Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5

Debora R Sobreira; Amelia C Joslin; Qi Zhang; Iain Williamson; Grace T Hansen; Kathryn M Farris; Noboru J Sakabe; Nasa Sinnott-Armstrong; Grazyna Bozek; Sharon O Jensen-Cody; Kyle H Flippe; Carole Ober; Wendy A Bickmore; Matthew Potthoff; Mengjie Chen; Melina Claussnitzer; Ivy Aneas; Marcelo A Nobrega

doi:10.1126/science.abf1008

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Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5

Journal article

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Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5

Debora R Sobreira, Amelia C Joslin, Qi Zhang, Iain Williamson, Grace T Hansen, Kathryn M Farris, Noboru J Sakabe, Nasa Sinnott-Armstrong, Grazyna Bozek, Sharon O Jensen-Cody, …

Science (American Association for the Advancement of Science), Vol.372(6546), p.1085

06/04/2021

DOI: 10.1126/science.abf1008

PMCID: PMC8386003

PMID: 34083488

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https://www.research.ed.ac.uk/en/publications/f8655a32-0332-4467-b5c4-31feb661cef8View

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Abstract

Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.

Gene Expression

Genes

Analysis

Genetic aspects

Details

Title: Subtitle: Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5
Creators: Debora R Sobreira
Amelia C Joslin
Qi Zhang
Iain Williamson
Grace T Hansen
Kathryn M Farris
Noboru J Sakabe
Nasa Sinnott-Armstrong
Grazyna Bozek
Sharon O Jensen-Cody
Kyle H Flippe
Carole Ober
Wendy A Bickmore
Matthew Potthoff
Mengjie Chen
Melina Claussnitzer
Ivy Aneas
Marcelo A Nobrega
Resource Type: Journal article
Publication Details: Science (American Association for the Advancement of Science), Vol.372(6546), p.1085
DOI: 10.1126/science.abf1008
PMID: 34083488
PMCID: PMC8386003
NLM abbreviation: Science
ISSN: 0036-8075
eISSN: 1095-9203
Publisher: American Association for the Advancement of Science
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01HL128075; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01119577; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01DK114661; DOI: 10.13039/100000002, name: National Institutes of Health, award: 5P30DK020595; DOI: 10.13039/100000002, name: National Institutes of Health, award: RO1HL085197; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01HL119577; DOI: 10.13039/501100009708, name: Novo Nordisk Fonden, award: NNF18OC0033754; DOI: 10.13039/501100011856, name: Mauritius Research Council, award: 00007/2
Language: English
Date published: 06/04/2021
Description audience: Academic
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984093783902771

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