Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers
Iryna O. Fedko,
Michel G. Nivard,
Cross Consortia Pleiotropy (XC-Pleiotropy) Group, CHARGE Inflammation working group,
Daniel I Chasman,
Mike A Nalls,
Christopher J. O’Donnell,
Paul M Ridker,
Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators,
Dorret I. Boomsma
Posted 28 Dec 2018
bioRxiv DOI: 10.1101/496802
Posted 28 Dec 2018
Purpose: Homeostasis Model Assessment of β-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. Methods: We 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. Results: We 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=2.13×10-4/2.54×10-3). HOMA-IR/-B were also correlated with C-Reactive Protein (rg=0.33/0.28, P=4.67×10-3/3.65×10-3). HOMA-IR was additionally correlated with T2D (rg=0.56, P=2.31×10-9), glycated haemoglobin (rg=0.28, P=0.024) and adiponectin (rg=-0.30, P=0.012). Conclusion: Using 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.
- Downloaded 268 times
- Download rankings, all-time:
- Site-wide: 57,857 out of 89,266
- In genetics: 3,231 out of 4,618
- Year to date:
- Site-wide: 42,263 out of 89,266
- Since beginning of last month:
- Site-wide: 32,011 out of 89,266
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!