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.

Highlights

  • Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction

  • We hypothesized that some genetic variants that are associated with risk of chronic obstructive pulmonary disease (COPD) contribute to the disease by altering RNA splicing

  • We identified genetic variants that are associated both with COPD risk and RNA splicing

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Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction. Genetic factors have been shown to contribute to COPD susceptibility, with the best characterized example being SERPINA1, the causal gene for α1-antitrypsin deficiency [1,2,3,4,5]. Genome-wide association studies (GWAS) have been used to identify common genetic variants associated with many complex diseases, including COPD. These studies have identified multiple well-replicated genome-wide significant loci, including a locus on 15q25 (CHRNA3/ CHRNA5/IREB2), FAM13A, HHIP, CYP2A6 and HTR4 [6,7,8,9,10]. A recent large meta-analysis identified twenty-two genome-wide significant loci in COPD, of which 13 were newly genome-wide significant [11, 12]. Since most GWAS variants are located in noncoding regions, it is possible that these variants could contribute to COPD susceptibility through transcriptional regulation of target genes, amongst other possible mechanisms

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