title: Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity.
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.
authors: Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: peter.kuehnen@charite.de.
authors: Peter
authors: P
authors: Kühnen
authors: Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors: Daniela
authors: D
authors: Handke
authors: USDA/ARS Children's Nutrition Research Center, Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Robert A
authors: RA
authors: Waterland
authors: MRC Unit, The Gambia and MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors: Branwen J
authors: BJ
authors: Hennig
authors: MRC Unit, The Gambia and MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors: Matt
authors: M
authors: Silver
authors: MRC Unit, The Gambia and MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors: Anthony J
authors: AJ
authors: Fulford
authors: Veterinary Epidemiology, Economics and Public Health Group, Royal Veterinary College, University of London, Hertfordshire AL10 9EU, UK; International Livestock Research Institute, 00100 Nairobi, Kenya.
authors: Paula
authors: P
authors: Dominguez-Salas
authors: 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.
authors: Sophie E
authors: SE
authors: Moore
authors: MRC Unit, The Gambia and MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors: Andrew M
authors: AM
authors: Prentice
authors: 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.
authors: Joachim
authors: J
authors: Spranger
authors: Department of Child and Adolescent Psychiatry, University Hospital Essen (AöR), University of Duisburg-Essen, 45141 Essen, Germany.
authors: Anke
authors: A
authors: Hinney
authors: Department of Child and Adolescent Psychiatry, University Hospital Essen (AöR), University of Duisburg-Essen, 45141 Essen, Germany.
authors: Johannes
authors: J
authors: Hebebrand
authors: Department of Neuropathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
authors: Frank L
authors: FL
authors: Heppner
authors: Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors: Lena
authors: L
authors: Walzer
authors: Department of Hepatology and Gastroenterology, Molecular Cancer Research Center (MKFZ), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors: Carsten
authors: C
authors: Grötzinger
authors: Centre of Reproductive Medicine and Andrology, University of Münster, 48149 Münster, Germany.
authors: Jörg
authors: J
authors: Gromoll
authors: Department of Pediatric Endocrinology and Diabetes, Charité Universitätsmedizin, 13353 Berlin, Germany.
authors: Susanna
authors: S
authors: Wiegand
authors: Department of Pediatric Endocrinology and Diabetes, Charité Universitätsmedizin, 13353 Berlin, Germany.
authors: Annette
authors: A
authors: Grüters
authors: Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors: Heiko
authors: H
authors: Krude
mesh_terms: D000328:Adult; D000483:Alleles; D015415:Biomarkers / Q000097:blood; D001835:Body Weight; D002244:Carbon / Q000378:metabolism; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000235:genetics*; D011247:Pregnancy; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D015415:Biomarkers; D011333:Pro-Opiomelanocortin; D002244:Carbon; D009074:Melanocyte-Stimulating Hormones