Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity

Item Type:	Article
Title:	Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity
Creators Name:	Kuehnen, P. and Handke, D. and Waterland, R.A. and Hennig, B.J. and Silver, M. and Fulford, A.J. and Dominguez-Salas, P. and Moore, S.E. and Prentice, A.M. and Spranger, J. and Hinney, A. and Hebebrand, J. and Heppner, F.L. and Walzer, L. and Groetzinger, C. and Gromoll, J. and Wiegand, S. and Grueters, A. and Krude, H.
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.
Keywords:	Alleles, Biomarkers, Body Weight, Carbon, Cohort Studies, CpG Islands, DNA Methylation, DNA Sequence Analysis, Genetic Variation, Melanocyte-Stimulating Hormones, Mononuclear Leukocytes, Obesity, Pregnancy, Pro-Opiomelanocortin
Source:	Cell Metabolism
ISSN:	1550-4131
Publisher:	Cell Press / Elsevier
Volume:	24
Number:	3
Page Range:	502-509
Date:	13 September 2016
Additional Information:	Copyright © 2016 Elsevier Inc.
Official Publication:	https://doi.org/10.1016/j.cmet.2016.08.001
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