Cited 24 times since 2022 (8 per year) source: EuropePMC Diabetes care, Volume 45, Issue 3, 1 1 2022, Pages 674-683 Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts. DiCorpo D, LeClair J, Cole JB, Sarnowski C, Ahmadizar F, Bielak LF, Blokstra A, Bottinger EP, Chaker L, Chen YI, Chen Y, de Vries PS, Faquih T, Ghanbari M, Gudmundsdottir V, Guo X, Hasbani NR, Ibi D, Ikram MA, Kavousi M, Leonard HL, Leong A, Mercader JM, Morrison AC, Nadkarni GN, Nalls MA, Noordam R, Preuss M, Smith JA, Trompet S, Vissink P, Yao J, Zhao W, Boerwinkle E, Goodarzi MO, Gudnason V, Jukema JW, Kardia SLR, Loos RJF, Liu CT, Manning AK, Mook-Kanamori D, Pankow JS, Picavet HSJ, Sattar N, Simonsick EM, Verschuren WMM, Willems van Dijk K, Florez JC, Rotter JI, Meigs JB, Dupuis J, Udler MS
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, termed 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.
