Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation
Abstract
Metabolic syndrome (MetSyn) is a cluster of dysregulated metabolic conditions that occur together to increase the risk for cardiometabolic disorders such as type 2 diabetes (T2D). One key condition associated with MetSyn, abdominal obesity, is measured by computing the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI). WHRadjBMI and T2D are complex traits with genetic and environmental components, which has enabled genome-wide association studies (GWAS) to identify hundreds of loci associated with both. Statistical genetics analyses of these GWAS have predicted that WHRadjBMI is a strong causal risk factor of T2D and that these traits share genetic architecture at many loci. To date, no variants have been described that are simultaneously associated with protection from T2D but with increased abdominal obesity. Here, we used colocalization analysis to identify genetic variants with a shared association for T2D and abdominal obesity. This analysis revealed the presence of five loci associated with discordant effects on T2D and abdominal obesity. The alleles of the lead genetic variants in these loci that were protective against T2D were also associated with increased abdominal obesity. We further used publicly available expression, epigenomic, and genetic regulatory data to predict the effector genes (eGenes) and functional tissues at the 2p21, 5q21.1, and 19q13.11 loci. We also computed the correlation between the subcutaneous adipose tissue (SAT) expression of predicted effector genes (eGenes) with metabolic phenotypes and adipogenesis. We proposed a model to resolve the discordant effects at the 5q21.1 locus. We find that eGenes gypsy retrotransposon integrase 1 (GIN1), diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2), and peptidylglycine alpha-amidating monooxygenase (PAM) represent the likely causal eGenes at the 5q21.1 locus. Taken together, these results are the first to describe a potential mechanism through which a genetic variant can confer increased abdominal obesity but protection from T2D risk. Understanding precisely how and which genetic variants confer increased risk for MetSyn will develop the basic science needed to design novel therapeutics for metabolic syndrome.
Data availability
The current manuscript is a computational investigation using publicly available data, so no data have been generated for this manuscript. All publicly obtained data sets are included in Supplementary Table 1. All analysis and figure-generating code uploaded to the following Github repository: https://github.com/aberrations/predicting-functional-mechanisms-discordant-loci.
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Meta-analysis of Body Fat Distribution GWASZenodo, 10.5281/zenodo.1251813.
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Meta-analysis of Type 2 Diabetes adjusted for BMI GWASDiagram Consortim, doi.org/10.1038/s41588-018-0241-6.
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GTEx Analysis V8 eQTLGoogle Cloud Platform, http://doi.org/10.1038/nature25160.
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Chromatin state predictions by tissue typeParker Lab Chromatin States, doi:10.1073/pnas.1621192114.
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STARNET eQTLOnline Portal, https://doi.org/0.1126/science.aad6970.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (2T32HL007284-46)
- Yonathan Tamrat Aberra
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tune H Pers, University of Copenhagen, Denmark
Version history
- Received: April 28, 2022
- Preprint posted: April 29, 2022 (view preprint)
- Accepted: May 31, 2023
- Accepted Manuscript published: June 30, 2023 (version 2)
- Version of Record published: June 16, 2023 (version 1)
Copyright
© 2023, Aberra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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