Genetic association and differential expression of PITX2 with acute appendicitis

Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value = 8.82 × 10(−14)) and was replicated in an independent sample of Caucasians (59 affected, 607 unaffected; p value = 0.005). Meta-analysis of the associated variant across our two cohorts and cohorts from Iceland and the Netherlands (in which this association had previously been reported) showed strong cumulative evidence of association (OR = 1.12; 95% CI 1.09–1.14; p value = 1.81 × 10(−23)) and some evidence for effect heterogeneity (p value = 0.03). Eight other loci were identified at suggestive significance in the discovery GWAS. Associations were followed up by measuring gene expression across resected appendices with varying levels of inflammation (N = 75). We measured expression of 27 genes based on physical proximity to the GWAS signals, evidence of being targeted by eQTLs near the signals according to RegulomeDB (score = 1), or both. Four of the 27 genes (including PITX2) showed significant evidence (p values < 0.0033) of differential expression across categories of appendix inflammation. An additional ten genes showed nominal evidence (p value < 0.05) of differential expression, which, together with the significant genes, is more than expected by chance (p value = 6.6 × 10(−12)). PITX2 impacts morphological development of intestinal tissue, promotes an anti-oxidant response, and its expression correlates with levels of intestinal bacteria and colonic inflammation. Further studies of the role of PITX2 in appendicitis are warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-018-1956-2) contains supplementary material, which is available to authorized users.