The importance of increasing population diversity in genetic studies of type 2 diabetes and related glycaemic traits

Type 2 diabetes has a global prevalence, with epidemiological data suggesting that some populations have a higher risk of developing this disease. However, to date, most genetic studies of type 2 diabetes and related glycaemic traits have been performed in individuals of European ancestry. The same is true for most other complex diseases, largely due to use of ‘convenience samples’. Rapid genotyping of large population cohorts and case–control studies from existing collections was performed when the genome-wide association study (GWAS) ‘revolution’ began, back in 2005. Although global representation has increased in the intervening 15 years, further expansion and inclusion of diverse populations in genetic and genomic studies is still needed. In this review, I discuss the progress made in incorporating multi-ancestry participants in genetic analyses of type 2 diabetes and related glycaemic traits, and associated opportunities and challenges. I also discuss how increased representation of global diversity in genetic and genomic studies is required to fulfil the promise of precision medicine for all. Graphical abstract

Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

<p><a></a><a>There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the <i>GIPR</i> locus. Using Bayesian multi-trait colocalisation, we identified a <i>GIPR</i> missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP_coloc>0.97; PP explained by the candidate variant; PP_explained=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in <i>APOE</i> (rs7412; distance to E354 ~770Kb; R² with E354 = 0.004; PP_coloc>0.99; PP_explained=1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (OR per copy of E354 after adjustment 1.03; 95% CI, 1.02, 1.04; P=0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272, (R² with E354=0.27), an intronic variant in <i>SNRPD2</i> (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the <i>GIPR</i> region, and higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.</a></p>

Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

<p><a></a><a>There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the <i>GIPR</i> locus. Using Bayesian multi-trait colocalisation, we identified a <i>GIPR</i> missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP_coloc>0.97; PP explained by the candidate variant; PP_explained=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in <i>APOE</i> (rs7412; distance to E354 ~770Kb; R² with E354 = 0.004; PP_coloc>0.99; PP_explained=1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (OR per copy of E354 after adjustment 1.03; 95% CI, 1.02, 1.04; P=0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272, (R² with E354=0.27), an intronic variant in <i>SNRPD2</i> (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the <i>GIPR</i> region, and higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.</a></p>

Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

<p><a></a><a>There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the <i>GIPR</i> locus. Using Bayesian multi-trait colocalisation, we identified a <i>GIPR</i> missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP_coloc>0.97; PP explained by the candidate variant; PP_explained=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in <i>APOE</i> (rs7412; distance to E354 ~770Kb; R² with E354 = 0.004; PP_coloc>0.99; PP_explained=1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (OR per copy of E354 after adjustment 1.03; 95% CI, 1.02, 1.04; P=0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272, (R² with E354=0.27), an intronic variant in <i>SNRPD2</i> (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the <i>GIPR</i> region, and higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.</a></p>

Deciphering how early life adiposity influences breast cancer risk using Mendelian randomization

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigated 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood body size, only IGF-1, testosterone, age at menarche and age at menopause influenced breast cancer risk. However, accounting for those traits in multivariable Mendelian randomization showed that the protective effect of childhood body size still remained. This suggests either a direct effect of childhood body size on breast cancer risk or mediation via other pathways not considered. Our work presents a framework for the systematic exploration of potential biological mediators of disease in Mendelian randomization analysis.

Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification

Homeostatic control of blood glucose requires different physiological responses in the fasting and post-prandial states. We reasoned that glucose measurements under non-standardised conditions (random glucose, RG) may capture diverse glucoregulatory processes more effectively than previous genome-wide association studies (GWAS) of fasting glycaemia or after standardised glucose loads. Through GWAS meta-analysis of RG in 493,036 individuals without diabetes of diverse ethnicities we identified 128 associated loci represented by 162 distinct signals, including 14 with sex-dimorphic effects, 9 discovered through trans-ethnic analysis, and 70 novel signals for glycaemic traits. Novel RG loci were particularly enriched in expression in the ileum and colon, indicating a prominent role for the gastrointestinal tract in the control of blood glucose. Functional studies and molecular dynamics simulations of coding variants of GLP1R, a well-established type 2 diabetes treatment target, provided a genetic framework for optimal selection of GLP-1R agonist therapy. We also provided new evidence from Mendelian randomisation that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Thus, our approach based on RG GWAS provided wide-ranging insights into the biology of glucose regulation, diabetes complications and the potential for treatment stratification.

TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes

Proteins involved in the spaciotemporal regulation of GLUT4 trafficking represent potential therapeutic targets for the treatment of insulin resistance and type 2 diabetes. A key regulator of insulin- and exercise-stimulated glucose uptake and GLUT4 trafficking is TBC1D1. This study aimed to identify proteins that regulate GLUT4 trafficking and homeostasis via TBC1D1. Using an unbiased quantitative proteomics approach, we identified proteins that interact with TBC1D1 in C2C12 myotubes including VPS13A and VPS13C, the Rab binding proteins EHBP1L1 and MICAL1, and the calcium pump SERCA1. These proteins associate with TBC1D1 via its phosphotyrosine binding (PTB) domains and their interactions with TBC1D1 were unaffected by AMPK activation, distinguishing them from the AMPK regulated interaction between TBC1D1 and AMPKα1 complexes. Depletion of VPS13A or VPS13C caused a post-transcriptional increase in cellular GLUT4 protein and enhanced cell surface GLUT4 levels in response to AMPK activation. The phenomenon was specific to GLUT4 because other recycling proteins were unaffected. Our results provide further support for a role of the TBC1D1 PTB domains as a scaffold for a range of Rab regulators, and also the VPS13 family of proteins which have been previously linked to fasting glycaemic traits and insulin resistance in genome wide association studies.