Journal
CELL METABOLISM
Volume 24, Issue 3, Pages 502-509Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2016.08.001
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Funding
- German Research Foundation (DFG) [KU 2673/2-1, KFO218, GK-1208, HI 865/2-1]
- BMBF (NGFN-Plus) [01GS0820]
- Helmholz Association (ICEMED)
- Charite/Berlin Institute of Health (BIH) Clinical Scientist Program
- Berlin Institute of Health (BIH)
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK081557]
- USDA [CRIS 6250-51000-055]
- German Ministry for Education and Research (BMBF) [03IP614, 03IPT614A]
- Wellcome Trust [WT086369MA]
- UK Medical Research Council (MRC) [MC-A760-5QX00]
- UK Department for the International Development (DFID) under MRC/DFID
- MRC [MR/P012019/1, MC_EX_MR/M01424X/1, MC_U123292700, MC_UP_1005/1] Funding Source: UKRI
- Medical Research Council [MC_UP_1005/1, MC_U123292700, MC_EX_MR/M01424X/1, MR/P012019/1] Funding Source: researchfish
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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.
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