Fig. 5: pPS genetic risk extremes, T2D phenotype and complications.

Extremes of genetic risk association with age (a) and BMI (b) at diagnosis and progression to microvascular complications (c), among 9,771 individuals with T2D in the Genes & Health study. For a and b, box plots are presented contrasting individuals in the top and bottom 10% of the genetic risk distributions for three key pPSs (Obesity (n = 1,120 top decile/708 bottom decile), Beta Cell 2 (n = 1,309 top/566 bottom) and Lipodystrophy 1 (n = 1,164 top/635 bottom)) and a global T2D PRS (n = 1,385 top/508 bottom) and for individuals in the top and bottom 10% of both the Beta Cell 2 and Lipodystrophy distributions (n = 291 top/83 bottom) (right-most panel). Distributions for all individuals with T2D are presented in the left-most panel for comparison (n = 9,771). The middle line of each box represents the median value; the upper and lower bounds of the box represent the upper and lower quartiles; and the whiskers are defined as upper or lower quartile plus or minus 1.5 times the interquartile range. Distributions were compared using two-way ANOVA; all statistically significant associations remained after Bonferroni correction. For c, HRs are presented for each genetic risk extreme comparison, comparing complication-free survival from diagnosis between the bottom 10% of each pPS distribution (reference) and the top 10%. HRs were estimated from Cox proportional hazard models adjusted for sex and ancestry. After Bonferroni correction, only associations between nephropathy and Beta Cell 2 and T2D PRS remained significant (Supplementary Table 8). Further data are presented in Supplementary Table 9 (Schoenfeld residuals for survival models) and Extended Data Fig. 10 (illustrative Kaplan–Meier survival plots for positive results).