DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

BIOS Consortium

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 (US)
Pages (from-to)888-902
Number of pages15
JournalAmerican Journal of Human Genetics
Volume101
Issue number6
DOIs
StatePublished - Dec 7 2017

Fingerprint

DNA Methylation
Blood Pressure
Methylation
Gene Expression
Mendelian Randomization Analysis
Genome-Wide Association Study
Random Allocation
Hispanic Americans
Epigenomics
African Americans
Meta-Analysis
Phosphates
Genome

Keywords

  • blood pressure
  • DNA methylation
  • epigenome-wide association study
  • gene expression
  • Mendelian randomization
  • sequence variation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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 journalArticle

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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.",
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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 Tsai, {Pei Chien} 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 Heijmans, {Bastiaan T.} and {’t Hoen}, {Peter A.C.} and {van Meurs}, Joyce and Aaron Isaacs and Rick Jansen and Lude Franke and Boomsma, {Dorret I.} and Ren{\'e} Pool and {van Dongen}, Jenny and Hottenga, {Jouke J.} and {van Greevenbroek}, {Marleen M.J.} and Stehouwer, {Coen D.A.} and {van der Kallen}, {Carla J.H.} and Schalkwijk, {Casper G.} and Cisca Wijmenga and Alexandra Zhernakova and Tigchelaar, {Ettje F.} and Slagboom, {P. Eline} and Marian Beekman and Joris Deelen and {van Heemst}, Diana and Veldink, {Jan H.} and {van den Berg}, {Leonard H.} and {van Duijn}, {Cornelia M.} and Albert Hofman and Uitterlinden, {Andr{\'e} G.} and Turner, {Stephen T}",
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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 - Heijmans, Bastiaan T.

AU - ’t Hoen, Peter A.C.

AU - van Meurs, Joyce

AU - Isaacs, Aaron

AU - Jansen, Rick

AU - Franke, Lude

AU - Boomsma, Dorret I.

AU - Pool, René

AU - van Dongen, Jenny

AU - Hottenga, Jouke J.

AU - van Greevenbroek, Marleen M.J.

AU - Stehouwer, Coen D.A.

AU - van der Kallen, Carla J.H.

AU - Schalkwijk, Casper G.

AU - Wijmenga, Cisca

AU - Zhernakova, Alexandra

AU - Tigchelaar, Ettje F.

AU - Slagboom, P. Eline

AU - Beekman, Marian

AU - Deelen, Joris

AU - van Heemst, Diana

AU - Veldink, Jan H.

AU - van den Berg, Leonard H.

AU - van Duijn, Cornelia M.

AU - Hofman, Albert

AU - Uitterlinden, André G.

AU - Turner, Stephen T

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 - blood pressure

KW - DNA methylation

KW - epigenome-wide association study

KW - gene expression

KW - Mendelian randomization

KW - sequence variation

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