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DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework

Lookup NU author(s): Professor Caroline Relton

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Abstract

Multiple differentially methylated sites and regions associated with adiposity have now been identified in large-scale cross-sectional studies. We tested for replication of associations between previously identified CpG sites at HIF3A and adiposity in approximate to 1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality. Overall, our results were discordant with those expected if HIF3A methylation has a causal effect on BMI and provided more evidence for causality in the reverse direction (i.e., an effect of BMI on HIF3A methylation). These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation. Our results also highlight an apparent long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity and HIF3A methylation. Further work is required to replicate and uncover the mechanisms underlying the direct and intergenerational effect of adiposity on DNA methylation.


Publication metadata

Author(s): Richmond RC, Sharp GC, Ward ME, Fraser A, Lyttleton O, McArdle WL, Ring SM, Gaunt TR, Lawlor DA, Smith GD, Relton CL

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2016

Volume: 65

Issue: 5

Pages: 1231-1244

Print publication date: 01/05/2016

Online publication date: 21/04/2016

Acceptance date: 01/02/2016

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association

URL: http://dx.doi.org/10.2337/db15-0996

DOI: 10.2337/db15-0996


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Funding

Funder referenceFunder name
U.K. Medical Research Council
U.K. Medical Research Council Integrative Epidemiology Unit
University of Bristol
099873/Z/12/ZWellcome Trust
102215/2/13/2Wellcome Trust
BB/I025263/1U.K. Biotechnology and Biological Sciences Research Council
C18281/A19169Cancer Research UK
BB/I025751/1U.K. Biotechnology and Biological Sciences Research Council
MC_UU_12013_2University of Bristol
MC_UU_12013_5University of Bristol
MC_UU_12013_1University of Bristol
MC_UU_12013_8University of Bristol
MR/M009351/1U.K. Medical Research Council
R01-DK-10324U.S. National Institute of Diabetes and Digestive and Kidney Diseases
RES-060-23-0011Economic and Social Research Council
WT088806Wellcome Trust
WT097097MFWellcome Trust

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