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

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Lawler, Katherine 
Davidson, Catherine M 
Keogh, Julia M 


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.


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


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

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Public Library of Science (PLoS)
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)