The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities

Abstract

Type 2 diabetes (T2D) is epidemiologically associated with a wide range of non-cardiovascular comorbidities, yet their shared etiology has not been fully elucidated. Leveraging eight non-overlapping mechanistic clusters of T2D genetic profiles, each representing distinct biological pathways, we investigate putative causal links between cluster-stratified T2D genetic predisposition and 21 non-cardiovascular comorbidities. Most of the identified putative causal effects are driven by distinct T2D genetic clusters. For example, the risk-increasing effects of T2D genetic predisposition on cataracts and erectile dysfunction are primarily attributed to obesity and glucose regulation mechanisms, respectively. When surveyed in populations across the globe, we observe opposing effect directions for depression, asthma and chronic obstructive pulmonary disease between populations. We identify a putative causal link between T2D genetic predisposition and osteoarthritis. To underscore the translational potential of our findings, we intersect high-confidence effector genes for osteoarthritis with targets of T2D-approved drugs and identify metformin as a potential candidate for drug repurposing in osteoarthritis.

Extended Figure 1:

Results of cluster-stratified two-sample Mendelian randomization (MR) analysis of genetic predisposition to type 2 diabetes (T2D) on non-cardiovascular comorbidities risk. Causal estimates are expressed as the odds ratio (OR) of each comorbidity per doubling (2-fold increase) in genetically determined dichotomous T2D risk. Filled circles mark estimates with a q-value < 0.05 that passed all sensitivity analyses to assess the validity of the MR assumptions. (T2DGGI = Type 2 Diabetes Global Genomics Initiative; CI = confidence interval; PI = proinsulin; CTS = Carpal tunnel syndrome; ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder; PCOS = polycystic ovary syndrome; COPD = chronic obstructive pulmonary disease)

Extended Figure 2:

Results of the single-ancestry cluster-stratified two-sample Mendelian randomization (MR) analysis of genetic predisposition to type 2 diabetes (T2D) on non-cardiovascular comorbidities risk. Causal estimates are expressed as the odds ratio (OR) of each comorbidity per doubling (2-fold increase) in genetically determined dichotomous T2D risk. Filled circles mark estimates with a q-value < 0.05 that passed all sensitivity analyses to assess the validity of the MR assumptions. (T2DGGI = Type 2 Diabetes Global Genomics Initiative; CI = confidence interval; PI = proinsulin; COPD = chronic obstructive pulmonary disease)

Figure 1:

Overview of study design (MR = Mendelian randomization; T2D = type 2 diabetes; IVs = genetic instrumental variables; P = p-value).

Figure 2:

Results of two-sample Mendelian randomization (MR) analysis of genetic predisposition to type 2 diabetes (T2D) on non-cardiovascular comorbidity risk for the putative causal relationships (q-value < 0.05). Causal estimates are expressed as the odds ratio (OR) for each comorbidity per doubling (2-fold increase) in genetically determined dichotomous T2D risk. Filled circles mark estimates that passed the sensitivity analyses to assess the validity of the MR assumptions. (CI = confidence interval; CTS = Carpal tunnel syndrome; ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder; PCOS = polycystic ovary syndrome)

Figure 3:

Results of cluster-stratified two-sample Mendelian randomization (MR) analysis of genetic predisposition to type 2 diabetes (T2D) on non-cardiovascular comorbidities risk for the putative causal relationships (q-value < 0.05). Causal estimates are expressed as the odds ratio (OR) for each comorbidity per doubling (2-fold increase) in genetically determined dichotomous T2D risk. Filled circles mark estimates that passed all sensitivity analyses to assess the validity of the MR assumptions. (T2DGGI = Type 2 Diabetes Global Genomics Initiative; CI = confidence interval; PI = proinsulin; CTS = Carpal tunnel syndrome; ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder; PCOS = polycystic ovary syndrome; COPD = chronic obstructive pulmonary disease)

Figure 4:

Mendelian randomization (MR) results for different global genetic ancestry groups using cluster-stratified genetic predisposition to T2D and risk for T2D non-cardiovascular comorbidities (EUR=individuals genetically similar to Europeans, EAS=individuals genetically similar to East Asians) for the putative causal relationships (q-value < 0.05). Causal estimates are expressed as the odds ratio (OR) of each comorbidity per doubling (2-fold increase) in genetically determined dichotomous T2D risk. Filled circles mark robust estimates that passed all sensitivity analyses (T2DGGI = Type 2 Diabetes Global Genomics Initiative; CI = confidence interval; PI = proinsulin).