DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

BIOS Consortium

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Original languageEnglish
Pages (from-to)888-902
Number of pages15
JournalAmerican journal of human genetics
Volume101
Issue number6
DOIs
Publication statusPublished - 7 Dec 2017
Externally publishedYes

Cite this

@article{0cdc2a158d8a47a68a35222f9c709a74,
title = "DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation",
abstract = "Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30{\%}) and independent of known BP genetic variants, explaining an additional 1.4{\%} and 2.0{\%} of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.",
keywords = "Aged, Blood Pressure/genetics, CpG Islands/genetics, Cross-Sectional Studies, DNA Methylation/genetics, Epigenesis, Genetic/genetics, Genetic Variation/genetics, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins/genetics, Quantitative Trait Loci/genetics, Tetraspanins/genetics",
author = "{BIOS Consortium} and Richard, {Melissa A} and Tianxiao Huan and Symen Ligthart and Rahul Gondalia and Jhun, {Min A} and Brody, {Jennifer A} and Irvin, {Marguerite R} and Riccardo Marioni and Jincheng Shen and Pei-Chien Tsai and Montasser, {May E} and Yucheng Jia and Catriona Syme and Salfati, {Elias L} and Eric Boerwinkle and Weihua Guan and Mosley, {Thomas H} and Jan Bressler and Morrison, {Alanna C} and Chunyu Liu and Mendelson, {Michael M} and Uitterlinden, {Andr{\'e} G} and {van Meurs}, {Joyce B} and Franco, {Oscar H} and Guosheng Zhang and Yun Li and Stewart, {James D} and Bis, {Joshua C} and Psaty, {Bruce M} and Chen, {Yii-Der Ida} and Kardia, {Sharon L R} and Wei Zhao and Turner, {Stephen T} and Devin Absher and Stella Aslibekyan and Starr, {John M} and McRae, {Allan F} and Lifang Hou and Just, {Allan C} and Schwartz, {Joel D} and Vokonas, {Pantel S} and Cristina Menni and Spector, {Tim D} and Alan Shuldiner and Damcott, {Coleen M} and Rotter, {Jerome I} and Walter Palmas and Yongmei Liu and Tom{\'a}š Paus and Steve Horvath",
note = "Copyright {\circledC} 2017 American Society of Human Genetics. All rights reserved.",
year = "2017",
month = "12",
day = "7",
doi = "10.1016/j.ajhg.2017.09.028",
language = "English",
volume = "101",
pages = "888--902",
journal = "American journal of human genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. / BIOS Consortium.

In: American journal of human genetics, Vol. 101, No. 6, 07.12.2017, p. 888-902.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

AU - BIOS Consortium

AU - Richard, Melissa A

AU - Huan, Tianxiao

AU - Ligthart, Symen

AU - Gondalia, Rahul

AU - Jhun, Min A

AU - Brody, Jennifer A

AU - Irvin, Marguerite R

AU - Marioni, Riccardo

AU - Shen, Jincheng

AU - Tsai, Pei-Chien

AU - Montasser, May E

AU - Jia, Yucheng

AU - Syme, Catriona

AU - Salfati, Elias L

AU - Boerwinkle, Eric

AU - Guan, Weihua

AU - Mosley, Thomas H

AU - Bressler, Jan

AU - Morrison, Alanna C

AU - Liu, Chunyu

AU - Mendelson, Michael M

AU - Uitterlinden, André G

AU - van Meurs, Joyce B

AU - Franco, Oscar H

AU - Zhang, Guosheng

AU - Li, Yun

AU - Stewart, James D

AU - Bis, Joshua C

AU - Psaty, Bruce M

AU - Chen, Yii-Der Ida

AU - Kardia, Sharon L R

AU - Zhao, Wei

AU - Turner, Stephen T

AU - Absher, Devin

AU - Aslibekyan, Stella

AU - Starr, John M

AU - McRae, Allan F

AU - Hou, Lifang

AU - Just, Allan C

AU - Schwartz, Joel D

AU - Vokonas, Pantel S

AU - Menni, Cristina

AU - Spector, Tim D

AU - Shuldiner, Alan

AU - Damcott, Coleen M

AU - Rotter, Jerome I

AU - Palmas, Walter

AU - Liu, Yongmei

AU - Paus, Tomáš

AU - Horvath, Steve

N1 - Copyright © 2017 American Society of Human Genetics. All rights reserved.

PY - 2017/12/7

Y1 - 2017/12/7

N2 - Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

AB - Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

KW - Aged

KW - Blood Pressure/genetics

KW - CpG Islands/genetics

KW - Cross-Sectional Studies

KW - DNA Methylation/genetics

KW - Epigenesis, Genetic/genetics

KW - Genetic Variation/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Nerve Tissue Proteins/genetics

KW - Quantitative Trait Loci/genetics

KW - Tetraspanins/genetics

U2 - 10.1016/j.ajhg.2017.09.028

DO - 10.1016/j.ajhg.2017.09.028

M3 - Article

VL - 101

SP - 888

EP - 902

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

IS - 6

ER -