Genome-wide association studies identify shared mechanisms between hypertension and type 2 diabetes independent of adiposity

Abstract

BackgroundHypertension and type 2 diabetes (T2D) are two of the most frequently co-occurring long-term conditions, but their shared mechanisms are not fully understood, often being attributed to adiposity pathways. Here, we aimed to identify shared genetic mechanisms independent of adiposity. MethodsWe performed genome-wide association study meta-analyses of T2D and, separately, hypertension. We investigated the bidirectional causal relationship using Mendelian randomisation and quantified genetic correlation before and after accounting for common modifiable risk factors. We then applied a Bayesian GWAS approach to re-estimate SNP-disease effects after accounting for the causal genetic effects of adiposity-related traits. Colocalisation analysis identified shared causal genetic variants, and we investigated the biological pathways involved. ResultsWe observed a bidirectional causal relationship, and substantial genetic correlation between the two traits (rg = 0.48, 95%CI 0.45-0.52), which persisted after accounting for the genetic contributions of BMI, waist-hip ratio (WHR), and triglycerides (rg = 0.29, 95%CI 0.24-0.34). This indicated shared mechanisms beyond those captured by standard measures of adiposity. We found 98 genetic loci containing variants significantly associated with both hypertension and T2D; colocalisation analysis identified 37 that contained specific shared causal variants. Of these, eight remained statistically significant after adjusting for genetic measures of adiposity, and four were identified only after removing the causal effect of adiposity measures. Shared variants include an allele within PCSK7 associated with risk of both T2D and hypertension and with circulating PCSK7 protein levels, as well as a variant in the 3' untranslated region of ZNF101, within the TM6SF2 locus, likely reflecting regulatory variation affecting hepatic lipid metabolism and cardiometabolic traits. ConclusionsWe identify shared causal mechanisms between hypertension and T2D independent of several measures of adiposity. These findings, particularly PCSK7, could uncover novel interventions or opportunities for prevention of this co-occurring condition pair.