Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity
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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2016-09
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dig-cgspace-10568-770182023-12-08T19:36:04Z Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity Kühnen, P. Handke, D. Waterland, R.A. Hennig, B.J. Silver, M. Fulford, A.J. Domínguez Salas, Paula Moore, S.E. Prentice, A.M. Spranger, J. Hinney, A. Hebebrand, J. Heppner, F.L. Walzer, L. Grötzinger, C. Gromoll, J. Wiegand, S. Grüters, A. Krude, H. health 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. 2016-09 2016-09-09T13:26:55Z 2016-09-09T13:26:55Z Journal Article Kühnen, P., Handke, D., Waterland, R.A., Hennig, B.J., Silver, M., Fulford, A.J., Dominguez-Salas, P., Moore, S.E., Prentice, A.M., Spranger, J., Hinney, A., Hebebrand, J., Heppner, F.L., Walzer, L., Grötzinger, C., Gromoll, J., Wiegand, S., Grüters, A. and Krude, H. 2016. Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity. Cell Metabolism 24(3): 502–509. 1550-4131 https://hdl.handle.net/10568/77018 https://doi.org/10.1016/j.cmet.2016.08.001 en Limited Access p. 502-509 Elsevier Cell Metabolism |
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health health Kühnen, P. Handke, D. Waterland, R.A. Hennig, B.J. Silver, M. Fulford, A.J. Domínguez Salas, Paula Moore, S.E. Prentice, A.M. Spranger, J. Hinney, A. Hebebrand, J. Heppner, F.L. Walzer, L. Grötzinger, C. Gromoll, J. Wiegand, S. Grüters, A. Krude, H. Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity |
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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. |
format |
Journal Article |
topic_facet |
health |
author |
Kühnen, P. Handke, D. Waterland, R.A. Hennig, B.J. Silver, M. Fulford, A.J. Domínguez Salas, Paula Moore, S.E. Prentice, A.M. Spranger, J. Hinney, A. Hebebrand, J. Heppner, F.L. Walzer, L. Grötzinger, C. Gromoll, J. Wiegand, S. Grüters, A. Krude, H. |
author_facet |
Kühnen, P. Handke, D. Waterland, R.A. Hennig, B.J. Silver, M. Fulford, A.J. Domínguez Salas, Paula Moore, S.E. Prentice, A.M. Spranger, J. Hinney, A. Hebebrand, J. Heppner, F.L. Walzer, L. Grötzinger, C. Gromoll, J. Wiegand, S. Grüters, A. Krude, H. |
author_sort |
Kühnen, P. |
title |
Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity |
title_short |
Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity |
title_full |
Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity |
title_fullStr |
Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity |
title_full_unstemmed |
Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity |
title_sort |
interindividual variation in dna methylation at a putative pomc metastable epiallele is associated with obesity |
publisher |
Elsevier |
publishDate |
2016-09 |
url |
https://hdl.handle.net/10568/77018 https://doi.org/10.1016/j.cmet.2016.08.001 |
work_keys_str_mv |
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