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. 2017 Jun 6;8:15789.
doi: 10.1038/ncomms15789.

Sequence Variants in ARHGAP15, COLQ and FAM155A Associate With Diverticular Disease and Diverticulitis

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Free PMC article

Sequence Variants in ARHGAP15, COLQ and FAM155A Associate With Diverticular Disease and Diverticulitis

Snaevar Sigurdsson et al. Nat Commun. .
Free PMC article

Abstract

Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10-18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10-10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10-11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study.

Conflict of interest statement

S.S., K.F.A., P.S., S.G., G.H.H., S.O., A.S., T.R., T.T., G.Th., G.M., U.T., D.F.G., I.J. and K.S. are employees of deCODE Genetics/Amgen Inc. The remaining authors declares no competing financial interests.

Figures

Figure 1
Figure 1. Manhattan plot for genome-wide association results.
The P values (−log10) are plotted against their respective positions on each chromosome. P value thresholds for the different annotation classes are indicated with gray lines. For intronic/intergenic variants outside DNAse hypersensitivity site: P=1.1 × 10−9, intronic/intergenic variants within DNAse hypersensitivity site P=2.3 × 10−9, low-impact variants: P=5.3 × 10−9, medium-impact variants: P=7.4 × 10−8 and high-impact variants: P=3.7 × 10−7. The plots were created using qqman: an R package for visualizing GWAS results using Q–Q and Manhattan plots. (a) GWAS results for diverticular disease (cases n=5,292; controls n=245,951). ARHGAP15 P=5.1 × 10−12, COLQ P=2.8 × 10−9 and FAM155A P=8.0 × 10−5. (b) GWAS results for diverticulitis (cases n=2,764 cases; controls n=245,951) (excluding diverticular disease). ARHGAP15 P=6.0 × 10−9, COLQ P=3.0 × 10−9 and FAM155A P=1.7 × 10−7. The three variants rs4662344, rs7609897 and rs67153654 are annotated as intronic variant within a DNase hypersensitivity site, giving the class-specific Bonferroni threshold for genome-wide significance as P<2.3 × 10−9 (ref. 12).
Figure 2
Figure 2. Regional association plot for the three associated loci.
P values (−log10) for the marker associations are plotted against the chromosomal location (human genome build 38) at each locus. The colour of the genomic variants reflects the linkage disequilibrium (r2 LD) with the lead SNP in the Icelandic dataset. The blue line indicates recombination rates from the Icelandic recombination map for males and females. Known genes and exons are shown below using data from the UCSC genes track. The plot was created with a stand-alone version of the LocusZoom Software. (a) Locus plot for the marker rs4662344-T (chr2:143,591,289) at the ARHGAP15 locus. P values plotted are for association with diverticular disease in Iceland. (b) Locus plot for the marker rs7609897-T (chr3:15,461,174) in intron of the COLQ gene. P values plotted are for the association with diverticular disease in Iceland. (c) Locus plot for the marker rs67153654-A (chr13:107,572,636) at the FAM155A locus. P values plotted are for the association with diverticulitis in Iceland.

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