Analysis of overlapping genetic association in type 1 and type 2 diabetes

Springer Science and Business Media LLC - Tập 64 Số 6 - Trang 1342-1347 - 2021
Jamie Inshaw1, Carlo Sidore2, Francesco Cucca2, M. Irina Stefana1, Crouch Djm.1, Mark McCarthy3, Anubha Mahajan3, John A. Todd1
1JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
2Institute for Research in Genetics and Biomedicine (IRGB), Cagliari, Sardinia, Italy
3Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Tóm tắt

Abstract Aims/hypothesis Given the potential shared aetiology between type 1 and type 2 diabetes, we aimed to identify any genetic regions associated with both diseases. For associations where there is a shared signal and the allele that increases risk to one disease also increases risk to the other, inference about shared aetiology could be made, with the potential to develop therapeutic strategies to treat or prevent both diseases simultaneously. Alternatively, if a genetic signal co-localises with divergent effect directions, it could provide valuable biological insight into how the association affects the two diseases differently. Methods Using publicly available type 2 diabetes summary statistics from a genome-wide association study (GWAS) meta-analysis of European ancestry individuals (74,124 cases and 824,006 controls) and type 1 diabetes GWAS summary statistics from a meta-analysis of studies on individuals from the UK and Sardinia (7467 cases and 10,218 controls), we identified all regions of 0.5 Mb that contained variants associated with both diseases (false discovery rate <0.01). In each region, we performed forward stepwise logistic regression to identify independent association signals, then examined co-localisation of each type 1 diabetes signal with each type 2 diabetes signal using coloc. Any association with a co-localisation posterior probability of ≥0.9 was considered a genuine shared association with both diseases. Results Of the 81 association signals from 42 genetic regions that showed association with both type 1 and type 2 diabetes, four association signals co-localised between both diseases (posterior probability ≥0.9): (1) chromosome 16q23.1, near CTRB1/BCAR1, which has been previously identified; (2) chromosome 11p15.5, near the INS gene; (3) chromosome 4p16.3, near TMEM129 and (4) chromosome 1p31.3, near PGM1. In each of these regions, the effect of genetic variants on type 1 diabetes was in the opposite direction to the effect on type 2 diabetes. Use of additional datasets also supported the previously identified co-localisation on chromosome 9p24.2, near the GLIS3 gene, in this case with a concordant direction of effect. Conclusions/interpretation Four of five association signals that co-localise between type 1 diabetes and type 2 diabetes are in opposite directions, suggesting a complex genetic relationship between the two diseases. Graphical abstract

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Tài liệu tham khảo

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Springer Science and Business Media LLC

Tập 64 Số 6

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