Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers

Fedko, I. O.; Nivard, M. G.; Hottenga, J.-J.; Zudina, L.; Cross Consortia Pleiotropy (XC-Pleiotropy) Group,; CHARGE Inflammation Working Group,; Balkhiyarova, Z.; Chasman, D. I.; Ganesh, S.; Huang, J.; Nalls, M. A.; O'Donnel, C. J.; Pare, G.; Ridker, P. M.; Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators,; Mägi, R.; Kaakinen, M.; Prokopenko, I.; Boomsma, D. I.

doi:10.1101/496802

bioRxiv · 10.1101/496802

Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers

Fedko, I. O.·Nivard, M. G.·Hottenga, J.-J.·Zudina, L.·Cross Consortia Pleiotropy (XC-Pleiotropy) Group,·CHARGE Inflammation Working Group,·Balkhiyarova, Z.·Chasman, D. I.·Ganesh, S.·Huang, J.·Nalls, M. A.·O'Donnel, C. J.·Pare, G.·Ridker, P. M.·Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators,·Mägi, R.·Kaakinen, M.·Prokopenko, I.·Boomsma, D. I.

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Abstract

PurposeHomeostasis Model Assessment of {beta}-cell function and Insulin Resistance (HOMA-B/-IR) indices are informative about the pathophysiological processes underlying type 2 diabetes (T2D). Data on both fasting glucose and insulin levels are required to calculate HOMA-B/-IR, leading to underpowered Genome-Wide Association studies (GWAS) of these traits.\n\nMethodsWe overcame such power loss issues by implementing Genome-Wide Inferred Statistics (GWIS) approach and subsequent dense genome-wide imputation of HOMA-B/-IR summary statistics with SS-imp to 1000 Genomes project variant density, reaching an analytical sample size of 75,240 European individuals without diabetes. We dissected mechanistic heterogeneity of glycaemic trait/T2D loci effects on HOMA-B/-IR and their relationships with 36 inflammatory and cardiometabolic phenotypes.\n\nResultsWe identified one/three novel HOMA-B (FOXA2)/HOMA-IR (LYPLAL1, PER4, PPP1R3B) loci. We detected novel strong genetic correlations between HOMA-IR/-B and Plasminogen Activator Inhibitor 1 (PAI-1, rg=0.92/0.78, P=2.13x10-4/2.54x10-3). HOMA-IR/-B were also correlated with C-Reactive Protein (rg=0.33/0.28, P=4.67x10-3/3.65x10-3). HOMA-IR was additionally correlated with T2D (rg=0.56, P=2.31x10-9), glycated haemoglobin (rg=0.28, P=0.024) and adiponectin (rg=-0.30, P=0.012).\n\nConclusionUsing innovative GWIS approach for composite phenotypes we report novel evidence for genetic relationships between fasting indices of insulin resistance/beta-cell function and inflammatory markers, providing further support for the role of inflammation in T2D pathogenesis.

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Fedko, I. O., Nivard, M. G., Hottenga, J.-J., Zudina, L., Cross Consortia Pleiotropy (XC-Pleiotropy) Group,, CHARGE Inflammation Working Group,, Balkhiyarova, Z., Chasman, D. I., Ganesh, S., Huang, J., Nalls, M. A., O'Donnel, C. J., Pare, G., Ridker, P. M., Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators,, Mägi, R., Kaakinen, M., Prokopenko, I., Boomsma, D. I.. 2018-12-28. Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers. https://doi.org/10.1101/496802

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