Analysis of overlapping genetic association in type 1 and ty
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Given the potential shared etiology 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 etiology could be made, with the potential to develop therapeutic strategies to treat or prevent both diseases simultaneously. Alternatively, if a genetic signal co-localizes with divergent effect directions, it could provide valuable biological insight into how the association affects the two diseases differently.

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), researchers identified all regions of 0.5 Mb that contained variants associated with both diseases. In each region, they performed forward stepwise logistic regression to identify independent association signals, then examined co-localization of each type 1 diabetes signal with each type 2 diabetes signal using coloc. Any association with a co-localization posterior probability of more than 0.9 was considered a genuine shared association with both diseases.

-- Of the 81 association signals from 42 genetic regions that showed association with both type 1 and type 2 diabetes, four association signals co-localized between both diseases: (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-localization on chromosome 9p24.2, near the GLIS3 gene, in this case with a concordant direction of effect.

Conclusively, four of five association signals that co-localize between type 1 diabetes and type 2 diabetes are in opposite directions, suggesting a complex genetic relationship between the two diseases.