Abstract
We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 195-205 |
| Number of pages | 11 |
| Journal | Hypertension |
| Volume | 76 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 1 2020 |
| Externally published | Yes |
Keywords
- DNA methylation
- Twin study
- blood pressure
- epigenome
- hypertension
ASJC Scopus subject areas
- Internal Medicine
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In: Hypertension, Vol. 76, No. 1, 01.07.2020, p. 195-205.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Identification, Heritability, and Relation with Gene Expression of Novel DNA Methylation Loci for Blood Pressure
AU - Huang, Yisong
AU - Ollikainen, Miina
AU - Muniandy, Maheswary
AU - Zhang, Tao
AU - Van Dongen, Jenny
AU - Hao, Guang
AU - Van Der Most, Peter J.
AU - Pan, Yue
AU - Pervjakova, Natalia
AU - Sun, Yan V.
AU - Hui, Qin
AU - Lahti, Jari
AU - Fraszczyk, Eliza
AU - Lu, Xueling
AU - Sun, Dianjianyi
AU - Richard, Melissa A.
AU - Willemsen, Gonneke
AU - Heikkila, Kauko
AU - Mateo Leach, Irene
AU - Mononen, Nina
AU - Kähönen, Mika
AU - Hurme, Mikko A.
AU - Raitakari, Olli T.
AU - Drake, Amanda J.
AU - Perola, Markus
AU - Nuotio, Marja Liisa
AU - Huang, Yunfeng
AU - Khulan, Batbayar
AU - Räikkönen, Katri
AU - Wolffenbuttel, Bruce H.R.
AU - Zhernakova, Alexandra
AU - Fu, Jingyuan
AU - Zhu, Haidong
AU - Dong, Yanbin
AU - Van Vliet-Ostaptchouk, Jana V.
AU - Franke, Lude
AU - Eriksson, Johan G.
AU - Fornage, Myriam
AU - Milani, Lili
AU - Lehtimäki, Terho
AU - Vaccarino, Viola
AU - Boomsma, Dorret I.
AU - Van Der Harst, Pim
AU - De Geus, Eco J.C.
AU - Salomaa, Veikko
AU - Li, Shengxu
AU - Chen, Wei
AU - Su, Shaoyong
AU - Wilson, James
AU - Snieder, Harold
AU - Kaprio, Jaakko
AU - Wang, Xiaoling
N1 - Funding Information: This study was supported by National Institutes of Health (NIH)/ NHLBI (grant HL104125). Funding specific to each cohort was list below. The Bogalusa Heart Study (BHS): The BHS is a joint effort of many investigators and staff members whose contribution is gratefully acknowledged. The current study was supported by grants R01AG016592 and R03AG060619 from National Institute of Aging, and P20GM109036 from the National Institute of General Medical Sciences of the National Institutes of Health. The Georgia Stress and Heart Study (GSH): The GSH has been supported by NIH/NHLBI Grant HL69999. The current study was supported by NIH/NHLBI HL125577 and NIH/NHLBI HL104125. We would like to thank all the participants in the study and the staff at the Georgia Prevention Institute. The Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) Study: The DILGOM study was supported by the Finnish Academy (grant #118065). V. Salomaa was also supported by the Finnish Foundation for Cardiovascular Research. The Emory Twin Study (ETS): The ETS has been supported by NIH R01HL68630, R01AG026255, R01HL125246, R01HL136205 and 2K24 HL077506. The current study was supported by NIH/NHLBI R21 HL106333-01A1. The Estonian Genome Center of the University of Tartu: The EGCUT studies were financed by University of Tartu (grant “Center of Translational Genomics”), by Estonian Government (grant #SF0180142s08) and by European Commission through the European Regional Development Fund in the frame of grant “Centre of Excellence in Genomics” and Estonian Research Infrastructure’s Roadmap and through FP7 grant #313010. The Finnish Twin Cohort (FTC): The FTC has been supported by the Academy of Finland (grants 265240, 263278, 308248, 312073 to J. Kaprio and 297908 to M. Ollikainen), and the Sigrid Juselius Foundation (to M. Ollikainen). The current DNA methylation study was supported by NIH/NHLBI grant HL104125. The Helsinki Birth Cohort Study (HBCS): The HBCS was supported by Finska Läkaresällskapet, the Finnish Special Governmental Subsidy for Health Sciences, Academy of Finland, Samfundet Folkhälsan, Liv och Hälsa, the Signe and Ane Gyllenberg Foundation, EU FP7 (DORIAN) project number 278603. A.J. Drake and B. Khulan were supported by a Scottish Senior Clinical Fellowship SCD/09 (to A.J. Drake). The Jackson Heart Study (JHS): The JHS is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The current DNA methylation study was supported by NIH/NHLBI grant HL104125. The authors also wish to thank the staff and participants of the JHS. J. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. The Lifelines Cohort Study: This work was supported by the National Consortium for Healthy Ageing (NCHA; NCHA NGI Grant 050-060-810), a grant from the National Institute for Public Health and the Environment (RIVM) and the Ministry of Health, Welfare and Sports of the Netherlands (S/132005), the European Union’s Seventh Framework programme (FP7/2007-2013) through the Biobank Standardisation and Harmonisation for Research Excellence in the European Union (BioSHaRE-EU) project, grant agreement 261433, and by the Dutch Diabetes Foundation (Diabetes Funds Junior Fellowship grant 2013.81.1673 to J.V. van Vliet-Ostaptchouk). The Netherlands Twin Register: Funding for the NTR was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, 016-115-035, Middelgroot-911-09-032, NWO-Groot 480-15-001/674, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI–NL, 184.021.007 and 184.033.111); Spinozapremie (NWO-56-464-14192), KNAW Academy Professor Award (PAH/6635), and University Research Fellow grant (URF) to DIB; Amsterdam Public Health research institute (former EMGO+); the European Science Foundation (ESF, EU/ QLRT-2001-01254), the European Community’s Seventh Framework Program (FP7-HEALTH-F4-2007-2013, grant 01413: ENGAGE and grant 602768: ACTION); the European Research Council (ERC Starting 284167, ERC Consolidator 771057, ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the National Institutes of Health (NIH, R01D0042157-01A1, MH081802, DA018673, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951); the Avera Institute for Human Genetics, Sioux Falls, South Dakota. Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by NWO through grant 2018/EW/00408559, BiG Grid, the Dutch e-Science Grid and SURFSARA. The Prevention of Renal and Vascular End stage Disease study: The PREVEND Study was funded by grants from the Dutch Kidney Foundation (grant E.033). The current DNA methylation study was supported by NIH/NHLBI grant HL104125. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; The Finnish Cultural Foundation—The Pirkanmaa Regional Fund; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To-AiTION); European Research Council (grant 742927 for MULTIEPIGEN project); Academy of Finland grant no. 322098; and Tampere University Hospital Supporting Foundation. The Epigenetic basis of Obesity induced cardiovascular disease and type 2 diabetes study: The EpiGO study was supported by NIH/NHLBI grant HL105689. The Lifestyle, Adiposity, and Cardiovascular Health in Youth study: The LACHY study was supported by NIH/NHLBI grant HL64157. The current DNA methylation study was supported by NIH/NHLBI grant HL105689 and AHA grant GRNT20480211. The Lifelines Deep Cohort: this project was funded by the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL) grant RP3 to L. Franke. L. Franke receives Nederlands Organisation for Scentific Research (NWO) ZonMW-VIDI 917.14.374, European Research Council ERC Starting grant Immrisk 637640 and financial support from Oncode Institute. A. Zhernakova is supported by ERC Starting Grant 715772, NWO-VIDI grant 016.178.056, and NWO Gravitation grant ExposomeNL. J. Fu is supported by NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001) and the Netherlands Heart Foundation CVON grant 2018-27. Publisher Copyright: © 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.
AB - We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.
KW - DNA methylation
KW - Twin study
KW - blood pressure
KW - epigenome
KW - hypertension
UR - http://www.scopus.com/inward/record.url?scp=85086355391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086355391&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.120.14973
DO - 10.1161/HYPERTENSIONAHA.120.14973
M3 - Article
C2 - 32520614
AN - SCOPUS:85086355391
SN - 0194-911X
VL - 76
SP - 195
EP - 205
JO - Hypertension
JF - Hypertension
IS - 1
ER -