Abstract
Autoimmune diseases (AIDs) are polygenic diseases affecting 7–10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h2). SNP-h2 estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h2 in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
Highlights
Autoimmune diseases (AIDs) are polygenic diseases affecting 7–10% of the population in the Western Hemisphere with few effective therapies
We excluded samples for low genotyping rates, cryptic relatedness and genetic outliers, leaving a cohort consisting of 4,956 cases distributed across nine paediatric AIDs (pAIDs) and 27,451 unrelated shared population-based controls (Table 1)
The results show that SNP-h2 estimates were significantly higher for the pAID cohorts as compared with those obtained for the non-immune-mediated disease EPI (Fig. 1a and Supplementary Tables 1 and 2)
Summary
Autoimmune diseases (AIDs) are polygenic diseases affecting 7–10% of the population in the Western Hemisphere with few effective therapies. Our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts. GWAS have identified single-nucleotide polymorphisms (SNPs) across hundreds of loci as being associated with an increased risk of developing AI5–12 These findings, coupled with those from epidemiological studies, strongly support the existence of (i) an overlapping ‘AI disease genetic landscape’[13,14] and (ii), a shared heritability across these diseases. We systematically quantified the narrow-sense heritability, h2, as well as the pairwise joint heritability of pAIDs attributable to common genomic variation using a single-centre accrued cohort of over 5,000 unrelated cases composed of nine independent pAIDs and 36,000 shared, population-based healthy controls. We contextualize these findings alongside a comprehensive review of available literature and epidemiological data sets, illustrate a method for quantifying genetic risk factor sharing across pAIDs, and provide considerations for how such genetic data can aid disease prediction
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