Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts

Abstract

OBJECTIVE Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters labeled: β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.

Genetics of Type 2 Diabetes: Past, Present, and Future

“…PRSs of top-weighted loci from the five clusters were associated with increased risk of coronary artery disease, stroke, and elevated systolic blood pressure. A recent study [ 77 ] reported that increased obesity and lipodystrophy cluster were significantly associated with hypertension and elevated blood pressure. The lipodystrophy and liver/lipid cluster included genetic variants of GCKR, PNPLA3 , and TM6SF2 , and were significantly associated with coronary artery disease.…”

Phenotypic and genetic classification of diabetes

“…Additionally, these type 2 diabetes partitioned polygenic scores have been shown to be associated with comorbid metabolic diseases. For instance, hypertension was more likely in people with a higher score in the 'obesity' cluster or the 'lipodystrophy' cluster; people with a higher 'liver/lipid' polygenic score were more likely to have CKD but less likely to have coronary artery disease [61,62].…”

“…Given the high discriminatory ability of the type 1 diabetes score, there is a potential role for it in improving diabetes classification in practice, for example, by applying it in patients with diagnostic uncertainty. In contrast, both the full and cluster-specific polygenic scores for type 2 diabetes currently have insufficient predictive ability to warrant use in standard practice [38,62]. While all five subgroups in the genetically driven subclassification of type 2 diabetes described in [61] had distinct replicable clinical phenotypes, phenotypic differences between subgroups were quantitatively small and unlikely to be appreciated clinically on an individual patient level [62].…”

“…In contrast, both the full and cluster-specific polygenic scores for type 2 diabetes currently have insufficient predictive ability to warrant use in standard practice [38,62]. While all five subgroups in the genetically driven subclassification of type 2 diabetes described in [61] had distinct replicable clinical phenotypes, phenotypic differences between subgroups were quantitatively small and unlikely to be appreciated clinically on an individual patient level [62]. Nevertheless, polygenic scores related to type 2 diabetes have the potential to become more predictive in future iterations, particularly with the inclusion of rarer genetic variation [64], which may lead to future use in clinical practice.…”

“…The efforts aimed at identifying genetic subtypes of type 2 diabetes can also potentially be applied to stratify people at risk of type 2 diabetes before they develop symptomatic disease. For instance, in an analysis of large cohorts containing people with and without diabetes, people with an elevated 'lipodystrophy' cluster polygenic score had an increased risk of hypertension even after adjusting for type 2 diabetes status [62], suggesting that pathway-specific polygenic scores can predict risk of specific combinations of future diseases (e.g. type 2 diabetes and hypertension).…”