Physical Interactions and Expression Quantitative Traits Loci Identify Regulatory Connections for Obesity and Type 2 Diabetes Associated SNPs

Frontiers in Genetics
Tayaza FadasonJustin M O'Sullivan

Abstract

The mechanisms that underlie the association between obesity and type 2 diabetes are not fully understood. Here, we investigated the role of the 3D genome organization in the pathogeneses of obesity and type-2 diabetes. We interpreted the combined and differential impacts of 196 diabetes and 390 obesity associated single nucleotide polymorphisms (SNPs) by integrating data on the genes with which they physically interact (as captured by Hi-C) and the functional [i.e., expression quantitative trait loci (eQTL)] outcomes associated with these interactions. We identified 861 spatially regulated genes (e.g., AP3S2, ELP5, SVIP, IRS1, FADS2, WFS1, RBM6, HORMAD1, PYROXD2), which are enriched in tissues (e.g., adipose, skeletal muscle, pancreas) and biological processes and canonical pathways (e.g., lipid metabolism, leptin, and glucose-insulin signaling pathways) that are important for the pathogenesis of type 2 diabetes and obesity. Our discovery-based approach also identifies enrichment for eQTL SNP-gene interactions in tissues that are not classically associated with diabetes or obesity. We propose that the combinatorial action of active obesity and diabetes spatial eQTL SNPs on their gene pairs within different tissues reduces the ...Continue Reading

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Citations

Jun 14, 2018·The Journal of Endocrinology·Frank H Bloomfield
Jan 31, 2019·Nucleic Acids Research·Valérie de Crécy-LagardJanusz M Bujnicki
Jun 20, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·William SchierdingJustin M O'Sullivan
Apr 12, 2019·Frontiers in Genetics·Daniel Sik Wai HoJustin O'Sullivan
Nov 17, 2020·Frontiers in Psychiatry·Evgeniia GolovinaJustin M O'Sullivan
Jan 30, 2021·The FEBS Journal·Takeshi Chujo, Kazuhito Tomizawa
Jul 3, 2021·International Journal of Molecular Sciences·Arina O DegtyarevaTatiana I Merkulova
Aug 28, 2021·Genes·Amarni L ThomasJulia A Horsfield
Jul 8, 2021·Scientific Reports·Denis M NyagaJustin M O'Sullivan
Jan 15, 2022·Nature Communications·Rafal CzapiewskiEric C Schirmer

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Methods Mentioned

BETA
Hi-C
proximity-ligation
proximity
RNA-Seq

Software Mentioned

CoDeS3D
Ingenuity® Pathway Analysis ( IPA®
GTEx
Hi

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