Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease

Abstract

Diverticular disease is common and has a high morbidity. Treatments are limited owing to the poor understanding of its pathophysiology. Here, to elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) from the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease; 39 of these loci are novel. Using data-driven expression-prioritized integration for complex traits (DEPICT), we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that have a role in vascular and mesenchymal biology. Genes in these associated loci have roles in immunity, extracellular matrix biology, cell adhesion, membrane transport and intestinal motility. Phenome-wide association analysis of the 42 variants shows a common etiology of diverticular disease with obesity and hernia. These analyses shed light on the genomic landscape of diverticular disease.

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Fig. 1: Study design.
Fig. 2: Enrichment analysis of tissue and cell types.
Fig. 3: Phenome-wide association matrix.
Fig. 4: Plausible biological pathways underlying risk loci associated with diverticular disease.

Data availability

The UKBB genomic and phenotypic data supporting this publication are publicly available from the Roslin Institute, University of Edinburgh (see URLs). The MGI genomic and phenotypic data are not publicly available owing to restrictions on participant privacy. MGI data can be made available upon reasonable request to the corresponding author with permission of the University of Michigan Institutional Review Board.

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Acknowledgements

We acknowledge the University of Michigan Medical School Central Biorepository/Michigan Genomics Initiative for providing biospecimen storage, management and distribution services in support of the research reported in this publication. L.H.M. is supported by the University of Michigan Department of Surgery. E.K.S., S.K.H., X.D. and Y.C. are supported by RO1 DK106621, RO1 DK107904, The University of Michigan Biological Sciences Scholars Program and The University of Michigan Department of Internal Medicine (all grants made to E.K.S.). T.H.P. is supported by Lundbeck Foundation and Benzon Foundation.

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L.H.M. contributed to study conception and design, data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript and final review of the submission. S.K.H. contributed to data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript and final review of the submission. X.D. contributed to data acquisition, analysis and interpretation, critical revision of the manuscript and final review of the submission. Y.C. contributed to data acquisition, analysis and interpretation, critical revision of the manuscript and final review of the submission. T.H.P. contributed to data acquisition, analysis and interpretation, critical revision of the manuscript and final review of the submission. E.K.S. contributed to study conception and design, data acquisition, analysis and interpretation, critical revision of the manuscript and final review of the submission.

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Correspondence to Lillias H. Maguire.

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Supplementary Text and Figures

Supplementary Figures 1–3

Reporting Summary

Supplementary Table 1

ICD-10 subcodes included within the root code K57

Supplementary Table 2

Complete list of variants associated with diverticular disease as identified in the UK Biobank (P < 1 × 10–5)

Supplementary Table 3

Complete list of genes associated with loci of interest and function, if known

Supplementary Table 4

Results of tissue and cell enrichment analysis performed with DEPICT in the UK Biobank (n = 27,444 cases, 382,284 controls)

Supplementary Table 5

Results of pathway enrichment analysis performed in DEPICT on the UK Biobank population (n = 27,444 cases, 382,284 controls)

Supplementary Table 6

Results of PheWAS performed in UK Biobank (n = 27,444 cases, 382,284 controls) for SNPs of interest

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Maguire, L.H., Handelman, S.K., Du, X. et al. Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease. Nat Genet 50, 1359–1365 (2018). https://doi.org/10.1038/s41588-018-0203-z

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