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1. Genome-wide analysis identifies novel susceptibility loci for myocardial infarction

Author

Hartiala, Jaana A, Han, Yi, Jia, Qiong, Hilser, James R, Huang, Pin, Gukasyan, Janet, Schwartzman, William S, Cai, Zhiheng, Biswas, Subarna, Trégouët, David-Alexandre, Smith, Nicholas L, Consortium, The INVENT, Group, The CHARGE Consortium Hemostasis Working, Consortium, The GENIUS-CHD, Seldin, Marcus, Pan, Calvin, Mehrabian, Margarete, Lusis, Aldons J, Bazeley, Peter, Sun, Yan V, Liu, Chang, Quyyumi, Arshed A, Scholz, Markus, Thiery, Joachim, Delgado, Graciela E, Kleber, Marcus E, März, Winfried, Howe, Laurence J, Asselbergs, Folkert W, van Vugt, Marion, Vlachojannis, Georgios J, Patel, Riyaz S, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Lehtimäki, Terho, Nieminen, Tuomo VM, Kuukasjärvi, Pekka, Laurikka, Jari O, Chang, Xuling, Heng, Chew-Kiat, Jiang, Rong, Kraus, William E, Hauser, Elizabeth R, Ferguson, Jane F, Reilly, Muredach P, Ito, Kaoru, Koyama, Satoshi, Kamatani, Yoichiro, Komuro, Issei, Japan, Biobank, Stolze, Lindsey K, Romanoski, Casey E, Khan, Mohammad Daud, Turner, Adam W, Miller, Clint L, Aherrahrou, Redouane, Civelek, Mete, Ma, Lijiang, Björkegren, Johan LM, Kumar, S Ram, Tang, WH Wilson, Hazen, Stanley L, and Allayee, Hooman

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Cardiovascular, Heart Disease, Clinical Research, Heart Disease - Coronary Heart Disease, Human Genome, Genetics, Aging, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Coronary Artery Disease, Endothelial Cells, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Japan, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Myocardial infarction, Genetic factors, Genome-wide association study, Meta-analysis, SLC44A3, INVENT Consortium, CHARGE Consortium Hemostasis Working Group, GENIUS-CHD Consortium, Biobank Japan, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

AimsWhile most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.Methods and resultsWe carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.ConclusionsA large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Published
2021

3. Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.

Author

Yu, Bing, Pulit, Sara L, Hwang, Shih-Jen, Brody, Jennifer A, Amin, Najaf, Auer, Paul L, Bis, Joshua C, Boerwinkle, Eric, Burke, Gregory L, Chakravarti, Aravinda, Correa, Adolfo, Dreisbach, Albert W, Franco, Oscar H, Ehret, Georg B, Franceschini, Nora, Hofman, Albert, Lin, Dan-Yu, Metcalf, Ginger A, Musani, Solomon K, Muzny, Donna, Palmas, Walter, Raffel, Leslie, Reiner, Alex, Rice, Ken, Rotter, Jerome I, Veeraraghavan, Narayanan, Fox, Ervin, Guo, Xiuqing, North, Kari E, Gibbs, Richard A, van Duijn, Cornelia M, Psaty, Bruce M, Levy, Daniel, Newton-Cheh, Christopher, Morrison, Alanna C, and CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*

Subjects
CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*, Humans, Hypertension, Chloride Channels, Risk Factors, Blood Pressure, Gene Frequency, Alleles, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Exome, blood pressure, exome, genetic variation, genome-wide association study, hypertension, CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*, Cardiovascular System & Hematology, Genetics, Cardiorespiratory Medicine and Haematology, Medical Biotechnology
Abstract

BackgroundRare genetic variants influence blood pressure (BP).Methods and resultsWhole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency,

Published
2016

4. Association of Forced Vital Capacity with the Developmental Gene NCOR2.

Author

Minelli, Cosetta, Dean, Charlotte H, Hind, Matthew, Alves, Alexessander Couto, Amaral, André FS, Siroux, Valerie, Huikari, Ville, Soler Artigas, María, Evans, David M, Loth, Daan W, Bossé, Yohan, Postma, Dirkje S, Sin, Don, Thompson, John, Demenais, Florence, Henderson, John, SpiroMeta consortium, CHARGE consortium, Bouzigon, Emmanuelle, Jarvis, Deborah, Järvelin, Marjo-Riitta, and Burney, Peter

Subjects
SpiroMeta consortium, CHARGE consortium, Lung, Humans, Forced Expiratory Volume, Gene Expression Profiling, Organogenesis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Adult, Aged, Middle Aged, Female, Male, Genes, Developmental, Genome-Wide Association Study, Young Adult, Genetic Association Studies, Nuclear Receptor Co-Repressor 2, Polymorphism, Single Nucleotide, Genes, Developmental, General Science & Technology
Abstract

BackgroundForced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes.MethodsPer-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p

Published
2016

5. Genetic variants for head size share genes and pathways with cancer

Author

Arts-assistenten Kinderen, Hart- en Vaatziekten Team A, Researchgr. Hart-brein as., ZL Cerebrovasculaire Ziekten Medisch, Onderzoeksgroep 2, Brain, Onderzoeksgroep 1, Hersenen-Bedrijfsvoering, Precision Imaging Group, Cancer, Infectieziekten onderzoek1 (Bont), The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, Arts-assistenten Kinderen, Hart- en Vaatziekten Team A, Researchgr. Hart-brein as., ZL Cerebrovasculaire Ziekten Medisch, Onderzoeksgroep 2, Brain, Onderzoeksgroep 1, Hersenen-Bedrijfsvoering, Precision Imaging Group, Cancer, Infectieziekten onderzoek1 (Bont), The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium

Published
2024

8. Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Author

Chen, Zhao, Tang, Hua, Qayyum, Rehan, Schick, Ursula M, Nalls, Michael A, Handsaker, Robert, Li, Jin, Lu, Yingchang, Yanek, Lisa R, Keating, Brendan, Meng, Yan, van Rooij, Frank JA, Okada, Yukinori, Kubo, Michiaki, Rasmussen-Torvik, Laura, Keller, Margaux F, Lange, Leslie, Evans, Michele, Bottinger, Erwin P, Linderman, Michael D, Ruderfer, Douglas M, Hakonarson, Hakon, Papanicolaou, George, Zonderman, Alan B, Gottesman, Omri, Project, CHARGE Consortium BioBank Japan, Thomson, Cynthia, Ziv, Elad, Singleton, Andrew B, Loos, Ruth JF, Sleiman, Patrick MA, Ganesh, Santhi, McCarroll, Steven, Becker, Diane M, Wilson, James G, Lettre, Guillaume, and Reiner, Alexander P

Subjects
Biological Sciences, Genetics, Human Genome, Minority Health, Hematology, Health Disparities, 2.1 Biological and endogenous factors, Blood, Adolescent, Adult, Black or African American, Child, Chromosomes, Human, Pair 16, Cohort Studies, Erythrocyte Count, Erythrocyte Indices, Erythrocytes, Female, Genome-Wide Association Study, Hemoglobins, Humans, Male, Polymorphism, Single Nucleotide, White People, Young Adult, alpha-Globins, BioBank Japan Project, CHARGE Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

Published
2013

10. Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W., Gretarsdottir, Solveig, Anderson, Christopher D., Chong, Michael, Adams, Hieab H. H., Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M., Benavente, Oscar R., Bevan, Steve, Boncoraglio, Giorgio B., Brown, Jr, Robert D., Butterworth, Adam S., Carrera, Caty, Carty, Cara L., Chasman, Daniel I., Chen, Wei-Min, Cole, John W., Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I. W., DeStefano, Anita L., den Hoed, Marcel, Duan, Qing, Engelter, Stefan T., Falcone, Guido J., Gottesman, Rebecca F., Grewal, Raji P., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B., Hassan, Ahamad, Havulinna, Aki S., Heckbert, Susan R., Holliday, Elizabeth G., Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I., Ikram, M. Arfan, Ingelsson, Erik, Irvin, Marguerite R., Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A., Jukema, J. Wouter, Kanai, Masahiro, Keene, Keith L., Kissela, Brett M., Kleindorfer, Dawn O., Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M., Lin, Wei-Yu, Lindgren, Arne G., Lorentzen, Erik, Magnusson, Patrik K., Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F., Meschia, James F., Mitchell, Braxton D., Mosley, Thomas H., Nalls, Michael A., Ninomiya, Toshiharu, O’Donnell, Martin J., Psaty, Bruce M., Pulit, Sara L., Rannikmäe, Kristiina, Reiner, Alexander P., Rexrode, Kathryn M., Rice, Kenneth, Rich, Stephen S., Ridker, Paul M., Rost, Natalia S., Rothwell, Peter M., Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Sakaue, Saori, Sale, Michele M., Salomaa, Veikko, Sapkota, Bishwa R., Schmidt, Reinhold, Schmidt, Carsten O., Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L. M., Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D., Thijs, Vincent N. S., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M., Walters, Matthew, Wareham, Nicholas J., Wassertheil-Smoller, Sylvia, Wilson, James G., Wiggins, Kerri L., Yang, Qiong, Yusuf, Salim, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, INVENT Consortium, STARNET, Bis, Joshua C., Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E., Koplev, Simon, Björkegren, Johan L. M., Codoni, Veronica, Civelek, Mete, Smith, Nicholas L., Trégouët, David A., Christophersen, Ingrid E., Roselli, Carolina, Lubitz, Steven A., Ellinor, Patrick T., Tai, E. Shyong, Kooner, Jaspal S., Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Chambers, John C., Takeuchi, Fumihiko, Johnson, Andrew D., BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera, Dharambir K., Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, Jr, W. T., Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C., Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B., Kittner, Steven J., Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S., Howson, Joanna M. M., Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Published
2019
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11. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Author

Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, Debette, S, Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, and Debette, S

Abstract

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

Published
2023

12. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author

Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen

Subjects
Genetics, QH426-470
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].

Published
2017
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13. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author

Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen

Subjects
Genetics, QH426-470
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017
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14. Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

Author

Pooja R Mandaviya, Roby Joehanes, Dylan Aïssi, Brigitte Kühnel, Riccardo E Marioni, Vinh Truong, Lisette Stolk, Marian Beekman, Marc Jan Bonder, Lude Franke, Christian Gieger, Tianxiao Huan, M Arfan Ikram, Sonja Kunze, Liming Liang, Jan Lindemans, Chunyu Liu, Allan F McRae, Michael M Mendelson, Martina Müller-Nurasyid, Annette Peters, P Eline Slagboom, John M Starr, David-Alexandre Trégouët, André G Uitterlinden, Marleen M J van Greevenbroek, Diana van Heemst, Maarten van Iterson, Philip S Wells, Chen Yao, Ian J Deary, France Gagnon, Bastiaan T Heijmans, Daniel Levy, Pierre-Emmanuel Morange, Melanie Waldenberger, Sandra G Heil, Joyce B J van Meurs, and CHARGE Consortium Epigenetics group and BIOS Consortium

Subjects
Medicine, Science
Abstract

BACKGROUND:DNA 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. METHODS:Methylation 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 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-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. CONCLUSIONS:Our 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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15. Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

Author

Bram P Prins, Ali Abbasi, Anson Wong, Ahmad Vaez, Ilja Nolte, Nora Franceschini, Philip E Stuart, Javier Guterriez Achury, Vanisha Mistry, Jonathan P Bradfield, Ana M Valdes, Jose Bras, Aleksey Shatunov, PAGE Consortium, International Stroke Genetics Consortium, Systemic Sclerosis consortium, Treat OA consortium, DIAGRAM Consortium, CARDIoGRAMplusC4D Consortium, ALS consortium, International Parkinson’s Disease Genomics Consortium, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, CKDGen consortium, GERAD1 Consortium, International Consortium for Blood Pressure, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Inflammation Working Group of the CHARGE Consortium, Chen Lu, Buhm Han, Soumya Raychaudhuri, Steve Bevan, Maureen D Mayes, Lam C Tsoi, Evangelos Evangelou, Rajan P Nair, Struan F A Grant, Constantin Polychronakos, Timothy R D Radstake, David A van Heel, Melanie L Dunstan, Nicholas W Wood, Ammar Al-Chalabi, Abbas Dehghan, Hakon Hakonarson, Hugh S Markus, James T Elder, Jo Knight, Dan E Arking, Timothy D Spector, Bobby P C Koeleman, Cornelia M van Duijn, Javier Martin, Andrew P Morris, Rinse K Weersma, Cisca Wijmenga, Patricia B Munroe, John R B Perry, Jennie G Pouget, Yalda Jamshidi, Harold Snieder, and Behrooz Z Alizadeh

Subjects
Medicine
Abstract

BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and findingsWe performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses.ConclusionsGenetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.

Published
2016
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16. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos

Subjects
Genetics, QH426-470
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Published
2016
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18. Stroke genetics informs drug discovery and risk prediction across ancestries.

Author

Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Trégouët, D-A, Trompet, S, Tuladhar, AM, Tybjærg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Kõrv, J, França, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Paré, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernández-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Trégouët, D-A, Trompet, S, Tuladhar, AM, Tybjærg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Kõrv, J, França, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Paré, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernández-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, and Debette, S

Abstract

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

19. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Neurogenetica, Cardiovasculaire Epi Team 7a, Brain, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Epidemiology & Health Economics, Cardiovasculaire Epi Team 3, Advanced Nursing, Onderzoek Precision medicine, Neurologen, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, Neurogenetica, Cardiovasculaire Epi Team 7a, Brain, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Epidemiology & Health Economics, Cardiovasculaire Epi Team 3, Advanced Nursing, Onderzoek Precision medicine, Neurologen, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, and Estonian Biobank

Published
2022

20. Association of Forced Vital Capacity with the Developmental Gene NCOR2.

Author

Cosetta Minelli, Charlotte H Dean, Matthew Hind, Alexessander Couto Alves, André F S Amaral, Valerie Siroux, Ville Huikari, María Soler Artigas, David M Evans, Daan W Loth, Yohan Bossé, Dirkje S Postma, Don Sin, John Thompson, Florence Demenais, John Henderson, SpiroMeta consortium, CHARGE consortium, Emmanuelle Bouzigon, Deborah Jarvis, Marjo-Riitta Järvelin, and Peter Burney

Subjects
Medicine, Science
Abstract

BACKGROUND:Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. METHODS:Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p

Published
2016
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21. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

Published
2015
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22. Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans.

Author

Giorgio Pistis, Shawntel U Okonkwo, Michela Traglia, Cinzia Sala, So-Youn Shin, Corrado Masciullo, Iwan Buetti, Roberto Massacane, Massimo Mangino, Swee-Lay Thein, Timothy D Spector, Santhi Ganesh, CHARGE Consortium Hematology Working, Nicola Pirastu, Paolo Gasparini, Nicole Soranzo, Clara Camaschella, Daniel Hart, Michael R Green, and Daniela Toniolo

Subjects
Medicine, Science
Abstract

The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.

Published
2013
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23. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.

Author

Ayşe Demirkan, Cornelia M van Duijn, Peter Ugocsai, Aaron Isaacs, Peter P Pramstaller, Gerhard Liebisch, James F Wilson, Åsa Johansson, Igor Rudan, Yurii S Aulchenko, Anatoly V Kirichenko, A Cecile J W Janssens, Ritsert C Jansen, Carsten Gnewuch, Francisco S Domingues, Cristian Pattaro, Sarah H Wild, Inger Jonasson, Ozren Polasek, Irina V Zorkoltseva, Albert Hofman, Lennart C Karssen, Maksim Struchalin, James Floyd, Wilmar Igl, Zrinka Biloglav, Linda Broer, Arne Pfeufer, Irene Pichler, Susan Campbell, Ghazal Zaboli, Ivana Kolcic, Fernando Rivadeneira, Jennifer Huffman, Nicholas D Hastie, Andre Uitterlinden, Lude Franke, Christopher S Franklin, Veronique Vitart, DIAGRAM Consortium, Christopher P Nelson, Michael Preuss, CARDIoGRAM Consortium, Joshua C Bis, Christopher J O'Donnell, Nora Franceschini, CHARGE Consortium, Jacqueline C M Witteman, Tatiana Axenovich, Ben A Oostra, Thomas Meitinger, Andrew A Hicks, Caroline Hayward, Alan F Wright, Ulf Gyllensten, Harry Campbell, Gerd Schmitz, and EUROSPAN consortium

Subjects
Genetics, QH426-470
Abstract

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value

Published
2012
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24. Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study

Author

Ding, Ming, Huang, Tao, Bergholdt, Helle Km, Nordestgaard, Børge G, Ellervik, Christina, Qi, Lu, CHARGE Consortium, and Apollo - University of Cambridge Repository

Subjects
Observational Studies as Topic, Hypertension, Humans, Blood Pressure, Genetic Predisposition to Disease, Dairy Products, Feeding Behavior, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Lactase, Randomized Controlled Trials as Topic
Abstract

Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P

Published
2019
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26. Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Author

Song, Ci, Burgess, Stephen, Eicher, John D., O'Donnell, Christopher J., Johnson, Andrew D., Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David-Alexandre, Shin, So Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Smith, Nicholas L., Williams, Scott M, Ikram, Mohammad Arfan, Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H, Williams, Frances M.K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M.C., Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H., Silveira, Angela, Navis, Gerjan J., Lohman, Kurt, Chen, Ming Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Lundmark, Per, Psaty, Bruce M., Strawbridge, Rona J., Boehm, Bernhard O., Onland-Moret, N. Charlotte, Uiterwaal, Cuno S.P.M., Grobbee, Diederick E., Bots, Michiel L., van der Schouw, Yvonne T., CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, and CHARGE Consortium Subclinical Working Group

Subjects
Coronary heart disease, Genome-wide association study, Mendelian randomization, Journal Article, Review, Cardiology and Cardiovascular Medicine, Plasminogen activator inhibitor type 1, Single nucleotide polymorphism
Abstract

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association wbetween PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

Published
2017

27. Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Author

Song, C, Burgess, S, Eicher, JD, CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, CHARGE Consortium Subclinical Working Group, O’Donnell, CJ, Johnson, AD, Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
plasminogen activator inhibitor type 1, genome-wide association study, single nucleotide polymorphism, Mendelian randomization, coronary heart disease
Abstract

$\textit{Background—}$Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. $\textit{Methods and Results—}$To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. $\textit{Conclusions—}$Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

Published
2017
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28. Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Author

Circulatory Health, Team Medisch, Cardiovasculaire Epi Team 3, Brain, Cancer, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Cardiovasculaire Epi Team 4, Cardiovasculaire Epi Team 9, Cardiovasculaire Epi Team 5, Cardiovasculaire Epidemiologie, Song, Ci, Burgess, Stephen, Eicher, John D., O'Donnell, Christopher J., Johnson, Andrew D., Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David-Alexandre, Shin, So Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Smith, Nicholas L., Williams, Scott M, Ikram, Mohammad Arfan, Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H, Williams, Frances M.K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M.C., Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H., Silveira, Angela, Navis, Gerjan J., Lohman, Kurt, Chen, Ming Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Lundmark, Per, Psaty, Bruce M., Strawbridge, Rona J., Boehm, Bernhard O., Onland-Moret, N. Charlotte, Uiterwaal, Cuno S.P.M., Grobbee, Diederick E., Bots, Michiel L., van der Schouw, Yvonne T., CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, CHARGE Consortium Subclinical Working Group, Circulatory Health, Team Medisch, Cardiovasculaire Epi Team 3, Brain, Cancer, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Cardiovasculaire Epi Team 4, Cardiovasculaire Epi Team 9, Cardiovasculaire Epi Team 5, Cardiovasculaire Epidemiologie, Song, Ci, Burgess, Stephen, Eicher, John D., O'Donnell, Christopher J., Johnson, Andrew D., Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David-Alexandre, Shin, So Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Smith, Nicholas L., Williams, Scott M, Ikram, Mohammad Arfan, Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H, Williams, Frances M.K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M.C., Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H., Silveira, Angela, Navis, Gerjan J., Lohman, Kurt, Chen, Ming Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Lundmark, Per, Psaty, Bruce M., Strawbridge, Rona J., Boehm, Bernhard O., Onland-Moret, N. Charlotte, Uiterwaal, Cuno S.P.M., Grobbee, Diederick E., Bots, Michiel L., van der Schouw, Yvonne T., CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, and CHARGE Consortium Subclinical Working Group

Published
2017

29. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, G., Adams, H.H.H., Satizabal, C.L., Bis, J.C., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A.V., Jian, X.Q., Malik, R., Traylor, M., Pulit, S.L., Amouyel, P., Mazoyer, B., Zhu, Y.C., Kaffashian, S., Schilling, S., Beecham, G.W., Montine, T.J., Schellenberg, G.D., Kjartansson, O., Gudnason, V., Knopman, D.S., Griswold, M.E., Windham, B.G., Gottesman, R.F., Mosley, T.H., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K.B., Aggarwal, N.T., Jager, P.L. de, Evans, D.A., Psaty, B.M., Rotter, J.I., Rice, K., Lopez, O.L., Liao, J.M., Chen, C., Cheng, C.Y., Wong, T.Y., Ikram, M.K., Lee, S.J. van der, Amin, N., Chouraki, V., DeStefano, A.L., Aparicio, H.J., Romero, J.R., Maillard, P., DeCarli, C., Wardlaw, J.M., Hernandez, M.D.V., Luciano, M., Liewald, D., Deary, I.J., Starr, J.M., Bastin, M.E., Maniega, S.M., Slagboom, P.E., Beekman, M., Deelen, J., Uh, H.W., Lemmens, R., Brodaty, H., Wright, M.J., Ames, D., Boncoraglio, G.B., Hopewell, J.C., Beecham, A.H., Blanton, S.H., Wright, C.B., Sacco, R.L., Wen, W., Thalamuthu, A., Armstrong, N.J., Chong, E., Schofield, P.R., Kwok, J.B., Grond, J. van der, Stott, D.J., Ford, I., Jukema, J.W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Lugt, A. van der, Wittfeld, K., Grabe, H.J., Hosten, N., Sarnowski, B. von, Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C.L.M., Rosand, J., Woo, D., Cole, J.W., Meschia, J.F., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R.P., Rundek, T., Rexrode, K., Rothwell, P.M., Arnett, D.K., Jern, C., Johnson, J.A., Benavente, O.R., Wasssertheil-Smoller, S., Lee, J.M., Wong, Q., Mitchell, B.D., Rich, S.S., McArdle, P.F., Geerlings, M.I., Graaf, Y. van der, Bakker, P.I.W. de, Asselbergs, F.W., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L.C.A., Bevan, S., Tzourio, C., Mather, K.A., Sachdev, P.S., Duijn, C.M. van, Worrall, B.B., Dichgans, M., Kittner, S.J., Markus, H.S., Ikram, M.A., Fornage, M., Launer, L.J., Seshadri, S., Longstreth, W.T., Debette, S., Stroke Genetics Network SiGN, ISGC, METASTROKE, ADGC, and CHARGE Consortium

Subjects
Meta-analysis, Mendelian Randomization, Blood Pressure, Polymorphisms, Genome-wide Association, Silent, Insights, Small Vessel Disease, Matter Hyperintensity Volume, Ischemic Stroke, Doenças Cardio e Cérebro-vasculares
Abstract

Collaborators (845): Astrid M. Vicente Free PMC article:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905/ Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. info:eu-repo/semantics/publishedVersion

Published
2019

30. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Subjects
Clinical Neurology, Journal Article
Abstract

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p[SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI] = 4.4 × 10-10; p[SSBI] = 1.2 × 10-4), diabetes (p[BI] = 1.7 × 10-8; p[SSBI] = 2.8 × 10-3), previous cardiovascular disease (p[BI] = 1.0 × 10-18; p[SSBI] = 2.3 × 10-7), stroke (p[BI] = 3.9 × 10-69; p[SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10-157; p[SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Published
2019

31. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab HH, Satizabal, Claudia L, Bis, Joshua C, Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L, Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W, Montine, Thomas J, Schellenberg, Gerard D, Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S, Griswold, Michael E, Windham, B Gwen, Gottesman, Rebecca F, Mosley, Thomas H, Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B, Aggarwal, Neelum T, De Jager, Philip L, Evans, Denis A, Psaty, Bruce M, Rotter, Jerome I, Rice, Kenneth, Lopez, Oscar L, Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y, Ikram, Mohammad K, van der Lee, Sven J, Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L, Aparicio, Hugo J, Romero, Jose R, Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M, Hernández, Maria Del C Valdés, Luciano, Michelle, Liewald, David, Deary, Ian J, Starr, John M, Bastin, Mark E, Muñoz Maniega, Susana, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J, Ames, David, Boncoraglio, Giorgio B, Hopewell, Jemma C, Beecham, Ashley H, Blanton, Susan H, Wright, Clinton B, Sacco, Ralph L, Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J, Chong, Elizabeth, Schofield, Peter R, Kwok, John B, van der Grond, Jeroen, Stott, David J, Ford, Ian, Jukema, J Wouter, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, van der Lugt, Aad, Wittfeld, Katharina, Grabe, Hans J, Hosten, Norbert, von Sarnowski, Bettina, Völker, Uwe, Levi, Christopher, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie LM, Rosand, Jonathan, Woo, Daniel, Cole, John W, Meschia, James F, Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P, Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M, Arnett, Donna K, Jern, Christina, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Mitchell, Braxton D, Rich, Stephen S, McArdle, Patrick F, Geerlings, Mirjam I, van der Graaf, Yolanda, de Bakker, Paul IW, Asselbergs, Folkert W, Srikanth, Velandai, Thomson, Russell, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes CA, Bevan, Steve, Tzourio, Christophe, Mather, Karen A, Sachdev, Perminder S, van Duijn, Cornelia M, Worrall, Bradford B, Dichgans, Martin, Kittner, Steven J, Markus, Hugh S, Ikram, Mohammad A, Fornage, Myriam, Launer, Lenore J, Seshadri, Sudha, Longstreth, WT, Debette, Stéphanie, Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Teumer, Alexander [0000-0002-8309-094X], Pulit, Sara L [0000-0002-2502-3669], Muñoz Maniega, Susana [0000-0001-5185-6384], Beekman, Marian [0000-0003-0585-6206], Schofield, Peter R [0000-0003-2967-9662], Kwok, John B [0000-0001-9574-6195], Grabe, Hans J [0000-0003-3684-4208], Thijs, Vincent [0000-0002-6614-8417], de Bakker, Paul IW [0000-0001-7735-7858], Asselbergs, Folkert W [0000-0002-1692-8669], Rutten-Jacobs, Loes CA [0000-0003-3223-885X], Tzourio, Christophe [0000-0002-6517-2984], and Apollo - University of Cambridge Repository

Subjects
Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
Abstract

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Published
2019

32. Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data

Author

Tylee, Daniel S, Sun, Jiayin, Hess, Jonathan L, Tahir, Muhammad A, Sharma, Esha, Malik, Rainer, Worrall, Bradford B, Levine, Andrew J, Martinson, Jeremy J, Nejentsev, Sergey, Speed, Doug, Fischer, Annegret, Mick, Eric, Walker, Brian R, Crawford, Andrew, Grant, Struan FA, Polychronakos, Constantin, Bradfield, Jonathan P, Sleiman, Patrick MA, Hakonarson, Hakon, Ellinghaus, Eva, Elder, James T, Tsoi, Lam C, Trembath, Richard C, Barker, Jonathan N, Franke, Andre, Dehghan, Abbas, 23 and Me Research Team, Inflammation Working Group of the CHARGE Consortium, METASTROKE Consortium of the International Stroke Genetics Consortium, Netherlands Twin Registry, neuroCHARGE Working Group, Obsessive Compulsive and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium, Faraone, Stephen V, and Glatt, Stephen J

Subjects
Male, rheumatoid arthritis, Multifactorial Inheritance, type 1 diabetes, Obsessive Compulsive and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium, Comorbidity, Linkage Disequilibrium, anorexia nervosa, systemic lupus erythematosus, 2.1 Biological and endogenous factors, neuroticism, Aetiology, bipolar disorder, Mental Disorders, and Me Research Team, METASTROKE Consortium of the International Stroke Genetics Consortium, neuroCHARGE Working Group, Single Nucleotide, Serious Mental Illness, genetic correlation, Crohn's disease, Mental Health, obsessive schizophrenia, Female, Clinical Sciences, Autoimmune Disease, White People, smoking, Autoimmune Diseases, C-reactive protein, Databases, childhood ear infection, Clinical Research, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Factual, tuberculosis susceptibility, Inflammation Working Group of the CHARGE Consortium, ulcerative colitis, Tourette syndrome, Prevention, Human Genome, Neurosciences, attention deficit-hyperactivity disorder, allergy, primary biliary cirrhosis, Brain Disorders, Netherlands Twin Registry, genome-wide association, Schizophrenia, hypothyroidism, autoimmune disorder, major depression, Digestive Diseases, celiac disease, Genome-Wide Association Study
Abstract

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

Published
2018

33. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations

Author

Demirkan, Ayşe, Van Duijn, Cornelia M, Ugocsai, Peter, Isaacs, Aaron, Pramstaller, Peter P, Liebisch, Gerhard, Wilson, James F, Johansson, Åsa, Rudan, Igor, Aulchenko, Yurii S, Kirichenko, Anatoly V, Janssens, A Cecile JW, Jansen, Ritsert C, Gnewuch, Carsten, Domingues, Francisco S, Pattaro, Cristian, Wild, Sarah H, Jonasson, Inger, Polasek, Ozren, Zorkoltseva, Irina V, Hofman, Albert, Karssen, Lennart C, Struchalin, Maksim, Floyd, James, Igl, Wilmar, Biloglav, Zrinka, Broer, Linda, Pfeufer, Arne, Pichler, Irene, Campbell, Susan, Zaboli, Ghazal, Kolcic, Ivana, Rivadeneira, Fernando, Huffman, Jennifer, Hastie, Nicholas D, Uitterlinden, Andre, Franke, Lude, Franklin, Christopher S, Vitart, Veronique, DIAGRAM Consortium, Nelson, Christopher P, Preuss, Michael, CARDIoGRAM Consortium, Bis, Joshua C, O'Donnell, Christopher J, Franceschini, Nora, CHARGE Consortium, Witteman, Jacqueline CM, Axenovich, Tatiana, Oostra, Ben A, Meitinger, Thomas, Hicks, Andrew A, Hayward, Caroline, Wright, Alan F, Gyllensten, Ulf, Campbell, Harry, Schmitz, Gerd, and EUROSPAN Consortium

Subjects
Sphingolipids, Delta-5 Fatty Acid Desaturase, Diabetes Mellitus, Type 2, Genetic Loci, Genome, Human, Databases, Genetic, Humans, lipids (amino acids, peptides, and proteins), Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, Phospholipids, White People, Genome-Wide Association Study
Abstract

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value

Published
2018
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34. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

UMC Utrecht, Circulatory Health, CMM Groep De Ridder, Biostatistiek Onderzoek, JC onderzoeksprogramma Methodologie, Cardiovasculaire Epi Team 7a, Brain, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 5, CMM Groep Kaaij, Team Medisch, Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, UMC Utrecht, Circulatory Health, CMM Groep De Ridder, Biostatistiek Onderzoek, JC onderzoeksprogramma Methodologie, Cardiovasculaire Epi Team 7a, Brain, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 5, CMM Groep Kaaij, Team Medisch, and Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Published
2019

35. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits.

Author

CHARGE Consortium Hematology Working Group, CHARGE Consortium Hematology Working Group, CHARGE Consortium Hematology Working Group, and CHARGE Consortium Hematology Working Group

Abstract

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

Published
2016

36. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author

Wain, Louise V, Verwoert, Germaine C, O'Reilly, Paul F, Shi, Gang, Johnson, Toby, Johnson, Andrew D, Bochud, Murielle, Rice, Kenneth M, Henneman, Peter, Smith, Albert V, Ehret, Georg B, Amin, Najaf, Larson, Martin G, Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile JW, Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'an, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U, Webster, Rebecca J, Zhang, Feng, Peden, John F, Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I, Trompet, Stella, Bragg-Gresham, Jennifer L, Alizadeh, Behrooz Z, Chambers, John C, Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M, Polašek, Ozren, Boban, Mladen, Nelson, Christopher P, Morrison, Alanna C, Pihur, Vasyl, Ganesh, Santhi K, Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco US, Rivadeneira, Fernando, Sijbrands, Eric JG, Uitterlinden, Andre G, Hwang, Shih-Jen, Vasan, Ramachandran S, Wang, Thomas J, Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Glazer, Nicole L, Taylor, Kent D, Harris, Tamara B, Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, Inês, Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M, Penninx, Brenda W, Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco, Fabiola M, Facheris, Maurizio, Collins, Francis S, Bergman, Richard N, Beilby, John P, Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S, Navarro, Pau, Wild, Sarah H, Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco JC, Willemsen, Gonneke, Parker, Alex N, Rose, Lynda M, Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, LifeLines Cohort Study, Van Der Klauw, Melanie M, Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M, Emilsson, Valur, Plump, Andrew, Lindeman, Jan H, Hoen, Peter AC 'T, König, Inke R, EchoGen Consortium, Felix, Janine F, Clarke, Robert, Hopewell, Jemma C, Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L, Fornage, Myriam, AortaGen Consortium, Mitchell, Gary F, CHARGE Consortium Heart Failure Working Group, Smith, Nicholas L, KidneyGen Consortium, Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, CKDGen Consortium, Cardiogenics Consortium, CardioGram, Samani, Nilesh J, Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J, Wichmann, H-Erich, Raitakari, Olli T, Palmas, Walter, Kooner, Jaspal S, Stolk, Ronald P, Jukema, J Wouter, Wright, Alan F, Boomsma, Dorret I, Bandinelli, Stefania, Gyllensten, Ulf B, Wilson, James F, Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D, Palmer, Lyle J, Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth JF, Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J, Oostra, Ben A, Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P, Beckmann, Jacques S, Witteman, Jacqueline CM, Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M, Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R, Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B, Psaty, Bruce M, Caulfield, Mark J, Rao, Dabeeru C, Tobin, Martin D, Elliott, Paul, and Van Duijn, Cornelia M

Subjects
Genetic Loci, Case-Control Studies, Hypertension, Humans, Blood Pressure, cardiovascular diseases, Arteries, Polymorphism, Single Nucleotide, Linkage Disequilibrium, circulatory and respiratory physiology, Follow-Up Studies, Genome-Wide Association Study
Abstract

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Published
2018
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37. Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Author

Christophersen, Ingrid E, Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E, Smith, Albert V, Albert, Christine M, Chaffin, Mark, Tucker, Nathan R, Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A, Low, Siew-Kee, Weeke, Peter E, Müller-Nurasyid, Martina, Smith, J Gustav, Brody, Jennifer A, Niemeijer, Maartje N, Dörr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E, Lyytikäinen, Leo-Pekka, Seppälä, Ilkka, Malik, Rainer, R V R Horimoto, Andrea, Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Thériault, Sébastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J, Shah, Svati H, Sun, Albert, Hopewell, Jemma C, Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B, Paré, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P, Verweij, Niek, Siland, Joylene E, Kubo, Michiaki, Smith, Jonathan D, Van Wagoner, David R, Bis, Joshua C, Perz, Siegfried, Psaty, Bruce M, Ridker, Paul M, Magnani, Jared W, Harris, Tamara B, Launer, Lenore J, Shoemaker, M Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M, Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E, Kähönen, Mika, Risch, Lorenz, Mansur, Alfredo J, Peters, Annette, Smith, Blair H, Lind, Lars, Scott, Stuart A, Lu, Yingchang, Bottinger, Erwin B, Hernesniemi, Jussi, Lindgren, Cecilia M, Wong, Jorge A, Huang, Jie, Eskola, Markku, Morris, Andrew P, Ford, Ian, Reiner, Alex P, Delgado, Graciela, Chen, Lin Y, Chen, Yii-Der Ida, Sandhu, Roopinder K, Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D, Taylor, Kent D, Campbell, Archie, Magnusson, Patrik K, Porteous, David, Hocking, Lynne J, Vlachopoulou, Efthymia, Pedersen, Nancy L, Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C, Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W, Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L, Sotoodehnia, Nona, Soliman, Elsayed Z, Uitterlinden, Andre G, Hofman, Albert, Franco, Oscar H, Völker, Uwe, Jöckel, Karl-Heinz, Sinner, Moritz F, Lin, Henry J, Guo, Xiuqing, METASTROKE Consortium of the ISGC, Neurology Working Group of the CHARGE Consortium, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, J F Loos, Ruth, Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J Wouter, Hayward, Caroline, Rotter, Jerome I, März, Winfried, Lehtimäki, Terho, Stricker, Bruno H, Chung, Mina K, Felix, Stephan B, Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M, Kääb, Stefan, Chasman, Daniel I, Heckbert, Susan R, Benjamin, Emelia J, Tanaka, Toshihiro, Lunetta, Kathryn L, Lubitz, Steven A, Ellinor, Patrick T, and AFGen Consortium

Subjects
Genetics, Journal Article, Medizin, Article
Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death.1,2 Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups.3–7 To further define the genetic basis of atrial fibrillation, we performed large-scale, multi-racial meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 18,398 individuals with atrial fibrillation and 91,536 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,806 cases and 132,612 referents. We identified 12 novel genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate new potential targets for drug discovery.8

Published
2017

38. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Haitjema, S., Meddens, C.A., Laan, S.W. van der, Kofink, D., Harakalova, M., Tragante, V., Asl, H.F., Setten, J. van, Brandt, M.M., Bis, J.C., O'Donnell, C., Cheng, C., Hoefer, I.E., Waltenberger, J., Biessen, E., Jukema, J.W., Doevendans, P.A.F.M., Nieuwenhuis, E.E.S., Erdmann, J., Bjorkegren, J.L.M., Pasterkamp, G., Asselbergs, F.W., Ruijter, H.M. den, Mokry, M., CHARGE Consortium, METASTROKE Grp Int Stroke Genetics, Cardiologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, Pathologie, and Cardiology

Subjects
Male, 0301 basic medicine, EXPRESSION, Candidate gene, PHOSPHATASE, Population, Genome-wide association study, Biology, VARIANTS, Monocytes, Cell Line, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetics, Journal Article, ischemic stroke, Humans, Genetic Predisposition to Disease, Epigenetics, GENOME-WIDE ASSOCIATION, education, Gene, Genetics (clinical), ChIA-PET, POPULATION, education.field_of_study, epigenetics, Endothelial Cells, Molecular Sequence Annotation, DNA, RISK LOCI, Chromatin, 030104 developmental biology, Genetic Loci, CARDIOVASCULAR-DISEASE, Expression quantitative trait loci, CELLS, CORONARY-ARTERY-DISEASE, Female, atherosclerosis, Cardiology and Cardiovascular Medicine, gene regulation, coronary artery disease, Genome-Wide Association Study
Abstract

Background— As genome-wide association efforts, such as CARDIoGRAM and METASTROKE, are ongoing to reveal susceptibility loci for their underlying disease—atherosclerotic disease—identification of candidate genes explaining the associations of these loci has proven the main challenge. Many disease susceptibility loci colocalize with DNA regulatory elements, which influence gene expression through chromatin interactions. Therefore, the target genes of these regulatory elements can be considered candidate genes. Applying these biological principles, we used an alternative approach to annotate susceptibility loci and identify candidate genes for human atherosclerotic disease based on circular chromosome conformation capture followed by sequencing. Methods and Results— In human monocytes and coronary endothelial cells, we generated 63 chromatin interaction data sets for 37 active DNA regulatory elements that colocalize with known susceptibility loci for coronary artery disease (CARDIoGRAMplusC4D) and large artery stroke (METASTROKE). By circular chromosome conformation capture followed by sequencing, we identified a physical 3-dimensional interaction with 326 candidate genes expressed in at least 1 of these cell types, of which 294 have not been reported before. We highlight 16 genes based on expression quantitative trait loci. Conclusions— Our findings provide additional candidate-gene annotation for 37 disease susceptibility loci for human atherosclerotic disease that are of potential interest to better understand the complex pathophysiology of cardiovascular diseases.

Published
2017

39. Genetic variation at 16q24.2 is associated with small vessel stroke

Author

Traylor, Matthew, Malik, Rainer, Nalls, Mike A, Cotlarciuc, Ioana, Radmanesh, Farid, Thorleifsson, Gudmar, Hanscombe, Ken B, Langefeld, Carl, Saleheen, Danish, Rost, Natalia S, Yet, Idil, Spector, Tim D, Bell, Jordana T, Hannon, Eilis, Mill, Jonathan, Chauhan, Ganesh, Debette, Stephanie, Bis, Joshua C, Longstreth, WT, Ikram, M Arfan, Launer, Lenore J, Seshadri, Sudha, METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium, Hamilton-Bruce, Monica Anne, Jimenez-Conde, Jordi, Cole, John W, Schmidt, Reinhold, Słowik, Agnieszka, Lemmens, Robin, Lindgren, Arne, Melander, Olle, Grewal, Raji P, Sacco, Ralph L, Rundek, Tatjana, Rexrode, Kathryn, Arnett, Donna K, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Pulit, Sara L, Wong, Quenna, Rich, Stephen S, de Bakker, Paul IW, McArdle, Patrick F, Woo, Daniel, Anderson, Christopher D, Xu, Huichun, Heitsch, Laura, Fornage, Myriam, Jern, Christina, Stefansson, Kari, Thorsteinsdottir, Unnur, Gretarsdottir, Solveig, Lewis, Cathryn M, Sharma, Pankaj, Sudlow, Cathie LM, Rothwell, Peter M, Boncoraglio, Giorgio B, Thijs, Vincent, Levi, Chris, Meschia, James F, Rosand, Jonathan, Kittner, Steven J, Mitchell, Braxton D, Dichgans, Martin, Worrall, Bradford B, Markus, Hugh S, International Stroke Genetics Consortium, Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Genetic Variation, Zinc Fingers, Middle Aged, Stroke, Genetic Loci, Cerebral Small Vessel Diseases, Stroke, Lacunar, Humans, Female, Chromosomes, Human, Pair 16, Aged, Genome-Wide Association Study
Abstract

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.

Published
2017

40. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, de Geus, Eco JC, de Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, van Dijk, Suzanne C, van Schoor, Natasja M, Asselbergs, Folkert W, de Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, Loos, Ruth JF, Division of Statistical Genomics, Washington University School of Medicine, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Metabolic Science, MRC, Brown University, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), King‘s College London, Groningen Bioinformatics Centre, GBB, University of Groningen [Groningen], University of Queensland [Brisbane], National Institut of Food Science and Technology, University of Agriculture, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of neurology, Leiden University Medical Center (LUMC), University of Washington [Seattle], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Limnology, Ecology, Department of Ecology and Evolutionary Biology, University of California, Core Genotyping Facility, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Chemical Engineering Taiwan (DCET - NTHU), National Tsing Hua University [Hsinchu] (NTHU), University of Oxford [Oxford], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Medical Sciences, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE Genetics, deCODE genetics [Reykjavik], Interuniversity Cardiology Institute Netherlands, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], Medical Department III, Universität Leipzig [Leipzig], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], GNS Science, Blackett Laboratory, Imperial College London, Medstar Research Institute, University of Rochester [USA], MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Dept Biochem & Mol Biol, Pennsylvania State University (Penn State), Penn State System-Penn State System, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Epidemiology, University Medical Centre Groningen, Unit for Molecular Epidemiology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (KU), Faculty of Medicine, Institute of Public Health, Aalborg University [Denmark] (AAU), Department of Nutrition-Dietetics, Harokopio University of Athens, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College of London [London] (UCL), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Research Center for Prevention and Health, Glostrup Hospital, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute of Public Health, University of Cambridge [UK] (CAM), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Queensland Institute of Medical Research, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Head of Medical Sequencing, Department of Biostatistics, University of Washington, Department of Chronic Disease Prevention, Molecular Epidemiology, Department of Genetics, Université Laval [Québec] (ULaval), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Université de Lausanne (UNIL), Carl Gustav Carus University Hospital, Loughborough University, Genomics and Bioinformatics Platform, Fondazione Filarete, Department of Medicine, Surgery, and Dentistry, University of Milano, Medizinische Klinik II, Universität zu Lübeck [Lübeck], Department of Genomic Medicine, University of Manchester [Manchester], The Wellcome Trust Centre for Human Genetics [Oxford], National Institutes of Health [Bethesda] (NIH), Department of Nephrology, University Medical Center, University of Groningen, Helmholtz-Zentrum München (HZM), Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Genetics and Pathology, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Franz-Volhard-Centrum für Klinische Forschung, ECRC, Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Finnish Institute of Occupational Health of Helsinki, Department of Clinical Chemistry, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Oncology, University of Tampere Medical School, University of Tampere, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, Department of Medicine, Montreal, Developmental Brain and Behaviour Unit, University of Southampton, Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Interdisciplinary Center for Psychiatric Epidemiology, Experimental Cardiology Laboratory, University Medical Center [Utrecht], Peter MacCallum Cancer Center, Faculty of Health Sciences, Aarhus University [Aarhus], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Department of Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Department of Epidemiology, University of Washington, Department of Medicine, University of Washington, Cardiovascular Health Research Unit, University of Washington, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital (TYKS), Erasmus Medical Centre, Cedars-Sinai Medical Center, Department of Pathological Biochemistry, Royal Infirmary, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Maastricht University [Maastricht], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Epidemiology & Biostatistics, Radboud University Medical Center [Nijmegen], Institute for Community Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), MRC epidemiology Unit, Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Department of Genetics and Biotechnology, Wellcome Trust, Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Department of Medical Genetics, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), P30 AG010161/AG/NIA NIH HHS/United States, Psychiatry, Epidemiology and Data Science, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, RS: CARIM - R3 - Vascular biology, MUMC+: DA BV AIOS Radiologie (9), Epidemiologie, Orthopedie, Institute for Molecular Medicine Finland, Helsinki Collegium for Advanced Studies, Behavioural Sciences, University of Helsinki, Transplantation Laboratory, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Marja-Liisa Lokki / Principal Investigator, Kardiologian yksikkö, Leif Groop Research Group, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Ehret, Georg Benedikt, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universiteit Leiden-Universiteit Leiden, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), University of California (UC), University of Oxford, Lund University [Lund], Universität Leipzig, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (UCPH), Université de Lausanne = University of Lausanne (UNIL), Universität zu Lübeck = University of Lübeck [Lübeck], Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Gothenburg (GU)-Institute of Medicine, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Luan, Jian'an [0000-0003-3137-6337], Tyrer, Jonathan [0000-0003-3724-4757], Forouhi, Nita [0000-0002-5041-248X], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Biochemistry, Surgery, Internal Medicine, Public Health, Medical Oncology, Pathology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Male, Cancer Research, endocrine system diseases, Biological pathways, QH426-470, Genome, Body Mass Index, Body Size, Genetics (clinical), ddc:616, Genetics & Heredity, Sex Characteristics, Loci, MAGIC Consortium, Mass index, Age Factors, Chromosome Mapping, Middle Aged, Genealogy, Self-reported height, Peripheral-blood, Scale (social sciences), ICBP Consortium, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, arcOGEN Consortium, musculoskeletal diseases, Adult, European Continental Ancestry Group, Natural menopause, Aged, Body Size/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Biology, Body size, DIAGRAM Consortium, Age and sex, White People, Fat distribution, GLGC Consortium, 03 medical and health sciences, Life-course, Genetics, Weight-gain, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0604 Genetics, Science & Technology, nutritional and metabolic diseases, Correction, 030104 developmental biology, GWAS meta-analysis, Global-BPGen Consortium, Common SNPS, CHARGE Consortium, 3111 Biomedicine, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR, Author Summary Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.

Published
2014
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41. Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Author

Natarajan, Pradeep, Bis, Joshua C, Bielak, Lawrence F, Cox, Amanda J, Dörr, Marcus, Feitosa, Mary F, Franceschini, Nora, Guo, Xiuqing, Hwang, Shih-Jen, Isaacs, Aaron, Jhun, Min A, Kavousi, Maryam, Li-Gao, Ruifang, Lyytikäinen, Leo-Pekka, Marioni, Riccardo E, Schminke, Ulf, Stitziel, Nathan O, Tada, Hayato, van Setten, Jessica, Smith, Albert V, Vojinovic, Dina, Yanek, Lisa R, Yao, Jie, Yerges-Armstrong, Laura M, Amin, Najaf, Baber, Usman, Borecki, Ingrid B, Carr, J Jeffrey, Chen, Yii-Der Ida, Cupples, L Adrienne, de Jong, Pim A, de Koning, Harry, de Vos, Bob D, Demirkan, Ayse, Fuster, Valentin, Franco, Oscar H, Goodarzi, Mark O, Harris, Tamara B, Heckbert, Susan R, Heiss, Gerardo, Hoffmann, Udo, Hofman, Albert, Išgum, Ivana, Jukema, J Wouter, Kähönen, Mika, Kardia, Sharon L R, Kral, Brian G, Launer, Lenore J, Massaro, Joseph, Mehran, Roxana, and CHARGE Consortium

Subjects
genome-wide association study, genomics, Journal Article, carotid intima–media thickness, coronary artery calcification, exome
Abstract

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD. METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)). CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

Published
2016

42. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole M, Kooijman, Marjolein N, Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R, Gaulton, Kyle J, Grarup, Niels, Bradfield, Jonathan P, Strachan, David P, Li-Gao, Ruifang, Ahluwalia, Tarunveer S, Kreiner, Eskil, Rueedi, Rico, Lyytikäinen, Leo-Pekka, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K, Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitkänen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A, Zondervan, Krina T, Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M, Bennett, Amanda J, Rahmioglu, Nilufer, Nyholt, Dale R, Ma, Ronald Ching Wan, Tam, Claudia Ha Ting, Tam, Wing Hung, CHARGE Consortium Hematology Working Group, Ganesh, Santhi K, van Rooij, Frank Ja, Jones, Samuel E, Loh, Po-Ru, Ruth, Katherine S, Tuke, Marcus A, Tyrrell, Jessica, Wood, Andrew R, Yaghootkar, Hanieh, Scholtens, Denise M, Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M, Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E, Murcia, Mario, van Beijsterveldt, Catharina Em, Willemsen, Gonneke, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Tiesler, Carla Mt, Standl, Marie, Kutalik, Zoltán, Bonas-Guarch, Sílvia, Hougaard, David M, Sánchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V, de Haan, Hugoline G, Rosendaal, Frits R, Medina-Gomez, Carolina, Ring, Susan M, Hemani, Gibran, McMahon, George, Robertson, Neil R, Groves, Christopher J, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Mentch, Frank D, MacKenzie, Scott M, Reynolds, Rebecca M, Early Growth Genetics (EGG) Consortium, Lowe, William L, Tönjes, Anke, Stumvoll, Michael, and Lindi, Virpi

Subjects
Adult, Male, Aging, Genotype, General Science & Technology, Datasets as Topic, Blood Pressure, Coronary Artery Disease, Low Birth Weight and Health of the Newborn, CHARGE Consortium Hematology Working Group, Cohort Studies, Genomic Imprinting, Fetus, Early Growth Genetics (EGG) Consortium, Preterm, Clinical Research, Infant Mortality, Diabetes Mellitus, Genetics, Humans, Birth Weight, Insulin, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Obesity, Aetiology, Nutrition, Pediatric, Anthropometry, Prevention, Human Genome, Genetic Variation, Perinatal Period - Conditions Originating in Perinatal Period, Chromatin Assembly and Disassembly, Glucose, Phenotype, Genetic Loci, Female, Type 2, Glycogen, Signal Transduction, Genome-Wide Association Study
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P

Published
2016

44. Pleiotropy between neuroticism and physical and mental health: findings from 108038 men and women in UK Biobank

Author

Gale, C.R., Hagenaars, S.P., Davies, G., Hill, W.D., Liewald, D.C.M., Cullen, B., Penninx, B.W., CHARGE consortium Aging & Longevity Group, [Unknown], Boomsma, D.I., Pell, J., McIntosh, A.M., Smith, D.J., Deary, I.J., and Harris, S.E.

Subjects
mental disorders
Abstract

People with higher levels of neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 17 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108?038 people in the UK Biobank and health-related measures from 14 large genome-wide association studies (GWASs). Summary information for the 17 GWASs was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa (rg=0.17), major depressive disorder (rg=0.66) and schizophrenia (rg=0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder, borderline personality, major depressive disorder, negative affect, neuroticism (Genetics of Personality Consortium), schizophrenia, coronary artery disease, and smoking (? between 0.009-0.043), and in a negative direction in the case of body mass index (?=-0.0095). A high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia.

Published
2016

45. CRTC3 links catecholamine signalling to energy balance

Author

Youngsup Song, Judith Altarejos, Mark O. Goodarzi, Hiroshi Inoue, Xiuqing Guo, Rebecca Berdeaux, Jeong-Ho Kim, Jason Goode, Motoyuki Igata, Jose C. Paz, Meghan F. Hogan, Pankaj K. Singh, Naomi Goebel, Lili Vera, Nina Miller, Jinrui Cui, Michelle R. Jones, CHARGE Consortium, GIANT Consortium, Yii-Der I. Chen, Kent D. Taylor, Willa A. Hsueh, Jerome I. Rotter, and Marc Montminy

Subjects
medicine.medical_specialty, Multidisciplinary, Leptin, Adipose tissue, Biology, CREB, CRTC2, chemistry.chemical_compound, Endocrinology, chemistry, Adipocyte, Internal medicine, biology.protein, medicine, Cyclic AMP Response Element-Binding Protein, CAMP response element binding, RGS2
Abstract

The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of β-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating β-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.

Published
2010
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46. Molecular genetic contributions to self-rated health.

Author

Harris, Sarah E., Hagenaars, Saskia P., Davies, Gail, Hill, W. David, Liewald, David C. M., Ritchie, Stuart J., Marioni, Riccardo E., Sudlow, Cathie L. M., Wardlaw, Joanna M., McIntosh, Andrew M., Gale, Catharine R., Deary, Ian J., David Hill, W, METASTROKE Consortium, International Consortium for Blood Pressure Genome-Wide Association Studies, International Consortium for Blood Pressure Genome-Wide Association Studies, CHARGE Consortium Aging and Longevity Group, and CHARGE Consortium Cognitive Group

Subjects
MOLECULAR genetics, MOLECULAR biology, BALANCE disorders, AUTOSOMAL recessive polycystic kidney, GENETIC disorders, GENETIC polymorphisms, GENETICS, HEALTH status indicators, MOLECULAR epidemiology, MORTALITY, RESEARCH funding, SELF diagnosis, STATISTICS
Abstract

Background: Poorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for objective measures of disease at time of rating. Twin studies indicate SRH has a heritability of up to 60% and that its genetic architecture may overlap with that of personality and cognition.Methods: We carried out a genome-wide association study (GWAS) of SRH on 111 749 members of the UK Biobank sample. Univariate genome-wide complex trait analysis (GCTA)-GREML analyses were used to estimate the proportion of variance explained by all common autosomal single nucleotide polymorphisms (SNPs) for SRH. Linkage disequilibrium (LD) score regression and polygenic risk scoring, two complementary methods, were used to investigate pleiotropy between SRH in the UK Biobank and up to 21 health-related and personality and cognitive traits from published GWAS consortia.Results: The GWAS identified 13 independent signals associated with SRH, including several in regions previously associated with diseases or disease-related traits. The strongest signal was on chromosome 2 (rs2360675, P = 1.77 x 10 -10 ) close to KLF7 . A second strong peak was identified on chromosome 6 in the major histocompatibility region (rs76380179, P = 6.15 x 10 -10 ). The proportion of variance in SRH that was explained by all common genetic variants was 13%. Polygenic scores for the following traits and disorders were associated with SRH: cognitive ability, education, neuroticism, body mass index (BMI), longevity, attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, lung function, blood pressure, coronary artery disease, large vessel disease stroke and type 2 diabetes.Conclusions: Individual differences in how people respond to a single item on SRH are partly explained by their genetic propensity to many common psychiatric and physical disorders and psychological traits. [ABSTRACT FROM AUTHOR]

Published
2017
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47. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author

Minelli, C. (Cosetta), Dean, C. H. (Charlotte H.), Hind, M. (Matthew), Alves, A. C. (Alexessander Couto), Amaral, A. F. (André F. S.), Siroux, V. (Valerie), Huikari, V. (Ville), Soler Artigas, M. (María), Evans, D. M. (David M.), Loth, D. W. (Daan W.), Bossé, Y. (Yohan), Postma, D. S. (Dirkje S.), Sin, D. (Don), Thompson, J. (John), Demenais, F. (Florence), Henderson, J. (John), S. c. (SpiroMeta consortium), C. c. (CHARGE consortium), Bouzigon, E. (Emmanuelle), Jarvis, D. (Deborah), Järvelin, M.-R. (Marjo-Riitta), Burney, P. (Peter), School of Medicine / Public Health, and Latzin, Philipp

Subjects
Adult, Male, General Science & Technology, CHARGE consortium, Organogenesis, Quantitative Trait Loci, lcsh:Medicine, Young Adult, Clinical Research, Forced Expiratory Volume, Genetics, 2.1 Biological and endogenous factors, Humans, SpiroMeta consortium, Developmental, Nuclear Receptor Co-Repressor 2, Aetiology, Polymorphism, lcsh:Science, Lung, Genetic Association Studies, Aged, Gene Expression Profiling, lcsh:R, Single Nucleotide, Middle Aged, Genes, Respiratory, lcsh:Q, Female, Genome-Wide Association Study
Abstract

Article, Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p, published version, peerReviewed

Published
2016

48. Structural Brain MRI Trait Polygenic Score Prediction of Cognitive Abilities

Author

Luciano, Michelle, Marioni, Riccardo E, Valdés Hernández, Maria, Muñoz Maniega, Susana, Hamilton, Iona F, Royle, Natalie A, Generation Scotland, Chauhan, Ganesh, Bis, Joshua C, Debette, Stephanie, DeCarli, Charles, Fornage, Myriam, Schmidt, Reinhold, Ikram, M Arfan, Launer, Lenore J, Seshadri, Sudha, Bastin, Mark E, Porteous, David J, Wardlaw, Joanna, Deary, Ian J, and CHARGE Consortium

Subjects
Male, Multifactorial Inheritance, Aging, intracranial volume, Clinical Sciences, hippocampal volume, Neuropsychological Tests, Basic Behavioral and Social Science, Paediatrics and Reproductive Medicine, Cognition, Clinical Research, Behavioral and Social Science, Humans, 2.1 Biological and endogenous factors, Aetiology, Genetics & Heredity, Prevention, Neurosciences, Brain, Middle Aged, white matter hyperintensities, Magnetic Resonance Imaging, general cognitive ability, Brain Disorders, polygenic prediction, Mental Health, brain infarct, total brain volume, Neurological, CHARGE Consortium, Biomedical Imaging, Female, Cognitive Sciences, Generation Scotland, Forecasting, Genome-Wide Association Study
Abstract

Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygenic scores for these traits in three Scottish samples: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115-8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction samples that closely match the demographics of the GWA samples from which prediction is based. Ideally, these analyses should be repeated in larger samples with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.

Published
2015

49. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W., Justice, Anne E., Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F., Chu, Su, Czajkowski, Jacek, Esko, Tonu, Fall, Tove, Kilpelainen, Tuomas O., Lu, Yingchang, Magi, Reedik, Mihailov, Evelin, Pers, Tune H., Rueeger, Sina, Teumer, Alexander, Ehret, Georg B., Ferreira, Teresa, Heard-Costa, Nancy L., Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D., Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M., Jansen, Rick, Westra, Harm-Jan, White, Charles C., Absher, Devin, Ahluwalia, Tarunveer S., Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L., de Craen, Anton J. M., Bis, Joshua C., Bonnefond, Amelie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston W. K., Haitjema, Saskia, van der Laan, Sander W., van Setten, Jessica, Asselbergs, Folkert W., de Bakker, Paul I. W., Moll, Frans L., Pasterkamp, Gerard, den Ruijter, Hester M., CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, and MAGIC Consortium

Subjects
COMMON SNPS, LIFE-COURSE, MASS INDEX, SELF-REPORTED HEIGHT, BIOLOGICAL PATHWAYS, LOCI, FAT DISTRIBUTION, NATURAL MENOPAUSE, PERIPHERAL-BLOOD, WEIGHT-GAIN
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Published
2015

50. Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.

Author

Brody, Jennifer A, Brody, Jennifer A, Morrison, Alanna C, Bis, Joshua C, O'Connell, Jeffrey R, Brown, Michael R, Huffman, Jennifer E, Ames, Darren C, Carroll, Andrew, Conomos, Matthew P, Gabriel, Stacey, Gibbs, Richard A, Gogarten, Stephanie M, Gupta, Namrata, Jaquish, Cashell E, Johnson, Andrew D, Lewis, Joshua P, Liu, Xiaoming, Manning, Alisa K, Papanicolaou, George J, Pitsillides, Achilleas N, Rice, Kenneth M, Salerno, William, Sitlani, Colleen M, Smith, Nicholas L, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, TOPMed Hematology and Hemostasis Working Group, CHARGE Analysis and Bioinformatics Working Group, Heckbert, Susan R, Laurie, Cathy C, Mitchell, Braxton D, Vasan, Ramachandran S, Rich, Stephen S, Rotter, Jerome I, Wilson, James G, Boerwinkle, Eric, Psaty, Bruce M, Cupples, L Adrienne, Brody, Jennifer A, Brody, Jennifer A, Morrison, Alanna C, Bis, Joshua C, O'Connell, Jeffrey R, Brown, Michael R, Huffman, Jennifer E, Ames, Darren C, Carroll, Andrew, Conomos, Matthew P, Gabriel, Stacey, Gibbs, Richard A, Gogarten, Stephanie M, Gupta, Namrata, Jaquish, Cashell E, Johnson, Andrew D, Lewis, Joshua P, Liu, Xiaoming, Manning, Alisa K, Papanicolaou, George J, Pitsillides, Achilleas N, Rice, Kenneth M, Salerno, William, Sitlani, Colleen M, Smith, Nicholas L, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, TOPMed Hematology and Hemostasis Working Group, CHARGE Analysis and Bioinformatics Working Group, Heckbert, Susan R, Laurie, Cathy C, Mitchell, Braxton D, Vasan, Ramachandran S, Rich, Stephen S, Rotter, Jerome I, Wilson, James G, Boerwinkle, Eric, Psaty, Bruce M, and Cupples, L Adrienne

Abstract

The exploding volume of whole-genome sequence (WGS) and multi-omics data requires new approaches for analysis. As one solution, we have created a cloud-based Analysis Commons, which brings together genotype and phenotype data from multiple studies in a setting that is accessible by multiple investigators. This framework addresses many of the challenges of multi-center WGS analyses, including data sharing mechanisms, phenotype harmonization, integrated multi-omics analyses, annotation, and computational flexibility. In this setting, the computational pipeline facilitates a sequence-to-discovery analysis workflow illustrated here by an analysis of plasma fibrinogen levels in 3996 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) WGS program. The Analysis Commons represents a novel model for transforming WGS resources from a massive quantity of phenotypic and genomic data into knowledge of the determinants of health and disease risk in diverse human populations.

Published
2017

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