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Cell Metab. 2016 Sep 13;24(3):502-509. doi: 10.1016/j.cmet.2016.08.001. Epub 2016 Aug 25.

Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity.

Author information

1
Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: peter.kuehnen@charite.de.
2
Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
3
USDA/ARS Children's Nutrition Research Center, Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4
MRC Unit, The Gambia and MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
5
Veterinary Epidemiology, Economics and Public Health Group, Royal Veterinary College, University of London, Hertfordshire AL10 9EU, UK; International Livestock Research Institute, 00100 Nairobi, Kenya.
6
MRC Unit, The Gambia and MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; Elsie Widdowson Laboratory, MRC Human Nutrition Research, Cambridge CB1 9NL, UK.
7
Department of Endocrinology, Diabetes, and Nutrition and Charité Center for Cardiovascular Research (CCR), Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; Experimental and Clinical Research Center (ECRC), Charité Universitätsmedizin Berlin and Max-Delbrück Centre, 10117 Berlin, Germany.
8
Department of Child and Adolescent Psychiatry, University Hospital Essen (AöR), University of Duisburg-Essen, 45141 Essen, Germany.
9
Department of Neuropathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
10
Department of Hepatology and Gastroenterology, Molecular Cancer Research Center (MKFZ), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
11
Centre of Reproductive Medicine and Andrology, University of Münster, 48149 Münster, Germany.
12
Department of Pediatric Endocrinology and Diabetes, Charité Universitätsmedizin, 13353 Berlin, Germany.

Abstract

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritability." We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation.

PMID:
27568547
DOI:
10.1016/j.cmet.2016.08.001
[Indexed for MEDLINE]
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