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Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

Published version
Peer-reviewed

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Article

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Authors

Lawler, Katherine 
Davidson, Catherine M 
Keogh, Julia M 

Abstract

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

Description

Funder: NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust


Funder: NHS National Institute for Health Research Clinical Research Network


Funder: Royal Society Darwin Trust Research Professorship


Funder: NIHR Senior Investigator Award


Funder: Health Data Research UK


Funder: Higher Education Funding Council for England Catalyst


Funder: NIHR Cambridge Biomedical Research Centre


Funder: Bernard Wolfe Health Neuroscience Endowment


Funder: The Botnar Fondation

Keywords

Age of Onset, Animals, Case-Control Studies, Drosophila Proteins, Drosophila melanogaster, Female, Genetic Association Studies, Genetic Testing, Homozygote, Humans, Male, Mutation, Obesity, Pedigree, Signal Transduction

Journal Title

PLoS Biol

Conference Name

Journal ISSN

1544-9173
1545-7885

Volume Title

19

Publisher

Public Library of Science (PLoS)
Sponsorship
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Wellcome Trust (103792/Z/14/Z)
Wellcome Trust (207462/Z/17/Z)
Wellcome Trust (208363/Z/17/Z)
British Heart Foundation (RG/18/13/33946)