| Volume: | 12 |
| ISSN: | 1664-8021 |
| Publisher: | Frontiers Media S.A. |
| Date Published: | 2021-04-14 |
| Start Page: | 609657 |
| Language: | English |
| DOI: | 10.3389/fgene.2021.609657 |
| PROVIDER: | scopus |
| PMCID: | PMC8081720 |
| PUBMED: | 33936159 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
