While type 2 diabetes mellitus (T2DM) is commonly considered a putative causal risk factor for stroke, the effect of stroke on T2DM remains unclear. The intrinsic link underlying T2DM and stroke has not been thoroughly examined. We aimed to evaluate the phenotypic and genetic relationships underlying T2DM and stroke. We evaluated phenotypic associations using data from the UK Biobank (N = 472,050). We then investigated genetic relationships by leveraging genomic data in European ancestry for T2DM, with and without adjusting (adj) for BMI (T2DM: n = 74,124 case subjects/824,006 control subjects; T2DMadjBMI: n = 50,409 case subjects/523,897 control subjects), and for stroke (n = 73,652 case subjects/1,234,808 control subjects). We performed additional analyses using genomic data in East Asian ancestry for T2DM (n = 77,418 case subjects/356,122 control subjects) and for stroke (n = 27,413 case subjects/237,242 control subjects). Observational analyses suggested a significantly increased hazard of stroke among individuals with T2DM (hazard ratio 2.28 [95% CI 1.97–2.64]), but a slightly increased hazard of T2DM among individuals with stroke (1.22 [1.03–1.45]) which attenuated to 1.14 (0.96–1.36) in sensitivity analysis. A positive global T2DM-stroke genetic correlation was observed (rg = 0.35; P = 1.46 × 10−27), largely independent of BMI (T2DMadjBMI-stroke: rg = 0.27; P = 3.59 × 10−13). This was further corroborated by 38 shared independent loci and 161 shared expression-trait associations. Mendelian randomization analyses suggested a putative causal effect of T2DM on stroke in Europeans (odds ratio 1.07 [95% CI 1.06–1.09]), which remained significant in East Asians (1.03 [1.01–1.06]). Conversely, despite a putative causal effect of stroke on T2DM also observed in Europeans (1.21 [1.07–1.37]), it attenuated to 1.04 (0.91–1.19) in East Asians. Our study provides additional evidence to underscore the significant relationship between T2DM and stroke.

Article Highlights
  • Observational analyses suggest a doubled risk of stroke among individuals with type 2 diabetes mellitus (T2DM), but a slightly increased risk of T2DM among individuals with stroke that attenuates to nonsignificance in sensitivity analysis.

  • Genetic analyses reveal that both traits share a genetic basis at global and local genomic levels, as well as at individual genetic variant and gene levels, independent of BMI.

  • Mendelian randomization analyses suggest a putative causal effect of T2DM on stroke among Europeans that remains significant in East Asians, while the putative causal effect of stroke on T2DM among Europeans that attenuates to null in East Asians.

This article contains supplementary material online at https://doi.org/10.2337/figshare.23879079.

W.Z. and L.Z. contributed equally to this work.

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