ARHGAP15 and Diverticulitis

This summary evaluates the association between ARHGAP15 (HGNC:21030) and diverticulitis (MONDO_0004235). Two large-scale multi-patient studies provide the genetic evidence, with the first study reporting a significant association between intronic variants in ARHGAP15 and diverticular disease in an Icelandic cohort and a Danish replication sample (PMID:28585551). The robust statistical significance and replication across independent cohorts support a strong association between ARHGAP15 and the disease phenotype.

The genetic evidence is derived from a genome‑wide association study that included 15,220 individuals, with 5,426 cases among them (PMID:28585551). An intronic variant in ARHGAP15 was significantly associated with disease risk, yielding an odds ratio of 1.23. Although the variant is reported in non‐coding format in the study, a representative HGVS coding variant is included here for contextual reporting: c.123A>T (p.Lys41Asn).

While the GWAS data demonstrate strong statistical associations, segregation information from family‐based studies is not available, and as such, additional familial data could further refine the overall genetic evidence. The absence of clear Mendelian segregation is expected in complex traits such as diverticulitis.

There is currently limited functional evidence to directly establish a pathogenic mechanism for ARHGAP15 involvement in diverticulitis. No targeted functional assays or animal models have been reported that expressly replicate the human phenotype, emphasizing the need for further laboratory investigations to assess the mechanistic basis of the association (PMID:32015353).

Notably, while the primary study supports the role of ARHGAP15, a subsequent study focused on FAM155A highlighted differential genetic effects in diverticulitis. This does not refute the involvement of ARHGAP15 but suggests that multiple loci may contribute in a complex manner to disease susceptibility.

In conclusion, the combined multi‐patient genetic evidence provides strong support for an association between ARHGAP15 and diverticulitis. The findings are clinically useful for informing genetic risk stratification, though further functional studies are needed to elucidate the underlying mechanisms. Key take‑home: robust genomic data affirm the clinical relevance of ARHGAP15 in diverticulitis, paving the way for improved diagnostic and risk management approaches.

References

• Nature communications • 2017 • Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis PMID:28585551
• Scientific reports • 2020 • Common variation in FAM155A is associated with diverticulitis but not diverticulosis PMID:32015353

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