Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease

Abstract

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.

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Data availability

The sample-phenotype information, summary statistics from the association analysis per cohort, and the results from the meta-analysis have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001003805.

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Acknowledgements

We thank the Argentinian clinicians for recruiting individuals with CeD to provide blood samples; the genotyping facility of the UMCG for help in generating the Immunochip data; Jeffrey Barrett, Rinse Weersma, and Ross McManus for providing genotypes from extra controls and the Irish cohort; all the participating CeD patients and controls; and Kate Mc Intyre for editing the manuscript.

Funding

This work was supported by an ERC Advanced grant [FP/2007-2013/ERC grant 2012-322698], an NWO Spinoza prize grant [NWO SPI 92-266], NWO-VIDI grants [864.13.013] to JF and [016.178.056] to AZ, Hypatia grant to VK from Radboud UMC, NWO Gravitation Netherlands Organ-on-Chip Initiative [024.003.001] to CW, a European Union Seventh Framework Programme grant (EU FP7) TANDEM project [HEALTH-F3-2012-305279] to CW and a ERC Starting Grant [715772] to AZ. GT is supported by the Wellcome Trust grant WT206194.

Consortium for the study of genetic associations of celiac disease in Latin-America

Emilia Sugai, María L. Moreno, Horacio Vázquez, Elsa Barrientos, Eduardo Mauriño, Martin Talamo, Analia Villarruel.

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Correspondence to Cisca Wijmenga.

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Ricaño-Ponce, I., Gutierrez-Achury, J., Costa, A.F. et al. Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease. Eur J Hum Genet 28, 313–323 (2020). https://doi.org/10.1038/s41431-019-0520-4

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