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Exome Sequencing Identifies Multiple Genes and Gene-Sets Contributing to Severe Childhood Obesity

45 Pages Posted: 14 Sep 2019 Sneak Peek Status: Under Review

See all articles by Gaëlle Marenne

Gaëlle Marenne

Wellcome Trust Sanger Institute

Audrey Hendricks

Wellcome Trust Sanger Institute

Aliki Perdikari

University of Cambridge - Metabolic Research Laboratories

Rebecca Bounds

University of Cambridge - Metabolic Research Laboratories

Felicity Payne

Wellcome Trust Sanger Institute

Julia M. Keogh

University of Cambridge - Metabolic Research Laboratories

Christopher J. Lelliott

Wellcome Trust Sanger Institute

Elana Henning

University of Cambridge - Metabolic Research Laboratories

Saad Pathan

University of Cambridge - Metabolic Research Laboratories

Sofie Ashford

University of Cambridge - Metabolic Research Laboratories

Elena G. Bochukova

University of Cambridge - Metabolic Research Laboratories

Vanisha Mistry

University of Cambridge - Metabolic Research Laboratories

Allan Daly

Wellcome Trust Sanger Institute

Caroline Hayward

University of Edinburgh - MRC Human Genetics Unit

INTERVAL

UK10K Consortium

Nicholas J. Wareham

University of Cambridge - Department of Public Health and Primary Care

Stephen O'Rahilly

NHS Foundation Trust - MRC Metabolic Diseases Unit

Claudia Langenberg

University of Cambridge - MRC Epidemiology Unit

Eleanor Wheeler

Wellcome Trust Sanger Institute

Eleftheria Zeggini

Wellcome Trust Sanger Institute

I.Sadaf Farooqi

University of Cambridge - Metabolic Research Laboratories

Ines Barroso

Wellcome Trust Sanger Institute

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Abstract

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome sequencing followed by targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, ZMYM4) with an excess burden in cases of variants (MAF<0.025%) predicted to affect function. In cells, we found that nuclear PHIP (Pleckstrin Homology domain Interacting Protein) directly enhances transcription of Pro-opiomelanocortin (POMC), a neuropeptide which suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. We found an excess burden of in silico deleterious variants (MAF<0.025%) in genes nearest to loci from obesity genome-wide association studies and genes intolerant to loss-of-function, in gene-set analyses. The discovery of genes and gene-sets influencing obesity in a non-fully penetrant manner provides mechanistic insights and has diagnostic and therapeutic implications.

Keywords: obesity, whole-exome, sequencing, genetics, gene-set, gene burden

Suggested Citation

Marenne, Gaëlle and Hendricks, Audrey and Perdikari, Aliki and Bounds, Rebecca and Payne, Felicity and Keogh, Julia M. and Lelliott, Christopher J. and Henning, Elana and Pathan, Saad and Ashford, Sofie and Bochukova, Elena G. and Mistry, Vanisha and Daly, Allan and Hayward, Caroline and , INTERVAL and Consortium, UK10K and Wareham, Nicholas J. and O'Rahilly, Stephen and Langenberg, Claudia and Wheeler, Eleanor and Zeggini, Eleftheria and Farooqi, I.Sadaf and Barroso, Ines, Exome Sequencing Identifies Multiple Genes and Gene-Sets Contributing to Severe Childhood Obesity (September 10, 2019). CELL-D-19-02544. Available at SSRN: https://ssrn.com/abstract=3452779 or http://dx.doi.org/10.2139/ssrn.3452779
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Gaëlle Marenne

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Audrey Hendricks

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Aliki Perdikari

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Rebecca Bounds

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Felicity Payne

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Julia M. Keogh

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Christopher J. Lelliott

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Elana Henning

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Saad Pathan

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Sofie Ashford

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Elena G. Bochukova

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Vanisha Mistry

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Allan Daly

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Caroline Hayward

University of Edinburgh - MRC Human Genetics Unit

Edinburgh
United Kingdom

Nicholas J. Wareham

University of Cambridge - Department of Public Health and Primary Care

Cambridge
United Kingdom

Stephen O'Rahilly

NHS Foundation Trust - MRC Metabolic Diseases Unit

United Kingdom

Claudia Langenberg

University of Cambridge - MRC Epidemiology Unit

United Kingdom

Eleanor Wheeler

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Eleftheria Zeggini

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

I.Sadaf Farooqi

University of Cambridge - Metabolic Research Laboratories

Hills Road
Box 289, Addenbrooke’s Hospital
Cambridge, CB2 0QQ
United Kingdom

Ines Barroso (Contact Author)

Wellcome Trust Sanger Institute ( email )

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

No contact information is available for INTERVAL
No contact information is available for UK10K Consortium

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