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1. Loss of epigenetic information as a cause of mammalian aging

Author

Yang, Jae-Hyun, Hayano, Motoshi, Griffin, Patrick T., Amorim, João A., Bonkowski, Michael S., Apostolides, John K., Salfati, Elias L., Blanchette, Marco, Munding, Elizabeth M., Bhakta, Mital, Chew, Yap Ching, Guo, Wei, Yang, Xiaojing, Maybury-Lewis, Sun, Tian, Xiao, Ross, Jaime M., Coppotelli, Giuseppe, Meer, Margarita V., Rogers-Hammond, Ryan, Vera, Daniel L., Lu, Yuancheng Ryan, Pippin, Jeffrey W., Creswell, Michael L., Dou, Zhixun, Xu, Caiyue, Mitchell, Sarah J., Das, Abhirup, O’Connell, Brendan L., Thakur, Sachin, Kane, Alice E., Su, Qiao, Mohri, Yasuaki, Nishimura, Emi K., Schaevitz, Laura, Garg, Neha, Balta, Ana-Maria, Rego, Meghan A., Gregory-Ksander, Meredith, Jakobs, Tatjana C., Zhong, Lei, Wakimoto, Hiroko, El Andari, Jihad, Grimm, Dirk, Mostoslavsky, Raul, Wagers, Amy J., Tsubota, Kazuo, Bonasera, Stephen J., Palmeira, Carlos M., Seidman, Jonathan G., Seidman, Christine E., Wolf, Norman S., Kreiling, Jill A., Sedivy, John M., Murphy, George F., Green, Richard E., Garcia, Benjamin A., Berger, Shelley L., Oberdoerffer, Philipp, Shankland, Stuart J., Gladyshev, Vadim N., Ksander, Bruce R., Pfenning, Andreas R., Rajman, Luis A., and Sinclair, David A.

Published
2023
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2. An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis

Author

Liu, Jun, Carnero-Montoro, Elena, van Dongen, Jenny, Lent, Samantha, Nedeljkovic, Ivana, Ligthart, Symen, Tsai, Pei-Chien, Martin, Tiphaine C, Mandaviya, Pooja R, Jansen, Rick, Peters, Marjolein J, Duijts, Liesbeth, Jaddoe, Vincent WV, Tiemeier, Henning, Felix, Janine F, Willemsen, Gonneke, de Geus, Eco JC, Chu, Audrey Y, Levy, Daniel, Hwang, Shih-Jen, Bressler, Jan, Gondalia, Rahul, Salfati, Elias L, Herder, Christian, Hidalgo, Bertha A, Tanaka, Toshiko, Moore, Ann Zenobia, Lemaitre, Rozenn N, Jhun, Min A, Smith, Jennifer A, Sotoodehnia, Nona, Bandinelli, Stefania, Ferrucci, Luigi, Arnett, Donna K, Grallert, Harald, Assimes, Themistocles L, Hou, Lifang, Baccarelli, Andrea, Whitsel, Eric A, van Dijk, Ko Willems, Amin, Najaf, Uitterlinden, André G, Sijbrands, Eric JG, Franco, Oscar H, Dehghan, Abbas, Spector, Tim D, Dupuis, Josée, Hivert, Marie-France, Rotter, Jerome I, Meigs, James B, Pankow, James S, van Meurs, Joyce BJ, Isaacs, Aaron, Boomsma, Dorret I, Bell, Jordana T, Demirkan, Ayşe, and van Duijn, Cornelia M

Subjects
Biological Sciences, Genetics, Nutrition, Diabetes, Human Genome, Obesity, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Aged, 80 and over, Computer Simulation, CpG Islands, DNA Methylation, Diabetes Mellitus, Type 2, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Glucose, Homeostasis, Humans, Insulin, Male, Metabolic Networks and Pathways, Middle Aged, Polymorphism, Single Nucleotide, Young Adult
Abstract

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.

Published
2019

3. GWAS of epigenetic aging rates in blood reveals a critical role for TERT.

Author

Lu, Ake T, Xue, Luting, Salfati, Elias L, Chen, Brian H, Ferrucci, Luigi, Levy, Daniel, Joehanes, Roby, Murabito, Joanne M, Kiel, Douglas P, Tsai, Pei-Chien, Yet, Idil, Bell, Jordana T, Mangino, Massimo, Tanaka, Toshiko, McRae, Allan F, Marioni, Riccardo E, Visscher, Peter M, Wray, Naomi R, Deary, Ian J, Levine, Morgan E, Quach, Austin, Assimes, Themistocles, Tsao, Philip S, Absher, Devin, Stewart, James D, Li, Yun, Reiner, Alex P, Hou, Lifang, Baccarelli, Andrea A, Whitsel, Eric A, Aviv, Abraham, Cardona, Alexia, Day, Felix R, Wareham, Nicholas J, Perry, John RB, Ong, Ken K, Raj, Kenneth, Lunetta, Kathryn L, and Horvath, Steve

Subjects
Leukocytes, Cells, Cultured, Telomere, Fibroblasts, Humans, Telomerase, DNA Methylation, Epigenesis, Genetic, CpG Islands, Aging, Menopause, Menarche, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Child, Female, Male, Genome-Wide Association Study, Young Adult, Mendelian Randomization Analysis, Cells, Cultured, Epigenesis, Genetic, and over
Abstract

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P

Published
2018

4. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A, Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A, Brody, Jennifer A, Irvin, Marguerite R, Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E, Jia, Yucheng, Syme, Catriona, Salfati, Elias L, Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H, Bressler, Jan, Morrison, Alanna C, Liu, Chunyu, Mendelson, Michael M, Uitterlinden, André G, van Meurs, Joyce B, Consortium, BIOS, Heijmans, Bastiaan T, Hoen, Peter AC ’t, van Meurs, Joyce, Isaacs, Aaron, Jansen, Rick, Franke, Lude, Boomsma, Dorret I, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, van Greevenbroek, Marleen MJ, Stehouwer, Coen DA, van der Kallen, Carla JH, Schalkwijk, Casper G, Wijmenga, Cisca, Zhernakova, Alexandra, Tigchelaar, Ettje F, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H, van den Berg, Leonard H, van Duijn, Cornelia M, Hofman, Albert, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, van ’t Hof, Peter, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Zhernakova, Dasha V, Luijk, René, Bonder, Marc Jan, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M, Swertz, Morris A, van Zwet, Erik W, Franco, Oscar H, Zhang, Guosheng, Li, Yun, Stewart, James D, Bis, Joshua C, Psaty, Bruce M, Chen, Yii-Der Ida, Kardia, Sharon LR, Zhao, Wei, Turner, Stephen T, Absher, Devin, Aslibekyan, Stella, Starr, John M, McRae, Allan F, Hou, Lifang, Just, Allan C, Schwartz, Joel D, Vokonas, Pantel S, Menni, Cristina, Spector, Tim D, Shuldiner, Alan, Damcott, Coleen M, Rotter, Jerome I, Palmas, Walter, Liu, Yongmei, and Paus, Tomáš

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins, BIOS Consortium, DNA methylation, Mendelian randomization, blood pressure, epigenome-wide association study, gene expression, sequence variation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
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  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.

Published
2017

5. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Author

Howson, Joanna MM, Zhao, Wei, Barnes, Daniel R, Ho, Weang-Kee, Young, Robin, Paul, Dirk S, Waite, Lindsay L, Freitag, Daniel F, Fauman, Eric B, Salfati, Elias L, Sun, Benjamin B, Eicher, John D, Johnson, Andrew D, Sheu, Wayne HH, Nielsen, Sune F, Lin, Wei-Yu, Surendran, Praveen, Malarstig, Anders, Wilk, Jemma B, Tybjærg-Hansen, Anne, Rasmussen, Katrine L, Kamstrup, Pia R, Deloukas, Panos, Erdmann, Jeanette, Kathiresan, Sekar, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, Do, Ron, Rader, Daniel J, Johnson, Julie A, Hazen, Stanley L, Quyyumi, Arshed A, Spertus, John A, Pepine, Carl J, Franceschini, Nora, Justice, Anne, Reiner, Alex P, Buyske, Steven, Hindorff, Lucia A, Carty, Cara L, North, Kari E, Kooperberg, Charles, Boerwinkle, Eric, Young, Kristin, Graff, Mariaelisa, Peters, Ulrike, Absher, Devin, Hsiung, Chao A, Lee, Wen-Jane, Taylor, Kent D, Chen, Ying-Hsiang, Lee, I-Te, Guo, Xiuqing, Chung, Ren-Hua, Hung, Yi-Jen, Rotter, Jerome I, Juang, Jyh-Ming J, Quertermous, Thomas, Wang, Tzung-Dau, Rasheed, Asif, Frossard, Philippe, Alam, Dewan S, Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Chen, Yii-Der Ida, Nordestgaard, Børge G, Assimes, Themistocles L, Danesh, John, Butterworth, Adam S, and Saleheen, Danish

Subjects
Biological Sciences, Genetics, Cardiovascular, Heart Disease, Human Genome, Clinical Research, Aging, Atherosclerosis, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Arteries, Cell Adhesion, Chemotaxis, Leukocyte, Coronary Artery Disease, Energy Metabolism, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Histone Code, Humans, Male, Muscle, Smooth, Vascular, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, CARDIoGRAMplusC4D, EPIC-CVD, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Published
2017

6. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

Author

Ehret, Georg B, Ferreira, Teresa, Chasman, Daniel I, Jackson, Anne U, Schmidt, Ellen M, Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Lousie A, Kanoni, Stavroula, Petersen, Ann-Kristin, Pihur, Vasyl, Strawbridge, Rona J, Shungin, Dmitry, Hughes, Maria F, Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M, Magnusson, Patrik K, Salfati, Elias L, Rallidis, Loukianos S, Theusch, Elizabeth, Smith, Andrew JP, Folkersen, Lasse, Witkowska, Kate, Pers, Tune H, Joehanes, Roby, Kim, Stuart K, Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D, Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O, Bochud, Murielle, CHARGE-EchoGen consortium, CHARGE-HF consortium, Wellcome Trust Case Control Consortium, Absher, Devin, Adair, Linda S, Amin, Najaf, Arking, Dan E, Axelsson, Tomas, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R, Barroso, Inês, Bevan, Stephen, Bis, Joshua C, Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L, Boomsma, Dorret I, Bornstein, Stefan R, Brown, Morris J, Burnier, Michel, Cabrera, Claudia P, Chambers, John C, Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S, Chung, Ren-Hua, Collins, Francis S, Connell, John M, Döring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F, Doney, Alex SF, Drenos, Fotios, Edkins, Sarah, Eicher, John D, Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farrall, Martin, Felix, Janine F, Ferrières, Jean, Ferrucci, Luigi, Fornage, Myriam, and Forrester, Terrence

Subjects
CHARGE-EchoGen consortium, CHARGE-HF consortium, Wellcome Trust Case Control Consortium, Cells, Cultured, Humans, Hypertension, Microarray Analysis, Blood Pressure, Polymorphism, Single Nucleotide, African Continental Ancestry Group, Asian Continental Ancestry Group, Genome-Wide Association Study, Cells, Cultured, Polymorphism, Single Nucleotide, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Published
2016

7. Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.

Author

Sazonova, Olga, Zhao, Yuqi, Nürnberg, Sylvia, Miller, Clint, Pjanic, Milos, Castano, Victor G, Kim, Juyong B, Salfati, Elias L, Kundaje, Anshul B, Bejerano, Gill, Assimes, Themistocles, Yang, Xia, and Quertermous, Thomas

Subjects
Coronary Vessels, Humans, DNA-Binding Proteins, Transcription Factor AP-1, Gene Expression Regulation, Binding Sites, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Atherosclerosis, Basic Helix-Loop-Helix Transcription Factors, Gene Regulatory Networks, Coronary Artery Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Developmental Biology, Genetics
Abstract

To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.

Published
2015

10. Ebola virus transmission initiated by systemic ebola virus disease relapse

Author

Mbala-Kingebeni, Placide, Pratt, Catherine, Ruffin, Mbusa Mutafali, Pauthner, Matthias G, Bile, Faustin, Rambaut, Andrew, Nkuba Ndaye, Antoine, Black, Allison, Kinganda Lusamaki, Eddy, Faye, Martin, Aziza, Amuri, Diagne, Moussa M, Mukadi, Daniel, White, Bailey, Hadfield, James, Gangavarapu, Karthik, Bisento, Nella, Kazadi, Donatien, Nsunda, Bibiche, Akonga, Marceline, Tshiani, Olivier, Misasi, John, Ploquin, Aurelie, Epaso, Victor, Sana Paka, Emilia, N’kasar, Yannick Tutu Tshia, Mambu, Fabrice, Edidi, Francois, Matondo, Meris, Bula Bula, Junior, Diallo, Boubacar, Keita, Mory, Darnycka Belizaire, Marie Roseline, Fall, Ibrahima Soce, Yam, Abdoulaye, Sabue, Mulangu, Rimion, Anne W., Salfati, Elias L, Torkamani, Ali, Suchard, Marc A., Crozier, Ian, Hensley, Lisa E., Faye, Ousmane, Sall, Amadou A., Sullivan, Nancy J., Bedford, Trevor, Andersen, Kristian G., Wiley, Michael R., Ahuka-Mundeke, Steve, and Muyembe-Tamfum, Jean-Jacques

Subjects
viruses
Abstract

During the 2018–2020 Ebola virus disease (EVD) outbreak in North Kivu province in the Democratic Republic of Congo, EVD was diagnosed in a patient who had received the recombinant vesicular stomatitis virus–based vaccine expressing aZEBOV glycoprotein (rVSV-ZEBOV) (Merck). His treatment included an Ebola virus(EBOV)–specific monoclonal antibody (mAb114), and he recovered within 14 days. However, 6 months later, he presented again with severe EVD-like illness and EBOV viremia, and he died. We initiated epidemiologic and genomic investigations that showed that the patient had had a relapse of acute EVD that led to a transmission chain resulting in 91 cases across six health zones over 4 months. (Funded by the Bill and Melinda Gates Foundation and others.)

Published
2021
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11. Additional file 2 of Genotype imputation and variability in polygenic risk score estimation

Author

Shang-Fu Chen, Dias, Raquel, Evans, Doug, Salfati, Elias L., Shuchen Liu, Wineinger, Nathan E., and Torkamani, Ali

Abstract

Additional file 2: Supplemental Fig. S1-S13. PRS Reproducibility Across Diseases and Score Derivation Methods. Supplemental Fig. S14-S27. PRS Reproducibility Across Diseases and Score Derivation Methods by Ancestry. Supplemental Fig. S28-S40. PRS Variability Across Diseases and Score Derivation Methods as a Function of Percentile Bin. Supplemental Fig. S41-S54. PRS Variability Across Diseases and Score Derivation Methods as a Function of Percentile Bin by Ancestry. Supplemental Fig. S55. SNP level variability by Score Impact Across Diseases and Score Derivation Methods.

Published
2020
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12. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Author

Howson, Joanna M.M., Zhao, Wei, Barnes, Daniel R., Ho, Weang-Kee, Young, Robin, Paul, Dirk S., Waite, Lindsay L., Freitag, Daniel F., Fauman, Eric B., Salfati, Elias L., Sun, Benjamin B., Eicher, John D., Johnson, Andrew D., Sheu, Wayne H.H., Nielsen, Sune F., Lin, Wei-Yu, Surendran, Praveen, Malarstig, Anders, Wilk, Jemma B., Tybjærg-Hansen, Anne, Rasmussen, Katrine L., Kamstrup, Pia R., Deloukas, Panos, Erdmann, Jeanette, Kathiresan, Sekar, Samani, Nilesh J., Schunkert, Heribert, Watkins, Hugh, Do, Ron, Rader, Daniel J., Johnson, Julie A., Hazen, Stanley L., Quyyumi, Arshed A., Spertus, John A., Pepine, Carl J., Franceschini, Nora, Justice, Anne, Reiner, Alex P., Buyske, Steven, Hindorff, Lucia A., Carty, Cara L., North, Kari E., Kooperberg, Charles, Boerwinkle, Eric, Young, Kristin, Graff, Mariaelisa, Peters, Ulrike, Absher, Devin, Hsiung, Chao A., Lee, Wen-Jane, Taylor, Kent D., Chen, Ying-Hsiang, Lee, I-Te, Guo, Xiuqing, Chung, Ren-Hua, Hung, Yi-Jen, Rotter, Jerome I., Juang, Jyh-Ming J., Quertermous, Thomas, Wang, Tzung-Dau, Rasheed, Asif, Frossard, Philippe, Alam, Dewan S., Majumder, Abdulla Al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Chen, Yii-Der Ida, Nordestgaard, Børge G., Assimes, Themistocles L., Danesh, John, Butterworth, Adam S., and Saleheen, Danish

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Published
2017

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

Author

Ligthart, Symen, Marzi, Carola, Aslibekyan, Stella, Mendelson, Michael M, Conneely, Karen N, Tanaka, Toshiko, Colicino, Elena, Waite, Lindsay L, Joehanes, Roby, Guan, Weihua, Brody, Jennifer A, Elks, Cathy, Marioni, Riccardo, Jhun, Min A, Agha, Golareh, Bressler, Jan, Ward-Caviness, Cavin K, Chen, Brian H, Huan, Tianxiao, Bakulski, Kelly, Salfati, Elias L, WHI-EMPC Investigators, Fiorito, Giovanni, CHARGE epigenetics of Coronary Heart Disease, Wahl, Simone, Schramm, Katharina, Sha, Jin, Hernandez, Dena G, Just, Allan C, Smith, Jennifer A, Sotoodehnia, Nona, Pilling, Luke C, Pankow, James S, Tsao, Phil S, Liu, Chunyu, Zhao, Wei, Guarrera, Simonetta, Michopoulos, Vasiliki J, Smith, Alicia K, Peters, Marjolein J, Melzer, David, Vokonas, Pantel, Fornage, Myriam, Prokisch, Holger, Bis, Joshua C, Chu, Audrey Y, Herder, Christian, Grallert, Harald, Yao, Chen, Shah, Sonia, McRae, Allan F, Lin, Honghuang, Horvath, Steve, Fallin, Daniele, Hofman, Albert, Wareham, Nicholas J, Wiggins, Kerri L, Feinberg, Andrew P, Starr, John M, Visscher, Peter M, Murabito, Joanne M, Kardia, Sharon LR, Absher, Devin M, Binder, Elisabeth B, Singleton, Andrew B, Bandinelli, Stefania, Peters, Annette, Waldenberger, Melanie, Matullo, Giuseppe, Schwartz, Joel D, Demerath, Ellen W, Uitterlinden, André G, van Meurs, Joyce BJ, Franco, Oscar H, Chen, Yii-Der Ida, Levy, Daniel, Turner, Stephen T, Deary, Ian J, Ressler, Kerry J, Dupuis, Josée, Ferrucci, Luigi, Ong, Ken K, Assimes, Themistocles L, Boerwinkle, Eric, Koenig, Wolfgang, Arnett, Donna K, Baccarelli, Andrea A, Benjamin, Emelia J, Dehghan, Abbas, Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
Male, Inflammation, DNA methylation, Quantitative Trait Loci, Diabetes, Gene Expression, Genetic Variation, White People, Epigenesis, Genetic, C-reactive protein, Black or African American, Coronary heart disease, Epigenome-wide association study, Humans, CpG Islands, Female, Nucleotide Motifs, Body mass index, Genome-Wide Association Study
Abstract

Background: Chronic 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.Results: We 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 –7) in the discovery panel of European ancestry and replicated (P –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 –5), ten (17%) CpG sites were associated with a nearby genetic variant (P –3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P –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.Conclusion: We 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.

Published
2016

14. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A., Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, Andre G., van Meurs, Joyce B., Franco, Oscar H., Zhang, Guosheng, Li, Yun, Stewart, James D., Bis, Joshua C., Psaty, Bruce M., Chen, Yii-Der Ida, Kardia, Sharon L. R., Zhao, Wei, Turner, Stephen T., Absher, Devin, Aslibekyan, Stella, Starr, John M., Mcrae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., BIOS Consortium, van Greevenbroek, Marleen, Stehouwer, Coen, van der Kallen, Carla, Schalkwijk, Casper, Fornage, Myriam, Richard, Melissa A., Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, Andre G., van Meurs, Joyce B., Franco, Oscar H., Zhang, Guosheng, Li, Yun, Stewart, James D., Bis, Joshua C., Psaty, Bruce M., Chen, Yii-Der Ida, Kardia, Sharon L. R., Zhao, Wei, Turner, Stephen T., Absher, Devin, Aslibekyan, Stella, Starr, John M., Mcrae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., BIOS Consortium, van Greevenbroek, Marleen, Stehouwer, Coen, van der Kallen, Carla, Schalkwijk, Casper, and Fornage, Myriam

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 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 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.

Published
2017

15. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Author

Howson, Joanna M. M., Zhao, Wei, Barnes, Daniel R, Ho, Weang Kee, Young, Robin, Paul, Dirk S, Waite, Lindsay, Freitag, Daniel F, Fauman, Eric B, Salfati, Elias L, Sun, Benjamin B, Eicher, John D, Johnson, Andrew D, Sheu, Wayne H-H, Nielsen, Sune F, Lin, Wei-Yu, Surendran, Praveen, Malarstig, Anders, Wilk, Jemma B, Tybjærg-Hansen, Anne, Rasmussen, Katrine L, Kamstrup, Pia R, Deloukas, Panos, Erdmann, Jeanette, Kathiresan, Sekar, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, Do, Ron, Rader, Daniel J, Johnson, Julie A, Hazen, Stanley L, Quyyumi, Arshed A, Spertus, John A, Pepine, Carl J, Franceschini, Nora, Justice, Anne E, Reiner, Alex P, Buyske, Steven, Hindorff, Lucia A, Carty, Cara L, North, Kari E, Kooperberg, Charles, Boerwinkle, Eric, Young, Kristin L, Graff, Mariaelisa, Peters, Ulrike, Absher, Devin, Hsiung, Chao A, Nordestgaard, Børge G, Assimes, Themistocles L, Danesh, J, Butterworth, Adam S, Saleheen, D, Howson, Joanna M. M., Zhao, Wei, Barnes, Daniel R, Ho, Weang Kee, Young, Robin, Paul, Dirk S, Waite, Lindsay, Freitag, Daniel F, Fauman, Eric B, Salfati, Elias L, Sun, Benjamin B, Eicher, John D, Johnson, Andrew D, Sheu, Wayne H-H, Nielsen, Sune F, Lin, Wei-Yu, Surendran, Praveen, Malarstig, Anders, Wilk, Jemma B, Tybjærg-Hansen, Anne, Rasmussen, Katrine L, Kamstrup, Pia R, Deloukas, Panos, Erdmann, Jeanette, Kathiresan, Sekar, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, Do, Ron, Rader, Daniel J, Johnson, Julie A, Hazen, Stanley L, Quyyumi, Arshed A, Spertus, John A, Pepine, Carl J, Franceschini, Nora, Justice, Anne E, Reiner, Alex P, Buyske, Steven, Hindorff, Lucia A, Carty, Cara L, North, Kari E, Kooperberg, Charles, Boerwinkle, Eric, Young, Kristin L, Graff, Mariaelisa, Peters, Ulrike, Absher, Devin, Hsiung, Chao A, Nordestgaard, Børge G, Assimes, Themistocles L, Danesh, J, Butterworth, Adam S, and Saleheen, D

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Published
2017

16. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author

Ehret, Georg B., Ferreira, Teresa, Chasman, Daniel I., Jackson, Anne U., Schmidt, Ellen M., Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Louise A., Kanoni, Stavroula, Petersen, Ann -Kristin, Pihurl, Vasyl, Strawbridge, Rona J., Shungin, Dmitry, Hughes, Maria F., Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E., Guo, Xiuqing, Lyytikainen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M., Magnusson, Patrik K., Salfati, Elias L., Rallidis, Loukianos S., Theusch, Elizabeth, Smith, Andrew J. P., Folkersen, Lasse, Witkowska, Kate, Pers, Tune H., Joehanes, Roby, Kim, Stuart K., Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D., Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O., Bochud, Murielle, Absher, Devin, Adair, Linda S., Amin, Najaf, Arkingl, Dan E., Axelsson, Tomas, Baldassarre, Damian, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R., Barroso, Ines, Bevan, Stephen, Bis, Joshua C., Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L., Boomsma, Dorret I., Bornstein, Stefan R., Brown, Morris J., Burnier, Michel, Cabrera, Claudia P., Chambers, John C., Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S., Chung, Ren-Hua, Collins, Francis S., Connell, John M., Doring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F., Doney, Alex S. F., Drenos, Fotios, Edkins, Sarah, Eicher, John D., Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farra, Martin, Felixl, Janine F., Ferrieres, Jean, Ferrucci, Luigi, Fornage, Myriam, Forrester, Terrence, Franceschinil, Nora, Franco, Oscar H., Franco-Cereceda, Anders, Fraser, Ross M., Ganesh, Santhi K., Gao, He, Gertow, Karl, Gianfagna, Francesco, Gigante, Bruna, Giulianini, Franco, Goe, Anuj, Goodall, Alison H., Goodarzi, Mark, Gorski, Mathias, Grassler, Jurgen, Groves, Christopher J., Gudnason, Vilmundur, Gyllensten, Ulf, Hallmans, Göran, Hartikainen, Anna-Liisa, Hassinen, Maija, Havulinna, Aki S., Hayward, Caroline, Hercberg, Serge, Herzig, Karl-Heinz, Hicks, Andrew A., Hingorani, Aroon D., Hirschhorn, Joel N., Hofmanl, Albert, Holmen, Jostein, Holmen, Oddgeir Lingaas, Hottenga, Jouke-Jan, Howard, Phil, Hsiung, Chao A., Hunt, Steven C., Ikram, M. Arfan, Illig, Thomas, Iribarren, Carlos, Jensen, Richard A., Kahonen, Mika, Kang, Hyun Min, Kathiresan, Sekar, Keating, Brendan J., Khaw, Kay-Tee, Kim, Yun Kyoung, Kim, Eric, Kivimaki, Mika, Klopp, Norman, Kolovou, Genovefa, Komulainen, Pirjo, Kooner, Jaspal S., Kosova, Gulum, Krauss, Ronald M., Kuh, Diana, Kutalik, Zoltan, Kuusisto, Johanna, Kvaloy, Kirsti, Lakka, Timo A., Lee, Nanette R., Lee, I-Te, Lee, Wen-Jane, Levy, Daniel, Li, Xiaohui, Liang, Kae-Woei, Lin, Honghuang, Lin, Li, Lindstrom, Jaana, Lobbens, Stephane, Mannisto, Satu, Muller, Gabriele, Muller-Nurasyid, Martina, Mach, Francois, Markus, Hugh S., Marouli, Eirini, McCarthy, Mark I., McKenzie, Colin A., Meneton, Pierre, Menni, Cristina, Metspalu, Andres, Mijatovic, Vladan, Moilanen, Leena, Montasser, May E., Morris, Andrew D., Morrison, Alanna C., Mulas, Antonella, Nagaraja, Ramaiah, Narisu, Narisu, Nikus, Kjell, O'Donnell, Christopher J., O'Reilly, Paul F., Ong, Ken K., Paccaud, Fred, Palmer, Cameron D., Parsa, Afshin, Pedersen, Nancy L., Penninx, Brenda W., Perola, Markus, Peters, Annette, Poulter, Neil, Pramstaller, Peter P., Psaty, Bruce M., Quertermous, Thomas, Rao, Dabeeru C., Rasheed, Asif, Rayner, N. William, Renstrom, Frida, Rettig, Rainer, Rice, Kenneth M., Roberts, Robert, Rose, Lynda M., Rossouw, Jacques, Samani, Nilesh J., Sanna, Serena, Saramies, Jouko, Schunkert, Heribert, Sebert, Sylvain, Sheu, Wayne H-H, Shin, Young-Ah, Sim, Xueling, Smit, Johannes H., Smith, Albert V., Sosa, Maria X., Spector, Tim D., Stancakova, Alena, Stanton, Alice V., Stirrups, Kathleen E., Stringham, Heather M., Sundström, Johan, Swift, Amy J., Syvänen, Ann-Christine, Tai, E-Shyong, Tanaka, Toshiko, Tarasov, Kirill V., Teumer, Alexander, Thorsteinsdottir, Unnur, Tobin, Martin D., Tremoli, Elena, Uitterlinden, Andre G., Uusitupa, Matti, Vaez, Ahmad, Vaidya, Dhananjay, van Duijn, Cornelia M., van Iperen, Erik P. A., Vasan, Ramachandran S., Verwoert, Germaine C., Virtamo, Jarmo, Vitart, Veronique, Voight, Benjamin F., Vollenweider, Peter, Wagner, Aline, Wain, Louise V., Wareham, Nicholas J., Watldns, Hugh, Weder, Alan B., Westra, Harm Jan, Wilks, Rainford, Wilsgaard, Tom, Wilson, James F., Wong, Tien Y., Yang, Tsun-Po, Yao, Jie, Yengo, Loic, Zhang, Weihua, Zhao, Jing Hua, Zhu, Xiaofeng, Bovet, Pascal, Cooper, Richard S., Mohlke, Karen L., Saleheen, Danish, Lee, Jong-Young, Elliott, Paul, Gierman, Hinco J., Willer, Cristen J., Franke, Lude, Hovingh, G. Kees, Taylor, Kent D., Dedoussis, George, Sever, Peter, Wong, Andrew, Lind, Lars, Assimes, Themistocles L., Njolstad, Inger, Schwarz, Peter E. H., Langenberg, Claudia, Snieder, Harold, Caulfield, Mark J., Melander, E., Laakso, Markku, Saltevo, Juha, Rauramaa, Rainer, Tuomilehto, Jaakko, Ingelsson, Erik, Lehtimaki, Terho, Hveem, Kristian, Palmas, Walter, Marz, Winfried, Kumar, Meena, Salomaa, Veikko, Chen, Yii-Der I., Rotter, Jerome I., Froguel, Philippe, Jarvelin, Marjo-Riitta, Lakatta, Edward G., Kuulasmaa, Kari, Franks, Paul W., Hamsten, Anders, Wichmann, H-Erich, Palmer, Colin N. A., Stefansson, Kari, Ridker, Paul M., Loos, Ruth J. F., Chalcravarti, Aravinda, Deloukas, Panos, Morris, Andrew P., Newton-Cheh, Christopher, Munroe, Patricia B., Ehret, Georg B., Ferreira, Teresa, Chasman, Daniel I., Jackson, Anne U., Schmidt, Ellen M., Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Louise A., Kanoni, Stavroula, Petersen, Ann -Kristin, Pihurl, Vasyl, Strawbridge, Rona J., Shungin, Dmitry, Hughes, Maria F., Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E., Guo, Xiuqing, Lyytikainen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M., Magnusson, Patrik K., Salfati, Elias L., Rallidis, Loukianos S., Theusch, Elizabeth, Smith, Andrew J. P., Folkersen, Lasse, Witkowska, Kate, Pers, Tune H., Joehanes, Roby, Kim, Stuart K., Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D., Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O., Bochud, Murielle, Absher, Devin, Adair, Linda S., Amin, Najaf, Arkingl, Dan E., Axelsson, Tomas, Baldassarre, Damian, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R., Barroso, Ines, Bevan, Stephen, Bis, Joshua C., Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L., Boomsma, Dorret I., Bornstein, Stefan R., Brown, Morris J., Burnier, Michel, Cabrera, Claudia P., Chambers, John C., Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S., Chung, Ren-Hua, Collins, Francis S., Connell, John M., Doring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F., Doney, Alex S. F., Drenos, Fotios, Edkins, Sarah, Eicher, John D., Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farra, Martin, Felixl, Janine F., Ferrieres, Jean, Ferrucci, Luigi, Fornage, Myriam, Forrester, Terrence, Franceschinil, Nora, Franco, Oscar H., Franco-Cereceda, Anders, Fraser, Ross M., Ganesh, Santhi K., Gao, He, Gertow, Karl, Gianfagna, Francesco, Gigante, Bruna, Giulianini, Franco, Goe, Anuj, Goodall, Alison H., Goodarzi, Mark, Gorski, Mathias, Grassler, Jurgen, Groves, Christopher J., Gudnason, Vilmundur, Gyllensten, Ulf, Hallmans, Göran, Hartikainen, Anna-Liisa, Hassinen, Maija, Havulinna, Aki S., Hayward, Caroline, Hercberg, Serge, Herzig, Karl-Heinz, Hicks, Andrew A., Hingorani, Aroon D., Hirschhorn, Joel N., Hofmanl, Albert, Holmen, Jostein, Holmen, Oddgeir Lingaas, Hottenga, Jouke-Jan, Howard, Phil, Hsiung, Chao A., Hunt, Steven C., Ikram, M. Arfan, Illig, Thomas, Iribarren, Carlos, Jensen, Richard A., Kahonen, Mika, Kang, Hyun Min, Kathiresan, Sekar, Keating, Brendan J., Khaw, Kay-Tee, Kim, Yun Kyoung, Kim, Eric, Kivimaki, Mika, Klopp, Norman, Kolovou, Genovefa, Komulainen, Pirjo, Kooner, Jaspal S., Kosova, Gulum, Krauss, Ronald M., Kuh, Diana, Kutalik, Zoltan, Kuusisto, Johanna, Kvaloy, Kirsti, Lakka, Timo A., Lee, Nanette R., Lee, I-Te, Lee, Wen-Jane, Levy, Daniel, Li, Xiaohui, Liang, Kae-Woei, Lin, Honghuang, Lin, Li, Lindstrom, Jaana, Lobbens, Stephane, Mannisto, Satu, Muller, Gabriele, Muller-Nurasyid, Martina, Mach, Francois, Markus, Hugh S., Marouli, Eirini, McCarthy, Mark I., McKenzie, Colin A., Meneton, Pierre, Menni, Cristina, Metspalu, Andres, Mijatovic, Vladan, Moilanen, Leena, Montasser, May E., Morris, Andrew D., Morrison, Alanna C., Mulas, Antonella, Nagaraja, Ramaiah, Narisu, Narisu, Nikus, Kjell, O'Donnell, Christopher J., O'Reilly, Paul F., Ong, Ken K., Paccaud, Fred, Palmer, Cameron D., Parsa, Afshin, Pedersen, Nancy L., Penninx, Brenda W., Perola, Markus, Peters, Annette, Poulter, Neil, Pramstaller, Peter P., Psaty, Bruce M., Quertermous, Thomas, Rao, Dabeeru C., Rasheed, Asif, Rayner, N. William, Renstrom, Frida, Rettig, Rainer, Rice, Kenneth M., Roberts, Robert, Rose, Lynda M., Rossouw, Jacques, Samani, Nilesh J., Sanna, Serena, Saramies, Jouko, Schunkert, Heribert, Sebert, Sylvain, Sheu, Wayne H-H, Shin, Young-Ah, Sim, Xueling, Smit, Johannes H., Smith, Albert V., Sosa, Maria X., Spector, Tim D., Stancakova, Alena, Stanton, Alice V., Stirrups, Kathleen E., Stringham, Heather M., Sundström, Johan, Swift, Amy J., Syvänen, Ann-Christine, Tai, E-Shyong, Tanaka, Toshiko, Tarasov, Kirill V., Teumer, Alexander, Thorsteinsdottir, Unnur, Tobin, Martin D., Tremoli, Elena, Uitterlinden, Andre G., Uusitupa, Matti, Vaez, Ahmad, Vaidya, Dhananjay, van Duijn, Cornelia M., van Iperen, Erik P. A., Vasan, Ramachandran S., Verwoert, Germaine C., Virtamo, Jarmo, Vitart, Veronique, Voight, Benjamin F., Vollenweider, Peter, Wagner, Aline, Wain, Louise V., Wareham, Nicholas J., Watldns, Hugh, Weder, Alan B., Westra, Harm Jan, Wilks, Rainford, Wilsgaard, Tom, Wilson, James F., Wong, Tien Y., Yang, Tsun-Po, Yao, Jie, Yengo, Loic, Zhang, Weihua, Zhao, Jing Hua, Zhu, Xiaofeng, Bovet, Pascal, Cooper, Richard S., Mohlke, Karen L., Saleheen, Danish, Lee, Jong-Young, Elliott, Paul, Gierman, Hinco J., Willer, Cristen J., Franke, Lude, Hovingh, G. Kees, Taylor, Kent D., Dedoussis, George, Sever, Peter, Wong, Andrew, Lind, Lars, Assimes, Themistocles L., Njolstad, Inger, Schwarz, Peter E. H., Langenberg, Claudia, Snieder, Harold, Caulfield, Mark J., Melander, E., Laakso, Markku, Saltevo, Juha, Rauramaa, Rainer, Tuomilehto, Jaakko, Ingelsson, Erik, Lehtimaki, Terho, Hveem, Kristian, Palmas, Walter, Marz, Winfried, Kumar, Meena, Salomaa, Veikko, Chen, Yii-Der I., Rotter, Jerome I., Froguel, Philippe, Jarvelin, Marjo-Riitta, Lakatta, Edward G., Kuulasmaa, Kari, Franks, Paul W., Hamsten, Anders, Wichmann, H-Erich, Palmer, Colin N. A., Stefansson, Kari, Ridker, Paul M., Loos, Ruth J. F., Chalcravarti, Aravinda, Deloukas, Panos, Morris, Andrew P., Newton-Cheh, Christopher, and Munroe, Patricia B.

Abstract

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Published
2016
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20. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author

Ehret, Georg B, Ferreira, Teresa, Chasman, Daniel I, Jackson, Anne U, Schmidt, Ellen M, Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Louise A, Kanoni, Stavroula, Petersen, Ann-Kristin, Pihur, Vasyl, Strawbridge, Rona J, Shungin, Dmitry, Hughes, Maria F, Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M, Magnusson, Patrik K, Salfati, Elias L, Rallidis, Loukianos S, Theusch, Elizabeth, Smith, Andrew J P, Folkersen, Lasse, Witkowska, Kate, Pers, Tune H, Joehanes, Roby, Kim, Stuart K, Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D, Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O, Bochud, Murielle, Absher, Devin, Adair, Linda S, Amin, Najaf, Arking, Dan E, Axelsson, Tomas, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R, Barroso, Inês, Bevan, Stephen, Bis, Joshua C, Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L, Boomsma, Dorret I, Bornstein, Stefan R, Brown, Morris J, Burnier, Michel, Cabrera, Claudia P, Chambers, John C, Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S, Chung, Ren-Hua, Collins, Francis S, Connell, John M, Döring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F, Doney, Alex S F, Drenos, Fotios, Edkins, Sarah, Eicher, John D, Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farrall, Martin, Felix, Janine F, Ferrières, Jean, Ferrucci, Luigi, Fornage, Myriam, Forrester, Terrence, Franceschini, Nora, Franco, Oscar H, Franco-Cereceda, Anders, Fraser, Ross M, Ganesh, Santhi K, Gao, He, Gertow, Karl, Gianfagna, Francesco, Gigante, Bruna, Giulianini, Franco, Goel, Anuj, Goodall, Alison H, Goodarzi, Mark O, Gorski, Mathias, Gräßler, Jürgen, Groves, Christopher J, Gudnason, Vilmundur, Gyllensten, Ulf, Hallmans, Göran, Hartikainen, Anna-Liisa, Hassinen, Maija, Havulinna, Aki S, Hayward, Caroline, Hercberg, Serge, Herzig, Karl-Heinz, Hicks, Andrew A, Hingorani, Aroon D, Hirschhorn, Joel N, Hofman, Albert, Holmen, Jostein, Holmen, Oddgeir Lingaas, Hottenga, Jouke-Jan, Howard, Phil, Hsiung, Chao A, Hunt, Steven C, Ikram, M Arfan, Illig, Thomas, Iribarren, Carlos, Jensen, Richard A, Kähönen, Mika, Kang, Hyun Min, Kathiresan, Sekar, Keating, Brendan J, Khaw, Kay-Tee, Kim, Yun Kyoung, Kim, Eric, Kivimaki, Mika, Klopp, Norman, Kolovou, Genovefa, Komulainen, Pirjo, Kooner, Jaspal S, Kosova, Gulum, Krauss, Ronald M, Kuh, Diana, Kutalik, Zoltan, Kuusisto, Johanna, Kvaløy, Kirsti, Lakka, Timo A, Lee, Nanette R, Lee, I-Te, Lee, Wen-Jane, Levy, Daniel, Li, Xiaohui, Liang, Kae-Woei, Lin, Honghuang, Lin, Li, Lindström, Jaana, Lobbens, Stéphane, Männistö, Satu, Müller, Gabriele, Müller-Nurasyid, Martina, Mach, François, Markus, Hugh S, Marouli, Eirini, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Menni, Cristina, Metspalu, Andres, Mijatovic, Vladan, Moilanen, Leena, Montasser, May E, Morris, Andrew D, Morrison, Alanna C, Mulas, Antonella, Nagaraja, Ramaiah, Narisu, Narisu, Nikus, Kjell, O'Donnell, Christopher J, O'Reilly, Paul F, Ong, Ken K, Paccaud, Fred, Palmer, Cameron D, Parsa, Afshin, Pedersen, Nancy L, Penninx, Brenda W, Perola, Markus, Peters, Annette, Poulter, Neil, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rao, Dabeeru C, Rasheed, Asif, Rayner, N William, Renström, Frida, Rettig, Rainer, Rice, Kenneth M, Roberts, Robert, Rose, Lynda M, Rossouw, Jacques, Samani, Nilesh J, Sanna, Serena, Saramies, Jouko, Schunkert, Heribert, Sebert, Sylvain, Sheu, Wayne H-H, Shin, Young-Ah, Sim, Xueling, Smit, Johannes H, Smith, Albert V, Sosa, Maria X, Spector, Tim D, Stančáková, Alena, Stanton, Alice V, Stirrups, Kathleen E, Stringham, Heather M, Sundstrom, Johan, Swift, Amy J, Syvänen, Ann-Christine, Tai, E-Shyong, Tanaka, Toshiko, Tarasov, Kirill V, Teumer, Alexander, Thorsteinsdottir, Unnur, Tobin, Martin D, Tremoli, Elena, Uitterlinden, Andre G, Uusitupa, Matti, Vaez, Ahmad, Vaidya, Dhananjay, van Duijn, Cornelia M, van Iperen, Erik P A, Vasan, Ramachandran S, Verwoert, Germaine C, Virtamo, Jarmo, Vitart, Veronique, Voight, Benjamin F, Vollenweider, Peter, Wagner, Aline, Wain, Louise V, Wareham, Nicholas J, Watkins, Hugh, Weder, Alan B, Westra, Harm-Jan, Wilks, Rainford, Wilsgaard, Tom, Wilson, James F, Wong, Tien Y, Yang, Tsun-Po, Yao, Jie, Yengo, Loic, Zhang, Weihua, Zhao, Jing Hua, Zhu, Xiaofeng, Bovet, Pascal, Cooper, Richard S, Mohlke, Karen L, Saleheen, Danish, Lee, Jong-Young, Elliott, Paul, Gierman, Hinco J, Willer, Cristen J, Franke, Lude, Hovingh, G Kees, Taylor, Kent D, Dedoussis, George, Sever, Peter, Wong, Andrew, Lind, Lars, Assimes, Themistocles L, Njølstad, Inger, Schwarz, Peter E H, Langenberg, Claudia, Snieder, Harold, Caulfield, Mark J, Melander, Olle, Laakso, Markku, Saltevo, Juha, Rauramaa, Rainer, Tuomilehto, Jaakko, Ingelsson, Erik, Lehtimäki, Terho, Hveem, Kristian, Palmas, Walter, März, Winfried, Kumari, Meena, Salomaa, Veikko, Chen, Yii-Der I, Rotter, Jerome I, Froguel, Philippe, Jarvelin, Marjo-Riitta, Lakatta, Edward G, Kuulasmaa, Kari, Franks, Paul W, Hamsten, Anders, Wichmann, H-Erich, Palmer, Colin N A, Stefansson, Kari, Ridker, Paul M, Loos, Ruth J F, Chakravarti, Aravinda, Deloukas, Panos, Morris, Andrew P, Newton-Cheh, Christopher, Munroe, Patricia B, Ehret, Georg B, Ferreira, Teresa, Chasman, Daniel I, Jackson, Anne U, Schmidt, Ellen M, Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Louise A, Kanoni, Stavroula, Petersen, Ann-Kristin, Pihur, Vasyl, Strawbridge, Rona J, Shungin, Dmitry, Hughes, Maria F, Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M, Magnusson, Patrik K, Salfati, Elias L, Rallidis, Loukianos S, Theusch, Elizabeth, Smith, Andrew J P, Folkersen, Lasse, Witkowska, Kate, Pers, Tune H, Joehanes, Roby, Kim, Stuart K, Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D, Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O, Bochud, Murielle, Absher, Devin, Adair, Linda S, Amin, Najaf, Arking, Dan E, Axelsson, Tomas, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R, Barroso, Inês, Bevan, Stephen, Bis, Joshua C, Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L, Boomsma, Dorret I, Bornstein, Stefan R, Brown, Morris J, Burnier, Michel, Cabrera, Claudia P, Chambers, John C, Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S, Chung, Ren-Hua, Collins, Francis S, Connell, John M, Döring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F, Doney, Alex S F, Drenos, Fotios, Edkins, Sarah, Eicher, John D, Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farrall, Martin, Felix, Janine F, Ferrières, Jean, Ferrucci, Luigi, Fornage, Myriam, Forrester, Terrence, Franceschini, Nora, Franco, Oscar H, Franco-Cereceda, Anders, Fraser, Ross M, Ganesh, Santhi K, Gao, He, Gertow, Karl, Gianfagna, Francesco, Gigante, Bruna, Giulianini, Franco, Goel, Anuj, Goodall, Alison H, Goodarzi, Mark O, Gorski, Mathias, Gräßler, Jürgen, Groves, Christopher J, Gudnason, Vilmundur, Gyllensten, Ulf, Hallmans, Göran, Hartikainen, Anna-Liisa, Hassinen, Maija, Havulinna, Aki S, Hayward, Caroline, Hercberg, Serge, Herzig, Karl-Heinz, Hicks, Andrew A, Hingorani, Aroon D, Hirschhorn, Joel N, Hofman, Albert, Holmen, Jostein, Holmen, Oddgeir Lingaas, Hottenga, Jouke-Jan, Howard, Phil, Hsiung, Chao A, Hunt, Steven C, Ikram, M Arfan, Illig, Thomas, Iribarren, Carlos, Jensen, Richard A, Kähönen, Mika, Kang, Hyun Min, Kathiresan, Sekar, Keating, Brendan J, Khaw, Kay-Tee, Kim, Yun Kyoung, Kim, Eric, Kivimaki, Mika, Klopp, Norman, Kolovou, Genovefa, Komulainen, Pirjo, Kooner, Jaspal S, Kosova, Gulum, Krauss, Ronald M, Kuh, Diana, Kutalik, Zoltan, Kuusisto, Johanna, Kvaløy, Kirsti, Lakka, Timo A, Lee, Nanette R, Lee, I-Te, Lee, Wen-Jane, Levy, Daniel, Li, Xiaohui, Liang, Kae-Woei, Lin, Honghuang, Lin, Li, Lindström, Jaana, Lobbens, Stéphane, Männistö, Satu, Müller, Gabriele, Müller-Nurasyid, Martina, Mach, François, Markus, Hugh S, Marouli, Eirini, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Menni, Cristina, Metspalu, Andres, Mijatovic, Vladan, Moilanen, Leena, Montasser, May E, Morris, Andrew D, Morrison, Alanna C, Mulas, Antonella, Nagaraja, Ramaiah, Narisu, Narisu, Nikus, Kjell, O'Donnell, Christopher J, O'Reilly, Paul F, Ong, Ken K, Paccaud, Fred, Palmer, Cameron D, Parsa, Afshin, Pedersen, Nancy L, Penninx, Brenda W, Perola, Markus, Peters, Annette, Poulter, Neil, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rao, Dabeeru C, Rasheed, Asif, Rayner, N William, Renström, Frida, Rettig, Rainer, Rice, Kenneth M, Roberts, Robert, Rose, Lynda M, Rossouw, Jacques, Samani, Nilesh J, Sanna, Serena, Saramies, Jouko, Schunkert, Heribert, Sebert, Sylvain, Sheu, Wayne H-H, Shin, Young-Ah, Sim, Xueling, Smit, Johannes H, Smith, Albert V, Sosa, Maria X, Spector, Tim D, Stančáková, Alena, Stanton, Alice V, Stirrups, Kathleen E, Stringham, Heather M, Sundstrom, Johan, Swift, Amy J, Syvänen, Ann-Christine, Tai, E-Shyong, Tanaka, Toshiko, Tarasov, Kirill V, Teumer, Alexander, Thorsteinsdottir, Unnur, Tobin, Martin D, Tremoli, Elena, Uitterlinden, Andre G, Uusitupa, Matti, Vaez, Ahmad, Vaidya, Dhananjay, van Duijn, Cornelia M, van Iperen, Erik P A, Vasan, Ramachandran S, Verwoert, Germaine C, Virtamo, Jarmo, Vitart, Veronique, Voight, Benjamin F, Vollenweider, Peter, Wagner, Aline, Wain, Louise V, Wareham, Nicholas J, Watkins, Hugh, Weder, Alan B, Westra, Harm-Jan, Wilks, Rainford, Wilsgaard, Tom, Wilson, James F, Wong, Tien Y, Yang, Tsun-Po, Yao, Jie, Yengo, Loic, Zhang, Weihua, Zhao, Jing Hua, Zhu, Xiaofeng, Bovet, Pascal, Cooper, Richard S, Mohlke, Karen L, Saleheen, Danish, Lee, Jong-Young, Elliott, Paul, Gierman, Hinco J, Willer, Cristen J, Franke, Lude, Hovingh, G Kees, Taylor, Kent D, Dedoussis, George, Sever, Peter, Wong, Andrew, Lind, Lars, Assimes, Themistocles L, Njølstad, Inger, Schwarz, Peter E H, Langenberg, Claudia, Snieder, Harold, Caulfield, Mark J, Melander, Olle, Laakso, Markku, Saltevo, Juha, Rauramaa, Rainer, Tuomilehto, Jaakko, Ingelsson, Erik, Lehtimäki, Terho, Hveem, Kristian, Palmas, Walter, März, Winfried, Kumari, Meena, Salomaa, Veikko, Chen, Yii-Der I, Rotter, Jerome I, Froguel, Philippe, Jarvelin, Marjo-Riitta, Lakatta, Edward G, Kuulasmaa, Kari, Franks, Paul W, Hamsten, Anders, Wichmann, H-Erich, Palmer, Colin N A, Stefansson, Kari, Ridker, Paul M, Loos, Ruth J F, Chakravarti, Aravinda, Deloukas, Panos, Morris, Andrew P, Newton-Cheh, Christopher, and Munroe, Patricia B

Abstract

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

21. Epigenome-wide Association Study of Measures of Fasting Glucose, Fasting Insulin, and Hba1c in Non-diabetic Individuals of European, African, and Hispanic Ancestry in the Charge Consortium.

Author

Hidalgo, Bertha A., Hivert, Marie-France, Wessel, Jennifer, Weihua Guan, Gondalia, Rahul B., Salfati, Elias L., Montoro Carnero, Elena, Moore, Ann Z., Brody, Jen, Kriebel, Jennifer, Smith, Jennifer, Wei Zhao, Ligthart, Symen, Hill, David, Pankow, James S., and Chu, Audrey Y.

Published
2017
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22. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.

Author

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 SL, Absher DM, Binder EB, Singleton AB, Bandinelli S, Peters A, Waldenberger M, Matullo G, Schwartz JD, Demerath EW, Uitterlinden AG, van Meurs JB, Franco OH, Chen YI, 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, and Dehghan A

Subjects
Black or African American, CpG Islands genetics, DNA Methylation genetics, Female, Gene Expression, Genetic Variation, Genome-Wide Association Study, Humans, Inflammation blood, Male, Nucleotide Motifs genetics, White People, C-Reactive Protein genetics, Epigenesis, Genetic, Inflammation genetics, Quantitative Trait Loci genetics
Abstract

Background: Chronic 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., Results: We 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., Conclusion: We 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.

Published
2016
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