1. Computational and Systems Biology
  2. Genetics and Genomics

Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation

  1. Yonathan Tamrat Aberra  Is a corresponding author
  2. Lijiang Ma
  3. Johan LM Björkegren
  4. Mete Civelek  Is a corresponding author
  1. University of Virginia, United States
  2. Icahn School of Medicine at Mount Sinai, United States
https://doi.org/10.7554/eLife.79834
Share this article
Cite this article
  1. Yonathan Tamrat Aberra
  2. Lijiang Ma
  3. Johan LM Björkegren
  4. Mete Civelek
(2023)
Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation
eLife 12:e79834.
https://doi.org/10.7554/eLife.79834
  2. Download BibTeX
  3. Download .RIS

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.

The following previously published data sets were used
    1. Raulerson CK
    2. Ko A
    3. Kidd JC
    4. et al.
    (2019) METSIM eQTL
    FTP, https://doi.org/10.1016/j.ajhg.2019.09.001.
    https://mohlke.web.unc.edu/data/

Article and author information

Author details

  1. Yonathan Tamrat Aberra

    Department of Biomedical Engineering, University of Virginia, Charlottesville, United States
    For correspondence
    ya8eb@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6055-2291

  2. Lijiang Ma

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Johan LM Björkegren

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Mete Civelek

    Department of Biomedical Engineering, University of Virginia, Charlottesville, United States
    For correspondence
    mete@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8141-0284

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.

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.

Metrics

  • 1,118
    views
  • 208
    downloads
  • 2
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yonathan Tamrat Aberra
  2. Lijiang Ma
  3. Johan LM Björkegren
  4. Mete Civelek
(2023)
Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation
eLife 12:e79834.
https://doi.org/10.7554/eLife.79834

Share this article

https://doi.org/10.7554/eLife.79834

Categories and tags

Research organism

Further reading

    1. Genetics and Genomics
    2. Computational and Systems Biology

    Special Issue: Systems Genetics

    Edited by David James et al.
    Collection

    In this Special Issue we present a range of studies that showcase novel approaches that researchers are exploring to better decipher the link between genotype and phenotype.

    1. Computational and Systems Biology
    2. Physics of Living Systems

    Emergence of planar cell polarity from the interplay of local interactions and global gradients

    Divyoj Singh, Sriram Ramaswamy ... Mohd Suhail Rizvi
    Research Article Updated

    Planar cell polarity (PCP) – tissue-scale alignment of the direction of asymmetric localization of proteins at the cell-cell interface – is essential for embryonic development and physiological functions. Abnormalities in PCP can result in developmental imperfections, including neural tube closure defects and misaligned hair follicles. Decoding the mechanisms responsible for PCP establishment and maintenance remains a fundamental open question. While the roles of various molecules – broadly classified into ‘global’ and ‘local’ modules – have been well-studied, their necessity and sufficiency in explaining PCP and connecting their perturbations to experimentally observed patterns have not been examined. Here, we develop a minimal model that captures the proposed features of PCP establishment – a global tissue-level gradient and local asymmetric distribution of protein complexes. The proposed model suggests that while polarity can emerge without a gradient, the gradient not only acts as a global cue but also increases the robustness of PCP against stochastic perturbations. We also recapitulated and quantified the experimentally observed features of swirling patterns and domineering non-autonomy, using only three free model parameters - rate of protein binding to membrane, the concentration of PCP proteins, and the gradient steepness. We explain how self-stabilizing asymmetric protein localizations in the presence of tissue-level gradient can lead to robust PCP patterns and reveal minimal design principles for a polarized system.

    1. Computational and Systems Biology
    2. Neuroscience

    Basolateral amygdala oscillations enable fear learning in a biophysical model

    Anna Cattani, Don B Arnold ... Nancy Kopell
    Research Article

    The basolateral amygdala (BLA) is a key site where fear learning takes place through synaptic plasticity. Rodent research shows prominent low theta (~3–6 Hz), high theta (~6–12 Hz), and gamma (>30 Hz) rhythms in the BLA local field potential recordings. However, it is not understood what role these rhythms play in supporting the plasticity. Here, we create a biophysically detailed model of the BLA circuit to show that several classes of interneurons (PV, SOM, and VIP) in the BLA can be critically involved in producing the rhythms; these rhythms promote the formation of a dedicated fear circuit shaped through spike-timing-dependent plasticity. Each class of interneurons is necessary for the plasticity. We find that the low theta rhythm is a biomarker of successful fear conditioning. The model makes use of interneurons commonly found in the cortex and, hence, may apply to a wide variety of associative learning situations.