224-LB: Shared Genetic Architecture of Complication of Diabetes

Introduction: Approximately 1 in 10 Americans have diabetes (~37 million), 90-95% of which is type 2 diabetes (T2D). T2D is the leading cause of kidney disease (DKD), retinopathy, neuropathy, peripheral vascular disease (PVD), stroke, and coronary heart disease (CHD). Inherited variation is known to contribute to the risk of T2D complications, however, the relationship between and role of genetic variants on risk across complications is not fully understood.

Method: We used data from our recently completed genomic investigations of a broad set of 18 diabetic complications, which included ~64K T2D subjects across five race-ethnic groups (Admixed Americas-, African-, East Asian-, European- and South Asian-ancestry samples) from 24 studies retrieved from dbGaP and UKBB biomedical repositories. Using these GWAS summary statistics, we calculated the genetic correlation between complication pairs with Z-scores (beta/SE) to investigate their relationship and guide post hoc pleiotropy analysis.

Results: Genetic correlation analysis revealed four clusters of complications that shared strong correlation. Pleiotropy analysis identified three novel pleiotropic loci for T2D complications at SNX17 (Albuminuria, CHD & PVD), UBE2E2 (Albuminuria & end-stage kidney disease) and GCKR (Albuminuria, DKD, retinopathy, fatty liver disease, CHD & PVD).

Conclusion: These findings support the hypothesis of shared heritability between diabetic complications. Additional work is needed to increase genetic discovery of pleiotropic variants across diabetic complications.