Nature Communications (May 2023)
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,
- William R. Scott
Affiliations
- Liam McAllan
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
- Damir Baranasic
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
- Sergio Villicaña
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Scarlett Brown
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
- Weihua Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Benjamin Lehne
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Marco Adamo
- UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing
- Andrew Jenkinson
- UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing
- Mohamed Elkalaawy
- UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing
- Borzoueh Mohammadi
- UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing
- Majid Hashemi
- UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing
- Nadia Fernandes
- Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London
- Nathalie Lambie
- Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London
- Richard Williams
- Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London
- Colette Christiansen
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Youwen Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Liudmila Zudina
- Department of Clinical & Experimental Medicine, University of Surrey
- Vasiliki Lagou
- Department of Microbiology and Immunology, Laboratory of Adaptive Immunity, KU Leuven
- Sili Tan
- Cancer Science Institute of Singapore, National University of Singapore
- Juan Castillo-Fernandez
- Department of Twin Research and Genetic Epidemiology, King’s College London
- James W. D. King
- MRC London Institute of Medical Sciences
- Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore
- Paul Elliott
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- James Scott
- National Heart and Lung Institute, Imperial College London
- Inga Prokopenko
- Department of Clinical & Experimental Medicine, University of Surrey
- Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Marie Loh
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Boris Lenhard
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
- Rachel L. Batterham
- UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing
- Jordana T. Bell
- Department of Twin Research and Genetic Epidemiology, King’s College London
- John C. Chambers
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Jaspal S. Kooner
- Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust
- William R. Scott
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
- DOI
- https://doi.org/10.1038/s41467-023-38439-z
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
