title: DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework.
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 ∼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.
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Rebecca C
authors: RC
authors: Richmond
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K. gemma.sharp@bristol.ac.uk.
authors: Gemma C
authors: GC
authors: Sharp
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Mary E
authors: ME
authors: Ward
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Abigail
authors: A
authors: Fraser
authors: School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Oliver
authors: O
authors: Lyttleton
authors: School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Wendy L
authors: WL
authors: McArdle
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Susan M
authors: SM
authors: Ring
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Tom R
authors: TR
authors: Gaunt
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: Debbie A
authors: DA
authors: Lawlor
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors: George
authors: G
authors: Davey Smith
authors: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. School of Social and Community Medicine, University of Bristol, Bristol, U.K. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, U.K.
authors: Caroline L
authors: CL
authors: Relton
mesh_terms: D050154:Adiposity; D000293:Adolescent; D041923:Adolescent Development; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001724:Birth Weight; D015992:Body Mass Index; D015984:Causality; D002648:Child; D002657:Child Development; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D004739:England / Q000453:epidemiology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D009035:Mothers; D050177:Overweight / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D012097:Repressor Proteins; D013851:Thinness / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C116973:HIF3A protein, human