Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci

Abstract

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

Fig. 1

Manhattan plot of genome-wide association analysis of self-reported ulcers in UK Biobank

Fig. 2

Forest plot detailing estimates from GWAS, replication and lookup samples for selected variants. Each panel (a–f) represents the effect size per allele of the variant on the mouth ulcer phenotype for that study. Estimates are odds ratios and errors bars indicate the 95% confidence interval. UK Biobank, ALSPAC and AG = ulcer case control phenotype, TW = severity ulcer phenotype. Chr = Chromosome, Pos = Genomic position (build 37)

Fig. 3

Effect of predicted increased transcription of all genes on mouth ulcers. Each dot represented the effect of increased transcription (averaged across all tissue-specific predictions using MultiXcan) on mouth ulcers. The size of the dot indicates the largest effect size in any tissue. The standard deviation (SD) of tissue-specific Z-score is an indicator of tissue specificity with high values (yellow) indicating higher tissue specificity

Fig. 4

Genetic correlation between mouth ulcers and 222 traits. Each dot represented the Rg between mouth ulcers and an individual trait. The red line represents the Bonferroni-corrected multiple testing threshold at the 5% level. Error bars showing 95% confidence intervals and labels are included for traits that pass the multiple testing threshold