作者
Melissa A. Richard,Tianxiao Huan,Symen Ligthart,Rahul Gondalia,Min A. Jhun,Jennifer A. Brody,Marguerite R. Irvin,Riccardo E. Marioni,Jincheng Shen,Pei-Chien Tsai,May E. Montasser,Yucheng Jia,Catriona Syme,Elias Salfati,Eric Boerwinkle,Weihua Guan,Thomas Hansen,Jan Bressler,Alanna C. Morrison,Chunyu Liu,Michael Mendelson,André G. Uitterlinden,Joyce B. J. van Meurs,Oscar H. Franco,Guosheng Zhang,Yun Li,James D. Stewart,Joshua C. Bis,Bruce M. Psaty,Yii‐Der Ida Chen,Sharon L. R. Kardia,Wei Zhao,Stephen T. Turner,Devin Absher,Stella Aslibekyan,John M. Starr,Allan F. McRae,Lifang Hou,Allan C. Just,Joel Schwartz,Pantel Vokonas,Cristina Menni,Tim D. Spector,Alan R. Shuldiner,Coleen Damcott,Jerome I. Rotter,Cornelia M. van Duijn,Yongmei Liu,Tomáš Paus,Steve Horvath,Jeffrey R. O’Connell,Xiuqing Guo,Zdenka Pausová,Themistocles L. Assimes,Nona Sotoodehnia,Jennifer A. Smith,Donna K. Arnett,Ian J. Deary,Andrea Baccarelli,Jordana T. Bell,Eric A. Whitsel,Abbas Dehghan,Daniel Lévy,Myriam Fornage,Bastiaan T. Heijmans,Peter A.C. ‘t Hoen,Joyce B. J. van Meurs,Aaron Isaacs,Rick Jansen,Lude Franke,Dorret I. Boomsma,René Pool,Jenny van Dongen,Jouke‐Jan Hottenga,Marleen M.J. van Greevenbroek,Coen D.A. Stehouwer,Carla Kallen,Casper G. Schalkwijk,Cisca Wijmenga,Alexandra Zhernakova,Marleen M.J. van Greevenbroek,P. Eline Slagboom,Marian Beekman,Joris Deelen,Diana O. Perkins,Jan H. Veldink,Leonard H. van den Berg,Cornelia M. van Duijn,Albert Hofman,André G. Uitterlinden,P. Mila Jhamai,Michaël Verbiest,H. Eka D. Suchiman,Marijn Verkerk,Jonathan Mill,Jeroen van Rooij,Jordana T. Bell,Hailiang Mei,Maarten van Iterson,Michiel van Galen,Jan Bot,Peter van ’t Hof,Patrick Deelen,Irene Nooren,Rick Jansen,Martijn Vermaat,Cisca Wijmenga,René Pool,Marc Jan Bonder,Freerk van Dijk,Wibowo Arindrarto,Szymon M. Kiełbasa,Morris A. Swertz,Erik W. van Zwet
摘要
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. 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.