Diabetic retinopathy and other diabetes complications arise more commonly among individuals of African ancestry compared with other ancestry groups. To gain insight into genetic factors influencing the risk of diabetes complications, particularly among individuals of African ancestry, Breeyear et al. performed multi-ancestry genome-wide association analyses, comprising 68,169 individuals with diabetic retinopathy (cases) and 129,188 individuals with diabetes who did not have diabetic retinopathy (controls). They identified nine loci associated with diabetic retinopathy at genome-wide significance, including a coding variant in G6PD that reached significance both in the combined analysis across all ancestry groups and in the non-Hispanic African subgroup. This G6PD variant, which confers glucose-6-phosphate dehydrogenase deficiency, has previously been associated with protection against severe malaria and is present at a higher frequency in populations of African ancestry. In the current study, this G6PD variant was found to be associated with higher plasma glucose levels, which mediate the effect of this variant on increased risk of diabetic retinopathy. Phenome-wide analyses across two biobanks provided additional evidence that this G6PD variant confers increased risk of other diabetes complications, including diabetic nephropathy. These findings suggest a fitness trade-off at G6PD between protection from severe malaria and risk of other adverse health outcomes.
Original reference: Nat. Med. https://doi.org/10.1038/s41591-024-03089-1 (2024)
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