A single nucleotide polymorphism genetic risk score to aid diagnosis of coeliac disease: a pilot study in clinical care

Summary Background Single nucleotide polymorphism–based genetic risk scores (GRS) model genetic risk as a continuum and can discriminate coeliac disease but have not been validated in clinic. Human leukocyte antigen (HLA) DQ gene testing is available in clinic but does not include non‐HLA attributed risk and is limited by discrete risk stratification. Aims To accurately characterise both HLA and non‐HLA coeliac disease genetic risk as a single nucleotide polymorphism–based GRS and evaluate diagnostic utility. Methods We developed a 42 single nucleotide polymorphism coeliac disease GRS from a European case‐control study (12 041 cases vs 12 228 controls) using HLA‐DQ imputation and published genome‐wide association studies. We validated the GRS in UK Biobank (1237 cases) and developed direct genotyping assays. We tested the coeliac disease GRS in a pilot clinical cohort of 128 children presenting with suspected coeliac disease. Results The GRS was more discriminative of coeliac disease than HLA‐DQ stratification in UK Biobank (receiver operating characteristic area under the curve [ROC‐AUC] = 0.88 [95% CIs: 0.87‐0.89] vs 0.82 [95% CIs: 0.80‐0.83]). We demonstrated similar discrimination in the pilot clinical cohort (114 cases vs 40 controls, ROC‐AUC = 0.84 [95% CIs: 0.76‐0.91]). As a rule‐out test, no children with coeliac disease in the clinical cohort had a GRS below 38th population centile. Conclusions A single nucleotide polymorphism–based GRS may offer more effective and cost‐efficient testing of coeliac disease genetic risk in comparison to HLA‐DQ stratification. As a comparatively inexpensive test it could facilitate non‐invasive coeliac disease diagnosis but needs detailed assessment in the context of other diagnostic tests and against current diagnostic algorithms.