ArticlePLoS genetics2019
Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- Overlap between COPD genetic association results and transcriptional quantitative trait loci.HGG advances · 2026Article
- HHIP protein interactions in lung cells provide insight into COPD pathogenesis.Human molecular genetics · 2025Article
- Characterisation of a COPD-associated nephronectin (The European respiratory journal · 2025Article
- Lung Transcriptomics Link Emphysema to Barrier Dysfunction and Macrophage Subpopulations.American journal of respiratory and critical care medicine · 2025Article
- A scoping review of statistical methods to investigate colocalization between genetic associations and microRNA expression in osteoarthritis.Osteoarthritis and cartilage open · 2024Article
- Article
- Blood Biomarkers of Emphysema: What Can They Really Tell Us?American journal of respiratory and critical care medicine · 2024Article
- Blood-based Transcriptomic and Proteomic Biomarkers of Emphysema.American journal of respiratory and critical care medicine · 2024Article
- FBXO38 regulates macrophage polarization to control the development of cancer and colitis.Cellular & molecular immunology · 2023Article
- Bridging the splicing gap in human genetics with long-read RNA sequencing: finding the protein isoform drivers of disease.Human molecular genetics · 2022Review
- Identification of Candidate mRNA Isoforms for Prostate Cancer-Risk SNPs Utilizing Iso-eQTL and sQTL Methods.International journal of molecular sciences · 2022Article
- Genetics of chronic obstructive pulmonary disease: understanding the pathobiology and heterogeneity of a complex disorder.The Lancet. Respiratory medicine · 2022Review
- The Importance of a Genome-Wide Association Analysis in the Study of Alternative Splicing Mutations in Plants with a Special Focus on Maize.International journal of molecular sciences · 2022Review
- Subcutaneous adipose tissue splice quantitative trait loci reveal differences in isoform usage associated with cardiometabolic traits.American journal of human genetics · 2022Article
- A spotter's guide to SNPtic exons: The common splice variants underlying some SNP-phenotype correlations.Molecular genetics & genomic medicine · 2022Article
- FBXO38 Ubiquitin Ligase Controls Sertoli Cell Maturation.Frontiers in cell and developmental biology · 2022Article
- Chromatin Landscapes of Human Lung Cells Predict Potentially Functional Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Variants.American journal of respiratory cell and molecular biology · 2021Article
- Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.Nature genetics · 2021Article
- Exploiting the GTEx resources to decipher the mechanisms at GWAS loci.Genome biology · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
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Authors and funding
19 authors at 4 institutions in 2 countries.
Funding
Abstract
While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 55.3% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.
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