A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular–kidney complications

• DOI: 10.1007/s00125-024-06320-3
• Publication Date: 2024-11-23T06:47:19Z
• Authors: Chun-Kwan O; Baoqi Fan; Sandra T. F. Tsoi; Claudia H. T. Tam; Raymond Wan; Eric S. H. Lau; Mai Shi; Cadmon K. P. Lim; Gechang Yu; Jane P. Y. Ho; Elaine Y. K. Chow; Alice P. S. Kong; Risa Ozaki; Wing Yee So; Ronald C. W. Ma; Andrea O. Y. Luk; Juliana C. N. Chan
• Keywords: Minor allele frequency

Abstract Aims/hypothesis Monogenic diabetes is caused by rare mutations in genes usually implicated beta cell biology. Common variants of monogenic (MDG) may jointly influence the risk young-onset type 2 (YOD, diagnosed before age 40 years) and cardiovascular kidney events. Methods Using whole-exome sequencing data, we constructed a weighted polygenic score (wPRS) consisting 135 common (minor allele frequency >0.01) 34 MDG based on r >0.2 for linkage disequilibrium discovery case–control cohort 453 adults with YOD (median [IQR] 39.7 [34.9–46.9] 405 without 56.7 [50.3–61.0] years), followed validation an independent cross-sectional array-based genotyping prospective individuals Results In cohort, OR ranged from 1.00 to 2.61. (920 4910 non-YOD), top-10%-wPRS was associated 1.42 (95% CI 1.03, 1.95, p =0.033) compared bottom-10%-wPRS. 2313 [IQR]: 53.4 [45.4–61.7] years; disease duration 4.0 [1.0–9.0] observed median (IQR) 17.5 (14.4–21.8) years, standardised wPRS increased HR incident events (1.16 [95% 1.06, 1.27], =0.001), (1.09 1.02, 1.16], =0.013) cardiovascular–kidney (1.10 =0.003). ‘bottom-20%-wPRS plus baseline <5 years’ group as referent, ‘top-20%-wPRS 5 <10 had unadjusted adjusted 1.60 1.17, 2.19, =0.003) 1.62 1.16, 2.26, =0.005), respectively, 1.38 0.97, 1.98, =0.075) 1.06 0.72, 1.57, =0.752) ≥10 group. Conclusions/interpretation Graphical