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. 2021 May 29;30(10):952-960.
doi: 10.1093/hmg/ddab067.

Genome-wide polygenic risk score for retinopathy of type 2 diabetes

Iain S Forrest  1   2   3   4 , Kumardeep Chaudhary  1   3   4 , Ishan Paranjpe  1   4   5 , Ha My T Vy  1   4 , Carla Marquez-Luna  1   4 , Ghislain Rocheleau  1   4 , Aparna Saha  1   3 , Lili Chan  1   3   6 , Tielman Van Vleck  3 , Ruth J F Loos  1   4   7 , Judy Cho  1   3   4   6 , Louis R Pasquale  8   9 , Girish N Nadkarni  1   3   4   5   6 , Ron Do  1   3   4
Affiliations

Genome-wide polygenic risk score for retinopathy of type 2 diabetes

Iain S Forrest et al. Hum Mol Genet. .

Abstract

Diabetic retinopathy (DR) is a common consequence in type 2 diabetes (T2D) and a leading cause of blindness in working-age adults. Yet, its genetic predisposition is largely unknown. Here, we examined the polygenic architecture underlying DR by deriving and assessing a genome-wide polygenic risk score (PRS) for DR. We evaluated the PRS in 6079 individuals with T2D of European, Hispanic, African and other ancestries from a large-scale multi-ethnic biobank. Main outcomes were PRS association with DR diagnosis, symptoms and complications, and time to diagnosis, and transferability to non-European ancestries. We observed that PRS was significantly associated with DR. A standard deviation increase in PRS was accompanied by an adjusted odds ratio (OR) of 1.12 [95% confidence interval (CI) 1.04-1.20; P = 0.001] for DR diagnosis. When stratified by ancestry, PRS was associated with the highest OR in European ancestry (OR = 1.22, 95% CI 1.02-1.41; P = 0.049), followed by African (OR = 1.15, 95% CI 1.03-1.28; P = 0.028) and Hispanic ancestries (OR = 1.10, 95% CI 1.00-1.10; P = 0.050). Individuals in the top PRS decile had a 1.8-fold elevated risk for DR versus the bottom decile (P = 0.002). Among individuals without DR diagnosis, the top PRS decile had more DR symptoms than the bottom decile (P = 0.008). The PRS was associated with retinal hemorrhage (OR = 1.44, 95% CI 1.03-2.02; P = 0.03) and earlier DR presentation (10% probability of DR by 4 years in the top PRS decile versus 8 years in the bottom decile). These results establish the significant polygenic underpinnings of DR and indicate the need for more diverse ancestries in biobanks to develop multi-ancestral PRS.

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Figures

Figure 1
Figure 1
Forest plot of PRS on OR of DR diagnosis in different ancestries and meta-analysis in BioMe. Four box plots depict the middle 50% estimate (blue boxes) and corresponding 95% CI (horizontal lines) of PRS on OR of DR among individuals in four ancestries, with the size of each box proportional to the sample size of its representative ancestry. One diamond plot depicts the point estimate (dashed vertical line) and corresponding 95% CI (horizontal points) of PRS on OR of DR in a fixed-effects meta-analysis of all four ancestries. Euro, European ancestry; Afric, African ancestry; Hisp, Hispanic ancestry; Other, other ancestry (includes Asian, Native American and miscellaneous ancestries); Meta, meta-analysis of all ancestries.
Figure 2
Figure 2
Cox proportional hazards model of time to DR diagnosis stratified by PRS in BioMe. The model adjusted for age, sex, body mass index, 20 genetic principal components, history of hypertension and glucose levels. PRS was associated with increased probability of DR over time (hazard ratio = 1.13 for DR diagnosis per SD increase in PRS, 95% CI 1.05–1.21; P = 9.4 × 10−4). Three Kaplan–Meier curves depict the probability of being DR-free over time in the bottom decile (orange), middle 50% (blue) and top decile (red) groups of PRS. Time to DR diagnosis was calculated as the difference in days between the date of diagnosis of T2D and the date of diagnosis of DR.
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