Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

Liam McAllan, Damir Baranasic, Sergio Villicaña, Scarlett Brown, Weihua Zhang, Benjamin Lehne, Marco Adamo, Andrew Jenkinson, Mohamed Elkalaawy, Borzoueh Mohammadi, Majid Hashemi, Nadia Fernandes, Nathalie Lambie, Richard Williams, Colette Christiansen, Youwen Yang, Liudmila Zudina, Vasiliki Lagou, Sili Tan, Juan Castillo-Fernandez, James W. D. King, Richie Soong, Paul Elliott, James Scott, Inga Prokopenko, Inês Cebola, Marie Loh, Boris Lenhard, Rachel L. Batterham, Jordana T. Bell, John C. Chambers, Jaspal S. Kooner and William R. Scott ()
Additional contact information
Liam McAllan: Imperial College London
Damir Baranasic: Imperial College London
Sergio Villicaña: King’s College London
Scarlett Brown: Imperial College London
Weihua Zhang: School of Public Health, Imperial College London
Benjamin Lehne: School of Public Health, Imperial College London
Marco Adamo: University College London Hospitals, Ground Floor West Wing
Andrew Jenkinson: University College London Hospitals, Ground Floor West Wing
Mohamed Elkalaawy: University College London Hospitals, Ground Floor West Wing
Borzoueh Mohammadi: University College London Hospitals, Ground Floor West Wing
Majid Hashemi: University College London Hospitals, Ground Floor West Wing
Nadia Fernandes: Faculty of Medicine, Imperial College London
Nathalie Lambie: Faculty of Medicine, Imperial College London
Richard Williams: Faculty of Medicine, Imperial College London
Colette Christiansen: King’s College London
Youwen Yang: School of Public Health, Imperial College London
Liudmila Zudina: University of Surrey
Vasiliki Lagou: KU Leuven
Sili Tan: National University of Singapore
Juan Castillo-Fernandez: King’s College London
James W. D. King: MRC London Institute of Medical Sciences
Richie Soong: National University of Singapore
Paul Elliott: School of Public Health, Imperial College London
James Scott: Imperial College London
Inga Prokopenko: University of Surrey
Inês Cebola: Imperial College London
Marie Loh: School of Public Health, Imperial College London
Boris Lenhard: Imperial College London
Rachel L. Batterham: University College London Hospitals, Ground Floor West Wing
Jordana T. Bell: King’s College London
John C. Chambers: School of Public Health, Imperial College London
Jaspal S. Kooner: Ealing Hospital, London North West University Healthcare NHS Trust
William R. Scott: Imperial College London

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P 500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

Date: 2023
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DOI: 10.1038/s41467-023-38439-z

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