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1. Transcriptome-wide association study of circulating IgE levels identifies novel targets for asthma and allergic diseases

Author

Joehanes Roby, O’Connor George, Levy Daniel, Lasky-Su Jessica, Yao Chen, Recto Kathryn, Huan Tianxiao, Lee Dong Heon, Lee Gha Young, Hwang Shih-Jen, Gereige Jessica, and Rachel S. Kelly

Subjects
biology, Immunology, Immunoglobulin E, medicine.disease, Transcriptome, Immune system, Genetic epidemiology, Mendelian randomization, Gene expression, biology.protein, medicine, Immunology and Allergy, Gene, Asthma
Abstract

Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate CLC, CCDC21, S100A13, and GCNT1) as putatively causal (pGCNT1 (beta=1.5, p=0.01)—which is a top result in the MR analysis of expression in relation to asthma and allergic diseases—plays a role in regulating T helper type 1 cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified—particularly those implicated in MR analysis—can be explored as promising therapeutic targets for asthma and IgE-related diseases.

Published
2023
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2. Epigenome-wide association study of mitochondrial genome copy number

Author

Wang, Penglong, Castellani, Christina A, Yao, Jie, Huan, Tianxiao, Bielak, Lawrence F, Zhao, Wei, Haessler, Jeffrey, Joehanes, Roby, Sun, Xianbang, Guo, Xiuqing, Longchamps, Ryan J, Manson, JoAnn E, Grove, Megan L, Bressler, Jan, Taylor, Kent D, Lappalainen, Tuuli, Kasela, Silva, Van Den Berg, David J, Hou, Lifang, Reiner, Alexander, Liu, Yongmei, Boerwinkle, Eric, Smith, Jennifer A, Peyser, Patricia A, Fornage, Myriam, Rich, Stephen S, Rotter, Jerome I, Kooperberg, Charles, Arking, Dan E, Levy, Daniel, Liu, Chunyu, and NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Subjects
Male, Genetics & Heredity, Genome, DNA Copy Number Variations, Human Genome, DNA, DNA Methylation, Middle Aged, Biological Sciences, Cardiovascular, Medical and Health Sciences, Mitochondrial, Epigenome, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Heart Disease, Genetics, Humans, Female, Generic health relevance, Aged
Abstract

We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57-67years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P

Published
2021

3. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author

Wyss, Annah B, Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N, Lahousse, Lies, Latourelle, Jeanne C, Smith, Albert Vernon, Bartz, Traci M, Feitosa, Mary F, Gao, Wei, Ahluwalia, Tarunveer S, Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K, Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E, Wang, Tianyuan, Obeidat, Ma'en, Hobbs, Brian D, Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M, Hu, Donglei, Mogil, Lauren S, Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B, Kalhan, Ravi, Heckbert, Susan R, Paternoster, Lavinia, Burkart, Kristin M, Liu, Yongmei, Holliday, Elizabeth G, Wilson, James G, Vonk, Judith M, Sanders, Jason L, Barr, R Graham, de Mutsert, Renée, Menezes, Ana Maria Baptista, Adams, Hieab HH, van den Berge, Maarten, Joehanes, Roby, Levin, Albert M, Liberto, Jennifer, Launer, Lenore J, Morrison, Alanna C, Sitlani, Colleen M, Celedón, Juan C, Kritchevsky, Stephen B, Scott, Rodney J, Christensen, Kaare, Rotter, Jerome I, Bonten, Tobias N, Wehrmeister, Fernando César, Bossé, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A, Kaplan, Robert C, Lohman, Kurt, McEvoy, Mark, Province, Michael A, Rosendaal, Frits R, Taylor, Kent D, Nickle, David C, Williams, L Keoki, Burchard, Esteban G, Wheeler, Heather E, Sin, Don D, Gudnason, Vilmundur, North, Kari E, Fornage, Myriam, Psaty, Bruce M, Myers, Richard H, O'Connor, George, Hansen, Torben, Laurie, Cathy C, Cassano, Patricia A, Sung, Joohon, Kim, Woo Jin, Attia, John R, Lange, Leslie, Boezen, H Marike, Thyagarajan, Bharat, Rich, Stephen S, Mook-Kanamori, Dennis O, Horta, Bernardo Lessa, Uitterlinden, André G, Im, Hae Kyung, Cho, Michael H, Brusselle, Guy G, and Gharib, Sina A

Subjects
Lung Diseases, Male, Chronic Obstructive, Vital Capacity, Quantitative Trait Loci, European Continental Ancestry Group, Black People, White People, Linkage Disequilibrium, Pulmonary Disease, Forced Expiratory Volume, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Lung, African Continental Ancestry Group, Asian, Human Genome, Smoking, Hispanic or Latino, Genomics, Single Nucleotide, Asian Americans, Sample Size, Regression Analysis, Female, Hispanic Americans, Biotechnology, Genome-Wide Association Study
Abstract

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Published
2018

4. 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

5. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author

Liu, Chunyu, Kraja, Aldi T, Smith, Jennifer A, Brody, Jennifer A, Franceschini, Nora, Bis, Joshua C, Rice, Kenneth, Morrison, Alanna C, Lu, Yingchang, Weiss, Stefan, Guo, Xiuqing, Palmas, Walter, Martin, Lisa W, Chen, Yii-Der Ida, Surendran, Praveen, Drenos, Fotios, Cook, James P, Auer, Paul L, Chu, Audrey Y, Giri, Ayush, Zhao, Wei, Jakobsdottir, Johanna, Lin, Li-An, Stafford, Jeanette M, Amin, Najaf, Mei, Hao, Yao, Jie, Voorman, Arend, CHD Exome+ Consortium, ExomeBP Consortium, GoT2DGenes Consortium, T2D-GENES Consortium, Larson, Martin G, Grove, Megan L, Smith, Albert V, Hwang, Shih-Jen, Chen, Han, Huan, Tianxiao, Kosova, Gulum, Stitziel, Nathan O, Kathiresan, Sekar, Samani, Nilesh, Schunkert, Heribert, Deloukas, Panos, Myocardial Infarction Genetics And CARDIoGRAM Exome Consortia, Li, Man, Fuchsberger, Christian, Pattaro, Cristian, Gorski, Mathias, CKDGen Consortium, Kooperberg, Charles, Papanicolaou, George J, Rossouw, Jacques E, Faul, Jessica D, Kardia, Sharon LR, Bouchard, Claude, Raffel, Leslie J, Uitterlinden, André G, Franco, Oscar H, Vasan, Ramachandran S, O'Donnell, Christopher J, Taylor, Kent D, Liu, Kiang, Bottinger, Erwin P, Gottesman, Omri, Daw, E Warwick, Giulianini, Franco, Ganesh, Santhi, Salfati, Elias, Harris, Tamara B, Launer, Lenore J, Dörr, Marcus, Felix, Stephan B, Rettig, Rainer, Völzke, Henry, Kim, Eric, Lee, Wen-Jane, Lee, I-Te, Sheu, Wayne H-H, Tsosie, Krystal S, Edwards, Digna R Velez, Liu, Yongmei, Correa, Adolfo, Weir, David R, Völker, Uwe, Ridker, Paul M, Boerwinkle, Eric, Gudnason, Vilmundur, Reiner, Alexander P, Van Duijn, Cornelia M, Borecki, Ingrid B, Edwards, Todd L, Chakravarti, Aravinda, Rotter, Jerome I, Psaty, Bruce M, Loos, Ruth JF, Fornage, Myriam, Ehret, Georg B, Newton-Cheh, Christopher, Levy, Daniel, Chasman, Daniel I, Smith, Jennifer A [0000-0002-3575-5468], Lin, Li-An [0000-0003-2731-1346], Smith, Albert V [0000-0003-1942-5845], Chen, Han [0000-0002-9510-4923], Deloukas, Panos [0000-0001-9251-070X], Li, Man [0000-0002-3839-0281], Correa, Adolfo [0000-0002-9501-600X], Edwards, Todd L [0000-0003-4318-6119], Ehret, Georg B [0000-0002-5730-0675], and Apollo - University of Cambridge Repository

Subjects
Genotype, Genome, Human, Hypertension, Genetic Variation, Humans, Blood Pressure, Exome, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Oligonucleotide Array Sequence Analysis
Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Published
2016

6. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author

Liu, Chunyu, Kraja, Aldi T, Smith, Jennifer A, Brody, Jennifer A, Franceschini, Nora, Bis, Joshua C, Rice, Kenneth, Morrison, Alanna C, Lu, Yingchang, Weiss, Stefan, Guo, Xiuqing, Palmas, Walter, Martin, Lisa W, Chen, Yii-Der Ida, Surendran, Praveen, Drenos, Fotios, Cook, James P, Auer, Paul L, Chu, Audrey Y, Giri, Ayush, Zhao, Wei, Jakobsdottir, Johanna, Lin, Li-An, Stafford, Jeanette M, Amin, Najaf, Mei, Hao, Yao, Jie, Voorman, Arend, CHD Exome+ Consortium, ExomeBP Consortium, GoT2DGenes Consortium, T2D-GENES Consortium, Larson, Martin G, Grove, Megan L, Smith, Albert V, Hwang, Shih-Jen, Chen, Han, Huan, Tianxiao, Kosova, Gulum, Stitziel, Nathan O, Kathiresan, Sekar, Samani, Nilesh, Schunkert, Heribert, Deloukas, Panos, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, Li, Man, Fuchsberger, Christian, Pattaro, Cristian, Gorski, Mathias, CKDGen Consortium, Kooperberg, Charles, Papanicolaou, George J, Rossouw, Jacques E, Faul, Jessica D, Kardia, Sharon LR, Bouchard, Claude, Raffel, Leslie J, Uitterlinden, André G, Franco, Oscar H, Vasan, Ramachandran S, O'Donnell, Christopher J, Taylor, Kent D, Liu, Kiang, Bottinger, Erwin P, Gottesman, Omri, Daw, E Warwick, Giulianini, Franco, Ganesh, Santhi, Salfati, Elias, Harris, Tamara B, Launer, Lenore J, Dörr, Marcus, Felix, Stephan B, Rettig, Rainer, Völzke, Henry, Kim, Eric, Lee, Wen-Jane, Lee, I-Te, Sheu, Wayne H-H, Tsosie, Krystal S, Edwards, Digna R Velez, Liu, Yongmei, Correa, Adolfo, Weir, David R, Völker, Uwe, Ridker, Paul M, Boerwinkle, Eric, Gudnason, Vilmundur, Reiner, Alexander P, van Duijn, Cornelia M, Borecki, Ingrid B, Edwards, Todd L, Chakravarti, Aravinda, Rotter, Jerome I, Psaty, Bruce M, Loos, Ruth JF, Fornage, Myriam, Ehret, Georg B, Newton-Cheh, Christopher, and Levy, Daniel

Subjects
Genotype, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, Blood Pressure, Cardiovascular, Medical and Health Sciences, Humans, 2.1 Biological and endogenous factors, Exome, GoT2DGenes Consortium, Polymorphism, Aetiology, Oligonucleotide Array Sequence Analysis, Genome, CHD Exome+ Consortium, CKDGen Consortium, Prevention, Genetic Variation, Single Nucleotide, Biological Sciences, T2D-GENES Consortium, Hypertension, ExomeBP Consortium, Human, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Published
2016

7. The transcriptional landscape of age in human peripheral blood

Author

Peters, Marjolein J, Joehanes, Roby, Pilling, Luke C, Schurmann, Claudia, Conneely, Karen N, Powell, Joseph, Reinmaa, Eva, Sutphin, George L, Zhernakova, Alexandra, Schramm, Katharina, Wilson, Yana A, Kobes, Sayuko, Tukiainen, Taru, NABEC/UKBEC Consortium, Ramos, Yolande F, Göring, Harald HH, Fornage, Myriam, Liu, Yongmei, Gharib, Sina A, Stranger, Barbara E, De Jager, Philip L, Aviv, Abraham, Levy, Daniel, Murabito, Joanne M, Munson, Peter J, Huan, Tianxiao, Hofman, Albert, Uitterlinden, André G, Rivadeneira, Fernando, van Rooij, Jeroen, Stolk, Lisette, Broer, Linda, Verbiest, Michael MPJ, Jhamai, Mila, Arp, Pascal, Metspalu, Andres, Tserel, Liina, Milani, Lili, Samani, Nilesh J, Peterson, Pärt, Kasela, Silva, Codd, Veryan, Peters, Annette, Ward-Caviness, Cavin K, Herder, Christian, Waldenberger, Melanie, Roden, Michael, Singmann, Paula, Zeilinger, Sonja, Illig, Thomas, Homuth, Georg, Grabe, Hans-Jörgen, Völzke, Henry, Steil, Leif, Kocher, Thomas, Murray, Anna, Melzer, David, Yaghootkar, Hanieh, Bandinelli, Stefania, Moses, Eric K, Kent, Jack W, Curran, Joanne E, Johnson, Matthew P, Williams-Blangero, Sarah, Westra, Harm-Jan, McRae, Allan F, Smith, Jennifer A, Kardia, Sharon LR, Hovatta, Iiris, Perola, Markus, Ripatti, Samuli, Salomaa, Veikko, Henders, Anjali K, Martin, Nicholas G, Smith, Alicia K, Mehta, Divya, Binder, Elisabeth B, Nylocks, K Maria, Kennedy, Elizabeth M, Klengel, Torsten, Ding, Jingzhong, Suchy-Dicey, Astrid M, Enquobahrie, Daniel A, Brody, Jennifer, Rotter, Jerome I, Chen, Yii-Der I, Houwing-Duistermaat, Jeanine, Kloppenburg, Margreet, Slagboom, P Eline, Helmer, Quinta, den Hollander, Wouter, Bean, Shannon, Raj, Towfique, Bakhshi, Noman, Wang, Qiao Ping, Oyston, Lisa J, Psaty, Bruce M, Tracy, Russell P, Montgomery, Grant W, and Turner, Stephen T

Subjects
Aging, Gene Expression Profiling, 1.1 Normal biological development and functioning, European Continental Ancestry Group, Human Genome, DNA Methylation, White People, NABEC/UKBEC Consortium, Underpinning research, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Transcriptome, Biomarkers, Biotechnology
Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

8. Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

Author

Mandaviya, Pooja, Joehanes, Roby, Aïssi, Dylan, Kühnel, Brigitte, Marioni, Riccardo, Truong, Vinh, Stolk, Lisette, Beekman, Marian, Bonder, Jan, Franke, Lude, Gieger, Christian, Huan, Tianxiao, Ikram, M. Arfan, Kunze, Sonja, Liang, Liming, Lindemans, Jan, Liu, Chunyu, McRae, Allan, Mendelson, Michael, Müller-Nurasyid, Martina, Peters, Annette, Slagboom, P. Eline, Starr, John, Trégouët, David-Alexandre, Uitterlinden, Andre, van Greevenbroek, Marleen, Van Heemst, Diana, van Iterson, Maarten, Wells, Philip, Yao, Chen, Deary, Ian, Gagnon, France, Heijmans, Bastiaan, Lévy, Daniel, Morange, Pierre-Emmanuel, Waldenberger, Melanie, Heil, Sandra, van Meurs, Joyce, Zeller, Tanja, Kü Hnel, Brigitte, Bonder, Marc, Tré Gouë T, David-Alexandre, Uitterlinden, André, Clinical Chemistry, Internal Medicine, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Molecular Epidemiology, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Metacohorts Consortium, Harvard T.H. Chan School of Public Health, Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Center For Narcolepsy, Stanford University, Leiden University Medical Center (LUMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of neurology, Paris-Jourdan Sciences Economiques (PSE), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Recherche Agronomique (INRA)-École des hautes études en sciences sociales (EHESS)-École des Ponts ParisTech (ENPC)-Centre National de la Recherche Scientifique (CNRS), Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Heart Center Hamburg, Netherlands Organization for Scientific Research (NWO) 184021007, Netherlands CardioVascular Research Initiative (Royal Netherlands Academy of Sciences) CVON2011-19, Dutch government NWO 184.021.007, CAN Institute for Cardiometabolism and Nutrition, ANR-10-IAHU-05 National Institutes of Health N01-HC-25195, UK's Biotechnology and Biological Sciences Research Council (BBSRC)1921, Age UK (The Disconnected Mind project) 1936, University of Edinburgh as part of the cross council Lifelong Health and Wellbeing initiative MR/K026992/1, Canadian Institutes of Health Research MOP 86466, Heart and Stroke Foundation of Canada T6484, European Project: 603288,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,SYSVASC(2014), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Czech Academy of Sciences [Prague] (ASCR), Stanford University [Stanford], École normale supérieure - Paris (ENS Paris)-Institut National de la Recherche Agronomique (INRA)-École des hautes études en sciences sociales (EHESS)-École des Ponts ParisTech (ENPC)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Universiteit Leiden, Universiteit Leiden-Universiteit Leiden, École normale supérieure - Paris (ENS-PSL), Interne Geneeskunde, and RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome

Subjects
0301 basic medicine, Homocysteine, health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], variabilité génétique, lcsh:Medicine, Social Sciences, Genome-wide association study, VARIANTS, Biochemistry, Cohort Studies, White Blood Cells, chemistry.chemical_compound, Mathematical and Statistical Techniques, 0302 clinical medicine, Sociology, Animal Cells, Consortia, mu-Crystallins, Medicine and Health Sciences, Leukocytes, lcsh:Science, health care economics and organizations, GENE-EXPRESSION, RISK, Genetics, Vegetal Biology, DNA methylation, Multidisciplinary, biology, Autosomes, FOLATE STATUS, Chemical Reactions, homocystéine, Methylation, CANCER, Chromatin, Nucleic acids, Chemistry, CpG site, 030220 oncology & carcinogenesis, Physical Sciences, MENDELIAN RANDOMIZATION, Epigenetics, Chromosomes, Human, Pair 6, Cellular Types, DNA modification, Chromatin modification, Statistics (Mathematics), Research Article, Chromosome biology, Adult, Cell biology, méthylation de l'adn, Immune Cells, education, Immunology, Single-nucleotide polymorphism, Research and Analysis Methods, Polymorphism, Single Nucleotide, Chromosomes, REGION, Molecular Genetics, 03 medical and health sciences, INSTRUMENTAL VARIABLES, Humans, analyse génomique, leucocyte, GENOME-WIDE ASSOCIATION, Statistical Methods, Molecular Biology, METAANALYSIS, Methylenetetrahydrofolate Reductase (NADPH2), Blood Cells, Biology and life sciences, lcsh:R, DNA, Chromosome Pairs, Molecular biology, 030104 developmental biology, chemistry, Genetic Loci, Methylenetetrahydrofolate reductase, biology.protein, lcsh:Q, CpG Islands, Gene expression, Biologie végétale, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Mathematics, Meta-Analysis
Abstract

BackgroundDNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.MethodsMethylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C> T and genetic-risk score (GRS) based on 18 homocysteineassociated SNPs, with genome-wide methylation.ResultsMeta-analysis revealed that the MTHFR 677C> T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C> T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5.ConclusionsOur results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.

Published
2017
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9. Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease

Author

Mäkinen, Ville-Petteri, Civelek, Mete, Meng, Qingying, Zhang, Bin, Zhu, Jun, Levian, Candace, Huan, Tianxiao, Segrè, Ayellet V, Ghosh, Sujoy, Vivar, Juan, Nikpay, Majid, Stewart, Alexandre FR, Nelson, Christopher P, Willenborg, Christina, Erdmann, Jeanette, Blakenberg, Stefan, O'Donnell, Christopher J, März, Winfried, Laaksonen, Reijo, Epstein, Stephen E, Kathiresan, Sekar, Shah, Svati H, Hazen, Stanley L, Reilly, Muredach P, Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium, Lusis, Aldons J, Samani, Nilesh J, Schunkert, Heribert, Quertermous, Thomas, McPherson, Ruth, Yang, Xia, Assimes, Themistocles L, and Attie, Alan

Subjects
Cancer Research, Gene regulatory network, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium, Gene Regulatory Networks, Aetiology, Genetics (clinical), Genetics, Regulation of gene expression, 0303 health sciences, Systems Biology, Genomics, 3. Good health, Heart Disease, Biotechnology, Research Article, Signal Transduction, lcsh:QH426-470, Systems biology, Biology, 03 medical and health sciences, Clinical Research, Genome-Wide Association Studies, Animals, Humans, Genetic Predisposition to Disease, Molecular Biology, Gene, Heart Disease - Coronary Heart Disease, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Peptidylprolyl isomerase, Inflammatory and immune system, Human Genome, Biology and Life Sciences, Computational Biology, Human Genetics, Atherosclerosis, Genome Analysis, Human genetics, lcsh:Genetics, Gene Expression Regulation, Genetics of Disease, Genome-Wide Association Study, Developmental Biology
Abstract

The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions., Author Summary Sudden death due to heart attack ranks among the top causes of death in the world, and family studies have shown that genetics has a substantial effect on heart disease risk. Recent studies suggest that multiple genetic factors each with modest effects are necessary for the development of CAD, but the genes and molecular processes involved remain poorly understood. We conducted an integrative genomics study where we used the information of gene-gene interactions to capture groups of genes that are most likely to increase heart disease risk. We not only confirmed the importance of several known CAD risk processes such as the metabolism and transport of cholesterol, immune response, and blood coagulation, but also revealed many novel processes such as neuroprotection, cell cycle, and proteolysis that were not previously implicated in CAD. In particular, we highlight several genes such as GLO1 with key regulatory roles within these processes not detected by the first wave of genetic analyses. These results highlight the value of integrating population genetic data with diverse resources that functionally annotate the human genome. Such integration facilitates the identification of novel molecular processes involved in the pathogenesis of CAD as well as potential novel targets for the development of efficacious therapeutic interventions.

Published
2014
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10. Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

Author

Yao, Chen, Chen, George, Song, Ci, Keefe, Joshua, Mendelson, Michael, Huan, Tianxiao, Sun, Benjamin B, Laser, Annika, Maranville, Joseph C, Wu, Hongsheng, Ho, Jennifer E, Courchesne, Paul, Lyass, Asya, Larson, Martin G, Gieger, Christian, Graumann, Johannes, Johnson, Andrew D, Danesh, John, Runz, Heiko, Hwang, Shih-Jen, Liu, Chunyu, Butterworth, Adam S, Suhre, Karsten, and Levy, Daniel

Subjects
Adult, Male, Gene Expression Profiling, Quantitative Trait Loci, Chromosome Mapping, Blood Proteins, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, Cardiovascular Diseases, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Signal Transduction
Abstract

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

11. A meta-analysis of gene expression signatures of blood pressure and hypertension

Author

Huan, Tianxiao, Esko, Tõnu, Peters, Marjolein J, Pilling, Luke C, Schramm, Katharina, Schurmann, Claudia, Chen, Brian H, Liu, Chunyu, Joehanes, Roby, Johnson, Andrew D, Yao, Chen, Ying, Sai-Xia, Courchesne, Paul, Milani, Lili, Raghavachari, Nalini, Wang, Richard, Liu, Poching, Reinmaa, Eva, Dehghan, Abbas, Hofman, Albert, Uitterlinden, André G, Hernandez, Dena G, Bandinelli, Stefania, Singleton, Andrew, Melzer, David, Metspalu, Andres, Carstensen, Maren, Grallert, Harald, Herder, Christian, Meitinger, Thomas, Peters, Annette, Roden, Michael, Waldenberger, Melanie, Dörr, Marcus, Felix, Stephan B, Zeller, Tanja, International Consortium For Blood Pressure GWAS (ICBP), Vasan, Ramachandran, O'Donnell, Christopher J, Munson, Peter J, Yang, Xia, Prokisch, Holger, Völker, Uwe, Van Meurs, Joyce BJ, Ferrucci, Luigi, and Levy, Daniel

Subjects
Gene Expression Regulation, Genotype, Hypertension, Humans, Blood Pressure, Genetic Predisposition to Disease, Transcriptome, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p

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