Journal Article

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

Zhou, Xiaobo, Silverman, Edwin K., Parker, Margaret M., Saferali, Aabida, Hersh, Craig P., Dai, Xiangpeng, Castaldi, Peter J., Sakornsakolpat, Phuwanat, Chase, Robert P., Lamb, Andrew, Beaty, Terri H., Wei, Wenyi, Hobbs, Brian D., de Jong, Kim, Yun, Jeong H., Cho, Michael H., Boezen, Marike H.

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aged / Aged, 80 and over / Alternative Splicing / Apoptosis / Arylsulfotransferase - genetics / Asthma / Biochemistry / Biology and Life Sciences / Blood / Chromosome 5 / Chromosomes / Chronic obstructive lung disease / Chronic obstructive pulmonary disease / Consortia / Critical care / Cyclin-Dependent Kinases - genetics / Disease susceptibility / EDTA / Epidemiology / Exons / F-Box Proteins - genetics / Female / Funding / Gene expression / Genes / Genetic aspects / Genetic engineering / Genetic polymorphisms / Genetic Predisposition to Disease / Genetic research / Genetics / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Genomics / Health aspects / Hospitals / Humans / Investigations / Localization / Lung diseases / Male / Medical research / Medical schools / Medicine / Medicine and Health Sciences / Middle Aged / Novels / Obstructive lung disease / Polymorphism, Single Nucleotide / Pulmonary Disease, Chronic Obstructive - genetics / Quantitative genetics / Quantitative Trait Loci / Ribonucleic acid / RNA / RNA sequencing / Sequence Analysis, RNA / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Software / Type 2 diabetes / Womens health