DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Symen Ligthart; Carola Marzi; Stella Aslibekyan; Michael M. Mendelson; Karen N. Conneely; Toshiko Tanaka; Elena Colicino; Lindsay L. Waite; Roby Joehanes; Weihua Guan; Jennifer A. Brody; Cathy Elks; Riccardo Marioni; Min A. Jhun; Golareh Agha; Jan Bressler; Cavin K. Ward-Caviness; Brian H. Chen; Tianxiao Huan; Kelly Bakulski; Elias L. Salfati; Giovanni Fiorito; Simone Wahl; Katharina Schramm; Jin Sha; Dena G. Hernandez; Allan C. Just; Jennifer A. Smith; Nona Sotoodehnia; Luke C. Pilling; James S. Pankow; Phil S. Tsao; Chunyu Liu; Wei Zhao; Simonetta Guarrera; Vasiliki J. Michopoulos; Alicia K. Smith; Marjolein J. Peters; David Melzer; Pantel Vokonas; Myriam Fornage; Holger Prokisch; Joshua C. Bis; Audrey Y. Chu; Christian Herder; Harald Grallert; Chen Yao; Sonia Shah; Allan F. McRae; Honghuang Lin; Steve Horvath; Daniele Fallin; Albert Hofman; Nicholas J. Wareham; Kerri L. Wiggins; Andrew P. Feinberg; John M. Starr; Peter M. Visscher; Joanne M. Murabito; Sharon L. R. Kardia; Devin M. Absher; Elisabeth B. Binder; Andrew B. Singleton; Stefania Bandinelli; Annette Peters; Melanie Waldenberger; Giuseppe Matullo; Joel D. Schwartz; Ellen W. Demerath; André G. Uitterlinden; Joyce B. J. van Meurs; Oscar H. Franco; Yii-Der Ida Chen; Daniel Levy; Stephen T. Turner; Ian J. Deary; Kerry J. Ressler; Josée Dupuis; Luigi Ferrucci; Ken K. Ong; Themistocles L. Assimes; Eric Boerwinkle; Wolfgang Koenig; Donna K. Arnett; Andrea A. Baccarelli; Emelia J. Benjamin; Abbas Dehghan

doi:10.1186/s13059-016-1119-5

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler, Cavin K. Ward-Caviness, Brian H. Chen, Tianxiao Huan, Kelly BakulskiElias L. Salfati, Giovanni Fiorito, Simone Wahl, Katharina Schramm, Jin Sha, Dena G. Hernandez, Allan C. Just, Jennifer A. Smith, Nona Sotoodehnia, Luke C. Pilling, James S. Pankow, Phil S. Tsao, Chunyu Liu, Wei Zhao, Simonetta Guarrera, Vasiliki J. Michopoulos, Alicia K. Smith, Marjolein J. Peters, David Melzer, Pantel Vokonas, Myriam Fornage, Holger Prokisch, Joshua C. Bis, Audrey Y. Chu, Christian Herder, Harald Grallert, Chen Yao, Sonia Shah, Allan F. McRae, Honghuang Lin, Steve Horvath, Daniele Fallin, Albert Hofman, Nicholas J. Wareham, Kerri L. Wiggins, Andrew P. Feinberg, John M. Starr, Peter M. Visscher, Joanne M. Murabito, Sharon L. R. Kardia, Devin M. Absher, Elisabeth B. Binder, Andrew B. Singleton, Stefania Bandinelli, Annette Peters, Melanie Waldenberger, Giuseppe Matullo, Joel D. Schwartz, Ellen W. Demerath, André G. Uitterlinden, Joyce B. J. van Meurs, Oscar H. Franco, Yii-Der Ida Chen, Daniel Levy, Stephen T. Turner, Ian J. Deary, Kerry J. Ressler, Josée Dupuis, Luigi Ferrucci, Ken K. Ong, Themistocles L. Assimes, Eric Boerwinkle, Wolfgang Koenig, Donna K. Arnett, Andrea A. Baccarelli, Emelia J. Benjamin, Abbas Dehghan

Research output: Contribution to journal › Article › peer-review

Abstract

BackgroundChronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
ResultsWe performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
ConclusionWe have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

Original language	English
Number of pages	15
Journal	Genome Biology
Volume	17
Issue number	255
DOIs	https://doi.org/10.1186/s13059-016-1119-5
Publication status	Published - 12 Dec 2016

Keywords / Materials (for Non-textual outputs)

Inflammation
DNA methylation
Epigenome-wide association study
C-reactive protein
Body mass index
Diabetes
Coronary heart disease

Access to Document

10.1186/s13059-016-1119-5

art%3A10.1186%2Fs13059-016-1119-5Final published version, 972 KBLicence: Creative Commons: Attribution (CC-BY)

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I. (Principal Investigator), Gale, C. (Co-investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), Maclullich, A. (Co-investigator), Porteous, D. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator), Wardlaw, J. (Co-investigator) & Okely, J. (Researcher)
1/09/13 → 31/08/19
Project: Research

Cite this

Ligthart, S., Marzi, C., Aslibekyan, S., Mendelson, M. M., Conneely, K. N., Tanaka, T., Colicino, E., Waite, L. L., Joehanes, R., Guan, W., Brody, J. A., Elks, C., Marioni, R., Jhun, M. A., Agha, G., Bressler, J., Ward-Caviness, C. K., Chen, B. H., Huan, T., ... Dehghan, A. (2016). DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biology, 17(255). https://doi.org/10.1186/s13059-016-1119-5

@article{53bc836278da4660896abf0c014e225f,

title = "DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases",

abstract = "BackgroundChronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.ResultsWe performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.ConclusionWe have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.",

keywords = "Inflammation , DNA methylation , Epigenome-wide association study, C-reactive protein , Body mass index , Diabetes , Coronary heart disease",

author = "Symen Ligthart and Carola Marzi and Stella Aslibekyan and Mendelson, {Michael M.} and Conneely, {Karen N.} and Toshiko Tanaka and Elena Colicino and Waite, {Lindsay L.} and Roby Joehanes and Weihua Guan and Brody, {Jennifer A.} and Cathy Elks and Riccardo Marioni and Jhun, {Min A.} and Golareh Agha and Jan Bressler and Ward-Caviness, {Cavin K.} and Chen, {Brian H.} and Tianxiao Huan and Kelly Bakulski and Salfati, {Elias L.} and Giovanni Fiorito and Simone Wahl and Katharina Schramm and Jin Sha and Hernandez, {Dena G.} and Just, {Allan C.} and Smith, {Jennifer A.} and Nona Sotoodehnia and Pilling, {Luke C.} and Pankow, {James S.} and Tsao, {Phil S.} and Chunyu Liu and Wei Zhao and Simonetta Guarrera and Michopoulos, {Vasiliki J.} and Smith, {Alicia K.} and Peters, {Marjolein J.} and David Melzer and Pantel Vokonas and Myriam Fornage and Holger Prokisch and Bis, {Joshua C.} and Chu, {Audrey Y.} and Christian Herder and Harald Grallert and Chen Yao and Sonia Shah and McRae, {Allan F.} and Honghuang Lin and Steve Horvath and Daniele Fallin and Albert Hofman and Wareham, {Nicholas J.} and Wiggins, {Kerri L.} and Feinberg, {Andrew P.} and Starr, {John M.} and Visscher, {Peter M.} and Murabito, {Joanne M.} and Kardia, {Sharon L. R.} and Absher, {Devin M.} and Binder, {Elisabeth B.} and Singleton, {Andrew B.} and Stefania Bandinelli and Annette Peters and Melanie Waldenberger and Giuseppe Matullo and Schwartz, {Joel D.} and Demerath, {Ellen W.} and Uitterlinden, {Andr{\'e} G.} and {van Meurs}, {Joyce B. J.} and Franco, {Oscar H.} and Chen, {Yii-Der Ida} and Daniel Levy and Turner, {Stephen T.} and Deary, {Ian J.} and Ressler, {Kerry J.} and Jos{\'e}e Dupuis and Luigi Ferrucci and Ong, {Ken K.} and Assimes, {Themistocles L.} and Eric Boerwinkle and Wolfgang Koenig and Arnett, {Donna K.} and Baccarelli, {Andrea A.} and Benjamin, {Emelia J.} and Abbas Dehghan",

year = "2016",

month = dec,

day = "12",

doi = "10.1186/s13059-016-1119-5",

language = "English",

volume = "17",

journal = "Genome Biology",

issn = "1474-760X",

publisher = "BioMed Central",

number = "255",

}

Ligthart, S, Marzi, C, Aslibekyan, S, Mendelson, MM, Conneely, KN, Tanaka, T, Colicino, E, Waite, LL, Joehanes, R, Guan, W, Brody, JA, Elks, C, Marioni, R, Jhun, MA, Agha, G, Bressler, J, Ward-Caviness, CK, Chen, BH, Huan, T, Bakulski, K, Salfati, EL, Fiorito, G, Wahl, S, Schramm, K, Sha, J, Hernandez, DG, Just, AC, Smith, JA, Sotoodehnia, N, Pilling, LC, Pankow, JS, Tsao, PS, Liu, C, Zhao, W, Guarrera, S, Michopoulos, VJ, Smith, AK, Peters, MJ, Melzer, D, Vokonas, P, Fornage, M, Prokisch, H, Bis, JC, Chu, AY, Herder, C, Grallert, H, Yao, C, Shah, S, McRae, AF, Lin, H, Horvath, S, Fallin, D, Hofman, A, Wareham, NJ, Wiggins, KL, Feinberg, AP, Starr, JM, Visscher, PM, Murabito, JM, Kardia, SLR, Absher, DM, Binder, EB, Singleton, AB, Bandinelli, S, Peters, A, Waldenberger, M, Matullo, G, Schwartz, JD, Demerath, EW, Uitterlinden, AG, van Meurs, JBJ, Franco, OH, Chen, Y-DI, Levy, D, Turner, ST, Deary, IJ, Ressler, KJ, Dupuis, J, Ferrucci, L, Ong, KK, Assimes, TL, Boerwinkle, E, Koenig, W, Arnett, DK, Baccarelli, AA, Benjamin, EJ & Dehghan, A 2016, 'DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases', Genome Biology, vol. 17, no. 255. https://doi.org/10.1186/s13059-016-1119-5

TY - JOUR

T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

AU - Ligthart, Symen

AU - Marzi, Carola

AU - Aslibekyan, Stella

AU - Mendelson, Michael M.

AU - Conneely, Karen N.

AU - Tanaka, Toshiko

AU - Colicino, Elena

AU - Waite, Lindsay L.

AU - Joehanes, Roby

AU - Guan, Weihua

AU - Brody, Jennifer A.

AU - Elks, Cathy

AU - Marioni, Riccardo

AU - Jhun, Min A.

AU - Agha, Golareh

AU - Bressler, Jan

AU - Ward-Caviness, Cavin K.

AU - Chen, Brian H.

AU - Huan, Tianxiao

AU - Bakulski, Kelly

AU - Salfati, Elias L.

AU - Fiorito, Giovanni

AU - Wahl, Simone

AU - Schramm, Katharina

AU - Sha, Jin

AU - Hernandez, Dena G.

AU - Just, Allan C.

AU - Smith, Jennifer A.

AU - Sotoodehnia, Nona

AU - Pilling, Luke C.

AU - Pankow, James S.

AU - Tsao, Phil S.

AU - Liu, Chunyu

AU - Zhao, Wei

AU - Guarrera, Simonetta

AU - Michopoulos, Vasiliki J.

AU - Smith, Alicia K.

AU - Peters, Marjolein J.

AU - Melzer, David

AU - Vokonas, Pantel

AU - Fornage, Myriam

AU - Prokisch, Holger

AU - Bis, Joshua C.

AU - Chu, Audrey Y.

AU - Herder, Christian

AU - Grallert, Harald

AU - Yao, Chen

AU - Shah, Sonia

AU - McRae, Allan F.

AU - Lin, Honghuang

AU - Horvath, Steve

AU - Fallin, Daniele

AU - Hofman, Albert

AU - Wareham, Nicholas J.

AU - Wiggins, Kerri L.

AU - Feinberg, Andrew P.

AU - Starr, John M.

AU - Visscher, Peter M.

AU - Murabito, Joanne M.

AU - Kardia, Sharon L. R.

AU - Absher, Devin M.

AU - Binder, Elisabeth B.

AU - Singleton, Andrew B.

AU - Bandinelli, Stefania

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Matullo, Giuseppe

AU - Schwartz, Joel D.

AU - Demerath, Ellen W.

AU - Uitterlinden, André G.

AU - van Meurs, Joyce B. J.

AU - Franco, Oscar H.

AU - Chen, Yii-Der Ida

AU - Levy, Daniel

AU - Turner, Stephen T.

AU - Deary, Ian J.

AU - Ressler, Kerry J.

AU - Dupuis, Josée

AU - Ferrucci, Luigi

AU - Ong, Ken K.

AU - Assimes, Themistocles L.

AU - Boerwinkle, Eric

AU - Koenig, Wolfgang

AU - Arnett, Donna K.

AU - Baccarelli, Andrea A.

AU - Benjamin, Emelia J.

AU - Dehghan, Abbas

PY - 2016/12/12

Y1 - 2016/12/12

N2 - BackgroundChronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.ResultsWe performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.ConclusionWe have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

AB - BackgroundChronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.ResultsWe performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.ConclusionWe have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

KW - Inflammation

KW - DNA methylation

KW - Epigenome-wide association study

KW - C-reactive protein

KW - Body mass index

KW - Diabetes

KW - Coronary heart disease

U2 - 10.1186/s13059-016-1119-5

DO - 10.1186/s13059-016-1119-5

M3 - Article

SN - 1474-760X

VL - 17

JO - Genome Biology

JF - Genome Biology

IS - 255

ER -

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Cite this