B4144 - Ability of adult blood pressure-related CpGs to predict blood pressure in childhood and adolescence - 20/09/2022

B number: 
Principal applicant name: 
Hannah Elliott | University of Bristol (UK)
Dr Paul Yousefi, Mr Mohammed el Sharkawy, Dr Leanne Kupers
Title of project: 
Ability of adult blood pressure-related CpGs to predict blood pressure in childhood and adolescence
Proposal summary: 

Hypertension is one of the strongest risk factors for cardiovascular disease, which is the leading cause of death worldwide (1). Early-life exposures have been associated with blood pressure and the development of hypertension (2), with differential DNA methylation suggested as a potential underlying mechanism (3). Two large epigenome-wide association studies (EWAS) on systolic and diastolic blood pressure in adults have identified associations with DNA methylation (DNAm) levels of multiple Cytosine-phosphate-Guanine (CpG) sites (4,5). In the CHARGE consortium, one large-scale multi-ethnic EWAS on blood pressure in n=9,828 adults identified 13 CpGs annotated to 8 genes that were associated with blood pressure (4). A DNAm risk score based on these CpGs explained 1.4% and 2.0% of the inter-individual variation in systolic and diastolic BP, respectively. Another, more recent, EWAS on 4,820 multi-ethnic adults (6), identified 33 CpGs that explained an additional 3.3% and 4.0% of the inter-individual variation in systolic and diastolic blood pressure, respectively, beyond the traditional blood pressure risk factors age, sex, and body mass index (BMI), with 3 CpGs overlapping with the CHARGE study. The majority of the discovered CpG sites have been linked with other metabolic phenotypes including obesity, lipids, CRP, insulin resistance, and type 2 diabetes mellitus by previous epigenome-wide association studies (6), indicating that DNAm may be one of the common factors related to the concurrence of multiple cardiometabolic abnormalities.

Much less is known about the associations between DNAm and blood pressure in children. It is also not known if blood pressure associations with DNAm found in adults are already apparent in early childhood, late childhood and adolescence. Therefore, in this project, we aim to test the ability of a methylation risk score, developed using CpGs previously identified to be associated with SBP and DBP in adult EWAS meta-analysis by Richard (4) and Huang (6), to predict blood pressure at multiple timepoints in childhood and adolescence, and its added value compared to a risk score constructed only from the basic covariates age, sex and BMI.
This weighted methylation risk score was developed using the CpGs from the adult studies that survived a penalized elastic net regression in the ALSPAC adult data.

1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessmentof burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet (London, England).2012;380(9859):2224-60.
2. Lackland DT. Fetal and Early Life Determinants of Hypertension in Adults. Hypertension. 2004;44(6):811-2.
3. Wang X, Falkner B, Zhu H, Shi H, Su S, Xu X, Sharma AK, Dong Y, Treiber F, Gutin B, et al.. A genome-wide methylation study on essential hypertension in young African American males. 2013; 8:e53938.
4. Richard MA, Huan T, Ligthart S, Gondalia R, Jhun MA, Brody JA, Irvin MR, Marioni R, Shen J, Tsai PC,Montasser ME, Jia Y, Syme C, Salfati EL, Boerwinkle E, Guan W, Mosley TH Jr, Bressler J, Morrison AC,Liu C, Mendelson MM, Uitterlinden AG, van Meurs JB; BIOS Consortium, Franco OH, Zhang G, Li Y, Stew-art JD, Bis JC, Psaty BM, Chen YI, Kardia SLR, Zhao W, Turner ST, Absher D, Aslibekyan S, Starr JM,McRae AF, Hou L, Just AC, Schwartz JD, Vokonas PS, Menni C, Spector TD, Shuldiner A, Damcott CM,Rotter JI, Palmas W, Liu Y, Paus T, Horvath S, O'Connell JR, Guo X, Pausova Z, Assimes TL, SotoodehniaN, Smith JA, Arnett DK, Deary IJ, Baccarelli AA, Bell JT, Whitsel E, Dehghan A, Levy D, Fornage M. DNAMethylation Analysis Identifies Loci for Blood Pressure Regulation. Am J Hum Genet. 2017 Dec7;101(1):888-902.
5. Kazmi N, Elliott HR, Burrows K, Tillin T, Hughes AD, Chaturvedi N, et al. (2020) Associations between highblood pressure and DNA methylation. PLoS ONE 15(1): e0227728.
6. Huang Y, Ollikainen M, Muniandy M, Zhang T, Dongen Jv, Hao G, et al. Identification, Heritability, and Re-lation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure. Hypertension.2020;76(1):195-205.
7. Gervin, K., Salas, L.A., Bakulski, K.M. et al. Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data. Clin Epigenet 11, 125 (2019).

Impact of research: 
This research will improve knowledge of the relationship between DNA methylation and BP across the lifecourse. This research will will improve current risk scores to predict blood pressure in children.
Date proposal received: 
Monday, 12 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Epidemiology, Hypertension, Statistical methods, Methylation analysis, Blood pressure, Cardiovascular, Epigenetics