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

Abstract

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.

Estimating population level disease prevalence using genetic risk scores

“…In diseases where one variant has the predominant effect on genetic risk e.g., HLA-DQ in coeliac disease, it might be possible to estimate prevalence using just this variant. However previous work has shown a GRS including the predominant variant as well as smaller effect variants has better discriminative ability than the predominant variant alone [15].…”

“…For each included genotype at the DQ locus, the odds ratio was derived from a previously described case-control dataset [18]. For each non-HLA locus, odds ratios from existing literature were used, and each weight was multiplied by individual risk allele dosage [15, 18].…”

“…The methods’ performance characteristics are evaluated over clinically relevant parameter ranges using genetic risk scores for type 1 diabetes (T1D), type 2 diabetes (T2D) and coeliac disease, as well as synthetic data. Clinical sample sets were taken from the following cohorts: T1D (n=1,963) and T2D (n=1,924) from the Wellcome Trust Case Control Consortium (WTCCCC) [8], Coeliac disease reference cases (n=12,018) from a combination of European studies [15] with non-cases (controls) and mixture (gluten-free diet) cohorts from UK Biobank (n=12,000 and n=12,757, respectively) [9].…”

Letter: improved parsimony of genetic risk scores for coeliac disease through refined HLA modelling

“…We read with interest the recent article by Sharp et al describing a single nucleotide polymorphism (SNP) genetic risk score (GRS) for coeliac disease 1 . The authors reported a 42 SNP model, combining the four established HLA risk alleles for coeliac disease (DQ2.5, DQ2.2, DQ8 and DQ7.5) and 38 non‐risk variants, which achieved a similar quality of prediction (AUC = 0.875) as the best previously reported GRS model with several hundreds of SNPs (AUC = 0.87‐0.89) 2 .…”

Beyond the HLA Genes in Gluten-Related Disorders

“…However, the possible use of non-HLA variants for the stratification of celiac patients has not yet been introduced in the clinical setting (Figure 1). A recent study selected 42 SNPs from a European case control study of about 12,000 patients and as many controls and showed that these SNPs can discriminate celiac disease more than HLA-DQ2/DQ8 in both adults (1,280 cases) and children (114 cases) cohorts (35). Moreover, since clinical presentation of celiac disease differs in siblings with similar HLA haplotypes, it has been suggested that non-HLA genes may play a significant role more so than HLA-concordance in siblings (36).…”