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1. Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis

Author

Felix O’Farrell, Benjamin Aleyakpo, Rima Mustafa, Xiyun Jiang, Rui Climaco Pinto, Paul Elliott, Ioanna Tzoulaki, Abbas Dehghan, Samantha H. Y. Loh, Jeff W. Barclay, L. Miguel Martins, and Raha Pazoki

Subjects
Medicine, Science
Abstract

Abstract Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD.

Published
2023
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2. Gene-diet interactions and cardiovascular diseases: a systematic review of observational and clinical trials

Author

Zayne M. Roa-Díaz, Julian Teuscher, Magda Gamba, Marvin Bundo, Giorgia Grisotto, Faina Wehrli, Edna Gamboa, Lyda Z. Rojas, Sergio A. Gómez-Ochoa, Sanne Verhoog, Manuel Frias Vargas, Beatrice Minder, Oscar H. Franco, Abbas Dehghan, Raha Pazoki, Pedro Marques-Vidal, and Taulant Muka

Subjects
Diet, Gene-diet interaction, Myocardial infarction, Stroke, Coronary heart disease, Cardiovascular diseases, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Both genetic background and diet are important determinants of cardiovascular diseases (CVD). Understanding gene-diet interactions could help improve CVD prevention and prognosis. We aimed to summarise the evidence on gene-diet interactions and CVD outcomes systematically. Methods We searched MEDLINE® via Ovid, Embase, PubMed®, and The Cochrane Library for relevant studies published until June 6th 2022. We considered for inclusion cross-sectional, case–control, prospective cohort, nested case–control, and case-cohort studies as well as randomised controlled trials that evaluated the interaction between genetic variants and/or genetic risk scores and food or diet intake on the risk of related outcomes, including myocardial infarction, coronary heart disease (CHD), stroke and CVD as a composite outcome. The PROSPERO protocol registration code is CRD42019147031. Results and discussion We included 59 articles based on data from 29 studies; six articles involved multiple studies, and seven did not report details of their source population. The median sample size of the articles was 2562 participants. Of the 59 articles, 21 (35.6%) were qualified as high quality, while the rest were intermediate or poor. Eleven (18.6%) articles adjusted for multiple comparisons, four (7.0%) attempted to replicate the findings, 18 (30.5%) were based on Han-Chinese ethnicity, and 29 (49.2%) did not present Minor Allele Frequency. Fifty different dietary exposures and 52 different genetic factors were investigated, with alcohol intake and ADH1C variants being the most examined. Of 266 investigated diet-gene interaction tests, 50 (18.8%) were statistically significant, including CETP-TaqIB and ADH1C variants, which interacted with alcohol intake on CHD risk. However, interactions effects were significant only in some articles and did not agree on the direction of effects. Moreover, most of the studies that reported significant interactions lacked replication. Overall, the evidence on gene-diet interactions on CVD is limited, and lack correction for multiple testing, replication and sample size consideration.

Published
2022
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3. Genetic analysis of over half a million people characterises C-reactive protein loci

Author

Saredo Said, Raha Pazoki, Ville Karhunen, Urmo Võsa, Symen Ligthart, Barbara Bodinier, Fotios Koskeridis, Paul Welsh, Behrooz Z. Alizadeh, Daniel I. Chasman, Naveed Sattar, Marc Chadeau-Hyam, Evangelos Evangelou, Marjo-Riitta Jarvelin, Paul Elliott, Ioanna Tzoulaki, and Abbas Dehghan

Subjects
Science
Abstract

Inflammation is associated with a variety of diseases. Here, the authors identify 266 genetic loci associated with C-reactive protein levels, a marker of inflammation, in >500,000 Europeans, along with associated pathways, clinical outcomes and potential causal associations with disease.

Published
2022
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4. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Author

Raha Pazoki, Marijana Vujkovic, Joshua Elliott, Evangelos Evangelou, Dipender Gill, Mohsen Ghanbari, Peter J. van der Most, Rui Climaco Pinto, Matthias Wielscher, Matthias Farlik, Verena Zuber, Robert J. de Knegt, Harold Snieder, André G. Uitterlinden, Lifelines Cohort Study, Julie A. Lynch, Xiyun Jiang, Saredo Said, David E. Kaplan, Kyung Min Lee, Marina Serper, Rotonya M. Carr, Philip S. Tsao, Stephen R. Atkinson, Abbas Dehghan, Ioanna Tzoulaki, M. Arfan Ikram, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Behrooz Z. Alizadeh, Christopher J. O’Donnell, Danish Saleheen, Benjamin F. Voight, Kyong-Mi Chang, Mark R. Thursz, Paul Elliott, and the VA Million Veteran Program

Subjects
Science
Abstract

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.

Published
2021
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5. Alcohol consumption in the general population is associated with structural changes in multiple organ systems

Author

Evangelos Evangelou, Hideaki Suzuki, Wenjia Bai, Raha Pazoki, He Gao, Paul M Matthews, and Paul Elliott

Subjects
alcohol consumption, imaging, brain, heart, aorta, liver, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample. Methods: We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol. Results: We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7 × 10−3 ± 0.76 × 10−3 per doubling of alcohol consumption, p=3.0 × 10−14). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption. Conclusions: Our results imply that there is not a ‘safe threshold’ below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited. Funding: See acknowledgements.

Published
2021
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6. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Amand F. Schmidt, Michael V. Holmes, David Preiss, Daniel I. Swerdlow, Spiros Denaxas, Ghazaleh Fatemifar, Rupert Faraway, Chris Finan, Dennis Valentine, Zammy Fairhurst-Hunter, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hypponen, Christine Power, Max Moldovan, Erik van Iperen, Kees Hovingh, Ilja Demuth, Kristina Norman, Elisabeth Steinhagen-Thiessen, Juri Demuth, Lars Bertram, Christina M. Lill, Stefan Coassin, Johann Willeit, Stefan Kiechl, Karin Willeit, Dan Mason, John Wright, Richard Morris, Goya Wanamethee, Peter Whincup, Yoav Ben-Shlomo, Stela McLachlan, Jackie F. Price, Mika Kivimaki, Catherine Welch, Adelaida Sanchez-Galvez, Pedro Marques-Vidal, Andrew Nicolaides, Andrie G. Panayiotou, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Giuseppe Matullo, Giovanni Fiorito, Simonetta Guarrera, Carlotta Sacerdote, Nicholas J. Wareham, Claudia Langenberg, Robert A. Scott, Jian’an Luan, Martin Bobak, Sofia Malyutina, Andrzej Pająk, Ruzena Kubinova, Abdonas Tamosiunas, Hynek Pikhart, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Tine Jess, Jackie Cooper, Steve E. Humphries, Murray Brilliant, Terrie Kitchner, Hakon Hakonarson, David S. Carrell, Catherine A. McCarty, Kirchner H. Lester, Eric B. Larson, David R. Crosslin, Mariza de Andrade, Dan M. Roden, Joshua C. Denny, Cara Carty, Stephen Hancock, John Attia, Elizabeth Holliday, Rodney Scott, Peter Schofield, Martin O’Donnell, Salim Yusuf, Michael Chong, Guillaume Pare, Pim van der Harst, M. Abdullah Said, Ruben N. Eppinga, Niek Verweij, Harold Snieder, Lifelines Cohort authors, Tim Christen, D. O. Mook-Kanamori, the ICBP Consortium, Stefan Gustafsson, Lars Lind, Erik Ingelsson, Raha Pazoki, Oscar Franco, Albert Hofman, Andre Uitterlinden, Abbas Dehghan, Alexander Teumer, Sebastian Baumeister, Marcus Dörr, Markus M. Lerch, Uwe Völker, Henry Völzke, Joey Ward, Jill P. Pell, Tom Meade, Ingrid E. Christophersen, Anke H. Maitland-van der Zee, Ekaterina V. Baranova, Robin Young, Ian Ford, Archie Campbell, Sandosh Padmanabhan, Michiel L. Bots, Diederick E. Grobbee, Philippe Froguel, Dorothée Thuillier, Ronan Roussel, Amélie Bonnefond, Bertrand Cariou, Melissa Smart, Yanchun Bao, Meena Kumari, Anubha Mahajan, Jemma C. Hopewell, Sudha Seshadri, the METASTROKE Consortium of the ISGC, Caroline Dale, Rui Providencia E. Costa, Paul M. Ridker, Daniel I. Chasman, Alex P. Reiner, Marylyn D. Ritchie, Leslie A. Lange, Alex J. Cornish, Sara E. Dobbins, Kari Hemminki, Ben Kinnersley, Marc Sanson, Karim Labreche, Matthias Simon, Melissa Bondy, Philip Law, Helen Speedy, James Allan, Ni Li, Molly Went, Niels Weinhold, Gareth Morgan, Pieter Sonneveld, Björn Nilsson, Hartmut Goldschmidt, Amit Sud, Andreas Engert, Markus Hansson, Harry Hemingway, Folkert W. Asselbergs, Riyaz S. Patel, Brendan J. Keating, Naveed Sattar, Richard Houlston, Juan P. Casas, and Aroon D. Hingorani

Subjects
Genetic association studies, Mendelian randomisation, LDL-cholesterol, Phenome-wide association scan, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Published
2019
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7. GWAS for urinary sodium and potassium excretion highlights pathways shared with cardiovascular traits

Author

Raha Pazoki, Evangelos Evangelou, David Mosen-Ansorena, Rui Climaco Pinto, Ibrahim Karaman, Paul Blakeley, Dipender Gill, Verena Zuber, Paul Elliott, Ioanna Tzoulaki, and Abbas Dehghan

Subjects
Science
Abstract

Levels of sodium and potassium in urine are associated with cardiovascular traits. Here, Pazoki et al. perform genome-wide association studies for urinary sodium and potassium secretion and identify 50 and 13 novel loci, respectively, some of which show a potential causal relationship with blood pressure based on MR analysis.

Published
2019
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8. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary

Subjects
Science
Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019
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9. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author

Tuomas O. Kilpeläinen, Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Lifelines Cohort Study, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao, and Ruth J. F. Loos

Subjects
Science
Abstract

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

Published
2019
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12. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary

Subjects
Science
Abstract

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Published
2018
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13. The effect of Buspirone on symptoms and quality of life in patients with functional dyspepsia

Author

Seyed masood Tabib, Khadijeh Nokani, and Raha Pazoki

Subjects
buspirone, amitriptyline, dyspepsia, quality of life, Medicine (General), R5-920
Abstract

Background: Functional dyspepsia (FD) is a heterogeneous disorder of yet unknown etiology which causes a significant reduction in the quality of life. In this study, we compared the effect of buspirone as an agonist of serotonin 5HT1A receptor with amitriptyline and placebo on improving the symptoms and quality of life in patients with functional dyspepsia. Methods: This study was a double-blinded, randomized controlled clinical trial. Using a sequential sampling, patients with the diagnostic criteria of Rome 2 and normal gastrointestinal findings were selected. The subjects were randomly divided into three therapeutic groups receiving amitriptyline, buspirone, and placebo. We used Nepean Dyspepsia Inde (NDI) to evaluate the quality of life before and after the treatment. Results: The mean age of subjects was 35.38±12.94 years. Symptom and quality of life scores of the three groups were equal at the beginning but at the end of treatment, these scores were different. Buspirone was more effective than both amitriptyline and placebo in reducing the symptom of early satiety. Buspirone showed a better improvement in quality of life compared to placebo. Both Buspirone and amitriptyline were more effective than placebo in decreasing the symptom of epigastric pain. Conclusion: Our study confirmed the positive effect of buspirone on the quality of life and symptoms (like early satiety and abdominal pain) in patients with functional dyspepsia. Since the mechanism of action of buspirone and also the pathophysiology of functional dyspepsia are still unknown, further studies are necessary to clarify every aspect of the disease and therapeutic effects of various treatments on it.

Published
2007

14. Reference range of serum homocysteine level for the northern Persian Gulf

Author

Seyed Mojtaba Jafary, raha Pazoki, kamran Mirzaie, Iraj Nabipour, Seyed Sajad Eghbali, and Zahra Sanjideh

Subjects
homocysteine, cardiovascular, vitamin B12, folic acid, Medicine (General), R5-920
Abstract

Background: Homocysteine (Hcy), an intermediate form generated during the metabolism of methionine, is associated with cardiovascular diseases. There is little information available about serum concentration of Hcy in healthy Iranian population. In the present study, we assessed the reference range of serum Hcy level among inhabitants of the northern Persian Gulf. Methods: In the Persian Gulf Healthy Heart Study (PGHHS) which used a multistage, stratified, clustered sampling, we measured fasting serum Hcy level using enzyme immunoassay method with an accuracy limit of 1 µmol/ L. Confounding factors such as smoking, alcohol consumption, drugs and chronic diseases were eliminated. Reference range for homocysteine level was considered between 5 and 95 percentiles. Results: A total of 886 participants (39.3% female, 60.7% male) were evaluated. Mean plasma Hcy level was 14.58 ± 7.29 µmol/ L and was higher in men than women. Reference range for Hcy level was 8.35-31.1 µmol/ L in males and 2.39-24.31 µmol/ L in females. There was no difference among age groups for serum Hcy level. Conclusion: The Hcy level in the northern Persian Gulf general population is high. Since high Hcy level has been shown as a risk factor of cardiovascular diseases in various studies, it is essential to study the reasons of this high level of Hcy in this region.

Published
2007

15. Clinical risk factors of febrile seizure in children in a university hospital in Bushehr port

Author

Anahita Sanaei Dashty, Allah karam Akhlaghi, and Raha Pazoki

Subjects
fever, seizure, tonic-clonic, atonic, myoclonic, Medicine (General), R5-920
Abstract

Background: Although the majority of febrile seizures are benign, it is clinically important to understand the underlying mechanism. In this study, we investigated characteristics of febrile convulsion and factors related to its recurrence and its relapse during a hospital course. Methods: A total of 102 patients with febrile seizure who were admitted serially at Fatemeh Zahra (S) University Hospital in Bushehr port were investigated. Demographic information and data of the history and physical examination were recorded. Children under the age of five with temperature of more than 37.8C or with history of fever accompanied by seizure entered the study those with meningitis or encephalitis according to the results of lumbar puncture or clinical diagnosis were ruled out. Results: Mean age of patients was 24±13.1 months, the most frequent type of convulsion was tonic-clonic (60.5%), and the least were atonic and myoclonic (each 7.9%). Focal convulsion was determined in 13.0% and complex type was observed in 32.5% of patients. Family history of febrile seizure was found in 59.0%. Female sex (RR=2.68, 95% CI: 1.20-5.99), history of previous febrile seizure (RR=2.56, 95% CI: 1.11-5.95), age at initial febrile seizure (RR=2.7, 95% CI: 1.16-6.29), and complex type of seizure (RR=3.86, 95% CI: 1-14.97) increased the risk of seizure relapses in a hospital course (P

Published
2007

16. Assessment of serum homocysteine level and hyperhomocysteinaemia in the northern Persian Gulf

Author

Ali Movahed, Seyed Mojtaba Jafary, Mohammad Zeki Abbasi, Raha Pazoki, Mehrnaz Katebi, and Iraj Nabipour

Subjects
homocysteine, cardiovascular system, vitamin B12, folic acid, Medicine (General), R5-920
Abstract

Background: Homocysteine is a non essential amino acid which is derived from metabolism of the essential amino acid, metionin. It has been shown that an elevated serum homocysteine level in adults is associated with vascular diseases. In this study, we determined serum homocysteine level and its gender and age distribution in three cities of Bushehr, Genaveh and Deilam in the northern Persian Gulf. Methods: A total of 1699 inhabitants of the north region of the Persian Gulf were selected based on a multi stage stratified clustered sampling and a fasting blood sample was taken from them. We measured serum homocysteine level using enzyme immuno assay method with accuracy limit of 1 µmol/L. Hyperhomocyteinaemia was defined as homocysteine more than 14 µmol/L. Results: Mean plasma homocysteine level was 14.63±7.08 µmol/L (17.72±6.63 µmol/L for men and 12.73±6.78 µmol/L for women). No correlation between homocysteine and age was found. The prevalence of hyperhomocysteinaemia was 51.2% (22.2% in male and 29% in female). Conclusion: The homocysteine level in the north region of the Persian Gulf general population is high. Further study is essential to reveal the reason of the high homocysteine serum level in the inhabitants of the northern Persian Gulf with emphasis on folic acid and vitamin B12 serum levels.

Published
2007

17. The correlation between changes of C-reactive protein (CRP) level and size of infarct in stroke

Author

Shahram Aboutalebi, Fahimeh Ahmadi, and Raha Pazoki

Subjects
acute stroke, C - reactive protein, inflammation, lacunar infarct, Medicine (General), R5-920
Abstract

Background: The presence of C-reactive protein (CRP) during different stages of stroke had been shown in several studies. There is still no definite document about the correlation of CRP level and size of infarct in stroke. We studied the correlation of the acute level of CRP with size of infarct in stroke. Methods: A total of 90 consecutive patients with acute stroke admitted in Fatemeh Zahra University Hospital in Bushehr city were studied. Levels of CRP were measured at admission time and 48 hours later. Sizes of infarct and types of stroke were determined with Computerized Tomography scanning. The excluded patients were those with infection, stroke in brain stem, a delay more than 24 hours after attack of stroke and Transient Ischemic Attacks. CRP level was measured quantitatively using ELISA method. Results: No correlation between the first CRP levels and variables of age, size of infarct and type of stroke was detected. Size of infarct was correlated with the second CRP (r=0.41, P

Published
2006

18. The knowledge assessment of stroke in over age 25 years old habitants of Bushehr port 2005

Author

Shahram Aboutalebi, Maryam moghadasian, Azam Moradi, and Raha Pazoki

Subjects
stroke, risk factors, warning signs, cardiovascular diseases, Medicine (General), R5-920
Abstract

Background: Decreasing the time from onset to hospital arrival and improving of stroke risk factors depend on public knowledge about stroke warning signs and its risk factors. A variety of programs were conducted in different countries for public knowledge assessment of stroke and its promotion. Methods: A total of 562 persons (66.4 female) aged over 25 years old were selected by random cluster sampling and their knowledge on stroke was evaluated using the revised 11 item questionnaire of NIH/NHLBI (National Institutes of Health/ National Heart Lung Blood Institute of USA). The complete score of the questionnaire was 54. Results: The mean stroke knowledge score of male and female participants were 23.45±9.0 and 24.14±7.8, respectively (P>5%). Meanwhile, the mean of stroke knowledge score was higher in those with hypertension and a history of stroke (P=0.001). Higher education had correlation with a higher score. At least one stroke warning sign was reported by 83.3 % of participants and 95.2 % of respondents mentioned at least one established stroke risk factor. The most recognized stroke risk factor was stress and the most identified warning sign for stroke was sudden weakness or numbness of the face, arm or leg on one side of the body. Conclusion: Those aged over 25 years old in Bushehr port had a higher knowledge score on stroke warning signs and its risk factors than other countries, including USA.

Published
2006

19. Lipid disorders in the first degree relatives with premature myocardial infarction in Bushehr port

Author

Ahmad Ryazi, Iraj Nabipour, Mohammad Reza Salehi, Nasrin Seyd Nezami, Raha Pazoki, Seyed Mojtaba Jafary, and Zahra Sanjideh

Subjects
premature myocardial infarction, lipid disorders, coronary artery risk factors, cholesterol, Medicine (General), R5-920
Abstract

Background: Family history of premature myocardial infarction (PMI) is an important risk factor thus diagnosis and therapeutic intervention of cardiovascular risk factors in the first degree relatives of the patients with PMI is the most effective measure for preventing myocardial infarction and its mortality rate. Methods: Cardiovascular risk factors were assessed in the relatives of 49 patients with PMI in Fatemeh-Zahra University Hospital using MONICA-WHO project and Behavioral Risk Factor Surveillance System (BRFSS) criteria. A control group with the age of over 25 years old was randomly selected among the subjects of the Persian Gulf Healthy Heart Study (PGHHS). Lipid and lipoprotein abnormalities were defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). Results: A total of 148 (88 females and 60 males) first degree relatives of 49 patients with PMI were evaluated. The frequency of hypercholesterolemia, high LDL-cholesterol, low HDL-cholesterol and hypertriglyceridemia in subjects with less than 20 years old (42 first degree relatives) were 33.3%, 28.5%, 71% and 16.6%. No significant difference in frequency of hyperlipidemia and the other cardiovascular risk factors was found between the first degree relatives of patients with PMI and their age – and sex – matched control subjects (P>0.05). We also found no significant difference in frequency of lipid abnormalities between the patients with PMI and their age – and sex – matched control subjects however these patients had a higher frequency of diabetes mellitus (28.1% versus 6.5%) and hypertension (56.3% versus 22.6%), in comparison to the control group. Conclusion: Lipid and lipoprotein abnormalities in the first degree relatives (≥25 years old) of patients with PMI are the same as normal general population therefore investigation of novel cardiovascular risk factors should be considered for further evaluation.

Published
2006

20. The knowledge of cardiovascular risk factors in elementary school students in Bushehr Port The Persian Gulf Healthy Heart Project

Author

Anahita Sanaei Dashty, Seyed Reza Emami, Raha Pazoki, and Fariba Ryahi

Subjects
healthy heart, children, schools, cardiovascular diseases, Medicine (General), R5-920
Abstract

Background: Cardiovascular diseases are among the first leading causes of death in the world, whose main risk factors such as hypercholesterolemia, obesity, hypertension and smoking are somehow closely related to childhood. The process of atherosclerosis may begin developing during childhood. Methods: In order to evaluate the knowledge of elementary school students of Bushehr Port regarding heart function and risk factors of cardiovascular diseases, 1128 students educating in 3rd and 4th grades were randomly selected and assessed with a 30-item questionnaire including four sections heart anatomy, smoking, exercise and nutrition. The minimum score was considered zero, the maximum 30 and the passing score was to gain 51% of the maximum score (or 15.30 out of 30). Results: The mean of total score was 13.1 5. The mean-score of the 3rd grade students was higher than the mean of the score in the 4th grade ones (P

Published
2005

21. SNPs identified as modulators of ECG traits in the general population do not markedly affect ECG traits during acute myocardial infarction nor ventricular fibrillation risk in this condition.

Author

Raha Pazoki, Jonas S S G de Jong, Roos F Marsman, Nienke Bruinsma, Lukas R C Dekker, Arthur A M Wilde, Connie R Bezzina, and Michael W T Tanck

Subjects
Medicine, Science
Abstract

BackgroundVentricular fibrillation (VF) in the setting of acute ST elevation myocardial infarction (STEMI) is a leading cause of mortality. Although the risk of VF has a genetic component, the underlying genetic factors are largely unknown. Since heart rate and ECG intervals of conduction and repolarization during acute STEMI differ between patients who do and patients who do not develop VF, we investigated whether SNPs known to modulate these ECG indices in the general population also impact on the respective ECG indices during STEMI and on the risk of VF.Methods and resultsThe study population consisted of participants of the Arrhythmia Genetics in the NEtherlandS (AGNES) study, which enrols patients with a first STEMI that develop VF (cases) and patients that do not develop VF (controls). SNPs known to impact on RR interval, PR interval, QRS duration or QTc interval in the general population were tested for effects on the respective STEMI ECG indices (stage 1). Only those showing a (suggestive) significant association were tested for association with VF (stage 2). On average, VF cases had a shorter RR and a longer QTc interval compared to non-VF controls. Eight SNPs showed a trend for association with the respective STEMI ECG indices. Of these, three were also suggestively associated with VF.ConclusionsRR interval and ECG indices of conduction and repolarization during acute STEMI differ between patients who develop VF and patients who do not. Although the effects of the SNPs on ECG indices during an acute STEMI seem to be similar in magnitude and direction as those found in the general population, the effects, at least in isolation, are too small to explain the differences in ECGs between cases and controls and to determine risk of VF.

Published
2013
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22. Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Author

Dan E Arking, M Juhani Junttila, Philippe Goyette, Adriana Huertas-Vazquez, Mark Eijgelsheim, Marieke T Blom, Christopher Newton-Cheh, Kyndaron Reinier, Carmen Teodorescu, Audrey Uy-Evanado, Naima Carter-Monroe, Kari S Kaikkonen, Marja-Leena Kortelainen, Gabrielle Boucher, Caroline Lagacé, Anna Moes, XiaoQing Zhao, Frank Kolodgie, Fernando Rivadeneira, Albert Hofman, Jacqueline C M Witteman, André G Uitterlinden, Roos F Marsman, Raha Pazoki, Abdennasser Bardai, Rudolph W Koster, Abbas Dehghan, Shih-Jen Hwang, Pallav Bhatnagar, Wendy Post, Gina Hilton, Ronald J Prineas, Man Li, Anna Köttgen, Georg Ehret, Eric Boerwinkle, Josef Coresh, W H Linda Kao, Bruce M Psaty, Gordon F Tomaselli, Nona Sotoodehnia, David S Siscovick, Greg L Burke, Eduardo Marbán, Peter M Spooner, L Adrienne Cupples, Jonathan Jui, Karen Gunson, Y Antero Kesäniemi, Arthur A M Wilde, Jean-Claude Tardif, Christopher J O'Donnell, Connie R Bezzina, Renu Virmani, Bruno H C H Stricker, Hanno L Tan, Christine M Albert, Aravinda Chakravarti, John D Rioux, Heikki V Huikuri, and Sumeet S Chugh

Subjects
Genetics, QH426-470
Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Published
2011
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23. Evidence for Involvement of the Alcohol Consumption WDPCP Gene in Lipid Metabolism, and Liver Cirrhosis

Author

Raha Pazoki, Felix O’Farrel, Benjamin Aleyakpo, Rima Mustafa, Xiyun Jiang, Rui Pinto, Paul Elliott, Ioanna Tzoulaki, Dehghan Abbas, Samantha Loh, Jeff Barclay, and Luis Martins

Abstract

Alcohol consumption continues to cause a significant health burden globally. The advent of genome-wide association studies has unraveled many genetic loci associated with alcohol consumption. However, biological effects of these loci and pathways involved in alcohol consumption and its health consequences such as alcohol liver disease (ALD) remain to be elucidated. We combined human studies with model organisms Drosophila melanogaster and Caenorhabditis elegans to shed light on molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a longitudinal study to investigate the health of employees of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption and found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways. We identified evidence of a potential causal relationship between alcohol consumption with several triradylglycerols (TAGs) and diradylglycerols (DAGs), a fatty ester (CAR DC18:1), an sphingomyelin (SM 40:2;O2), and an alkaloid (Piperine). We selected a set of genes annotated to genetic variants that (1) are known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with the expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes in C. elegans and Drosophila. Testing the differences in locomotion of C. elegans showed that RNAi knockdown of ACTR1B and MAPT reduced locomotion rate in C. elegans after exposure to ethanol. We showed that RNAi knockdown of several genes (WDPCP, TENM2, GPN1, ARPC1B, SCN8A) in Drosophila changed the sedative effect of ethanol whilst RNAi knockdown of TENM2 reduced ethanol consumption. We also investigated alcohol-induced changes in TAG levels in Drosophila and demonstrated that RNAi knockdown of WDPCP, TENM2 and GPN1 reduce TAG levels. Finally, using publicly available human data, we showed that gene expression of WDPCP is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on the metabolism of lipids and pinpoint WDPCP as a gene with a potential impact on lipid accumulation upon exposure to ethanol suggesting a possible pathway to ALD.

Published
2023

24. Evidence for Involvement ofWDPCPGene in Alcohol Consumption, Lipid Metabolism, and Liver Cirrhosis

Author

Felix O’Farrell, Benjamin Aleyakpo, Rima Mustafa, Xiyun Jiang, Rui Climaco Pinto, Paul Elliott, Ioanna Tzoulaki, Abbas Dehghan, Samantha H. Y. Loh, Jeff W. Barclay, L. Miguel Martins, and Raha Pazoki

Abstract

Alcohol consumption continues to cause a significant health burden globally. The advent of genome-wide association studies has unraveled many genetic loci associated with alcohol consumption. However, the biological effect of these loci and the pathways involved in alcohol consumption and its health consequences such as alcohol liver disease (ALD) remain to be elucidated. We combined human studies with model organismsDrosophila melanogasterandCaenorhabditis elegansto shed light on the molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a sample of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption. We selected a set of genes annotated to genetic variants that are (1) known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes inC. elegansandDrosophila. We examined the effect of this suppression on ethanol consumption and on the sedative effects of ethanol. We also investigated the alcohol-induced changes in triacylglycerol (TGA) levels inDrosophilaand tested differences in locomotion ofC. elegansafter acute exposure to ethanol. In human population, we found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha linolenic acid (ALA) metabolism pathway. We further showed the effect ofACTR1BandMAPTon locomotionin C. elegansafter exposure to ethanol. We demonstrated that three genes namelyWDPCP, TENM2andGPN1modify TAG levels inDrosophila. Finally, we showed that gene expression ofWDPCPin human population is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on metabolism of lipids and pinpointsWDPCPas a gene with potential impact on fat accumulation upon exposure to ethanol suggesting a possible pathway to ALD.

Published
2023

25. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Author

Stephen R. Atkinson, Philip S. Tsao, Evangelos Evangelou, VA Million Veteran Program, Karl-Heinz Herzig, David E. Kaplan, Marina Serper, Behrooz Z. Alizadeh, Benjamin F. Voight, Xiyun Jiang, Julie A. Lynch, Dipender Gill, Danish Saleheen, Marjo-Riitta Järvelin, André G. Uitterlinden, Rui Pinto, Raha Pazoki, Peter J. van der Most, Paul Elliott, Verena Zuber, Matthias Farlik, Ioanna Tzoulaki, Mark Thursz, Harold Snieder, Marijana Vujkovic, Christopher J. O'Donnell, Mohsen Ghanbari, Kyung Min Lee, Saredo Said, Matthias Wielscher, Kyong-Mi Chang, M. Arfan Ikram, Joshua Elliott, Rotonya M. Carr, Robert J. de Knegt, Abbas Dehghan, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Medical Research Council (MRC), Epidemiology, Gastroenterology & Hepatology, and Internal Medicine

Subjects
Enzymologic, Male, 0301 basic medicine, LD SCORE REGRESSION, General Physics and Astronomy, Physiology, Genome-wide association study, Cardiovascular, Oral and gastrointestinal, DISEASE, Cohort Studies, Rotterdam Study, 0302 clinical medicine, Risk Factors, Databases, Genetic, 2.1 Biological and endogenous factors, Aetiology, POPULATION, RISK, education.field_of_study, Multidisciplinary, biology, medicine.diagnostic_test, HERITABILITY, Liver Disease, Alanine Transaminase, gamma-Glutamyltransferase, Single Nucleotide, Middle Aged, Heart Disease, Liver, Cardiovascular Diseases, VA Million Veteran Program, MENDELIAN RANDOMIZATION, Female, 030211 gastroenterology & hepatology, HEALTH, Science, Population, Single-nucleotide polymorphism, BIOBANK, Polymorphism, Single Nucleotide, Gene Expression Regulation, Enzymologic, White People, General Biochemistry, Genetics and Molecular Biology, Databases, 03 medical and health sciences, Insulin resistance, Metabolic Diseases, Genetic, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, GENOME-WIDE ASSOCIATION, education, Metabolic and endocrine, METAANALYSIS, Aged, Genetic testing, business.industry, General Chemistry, Mendelian Randomization Analysis, Alkaline Phosphatase, Lipid Metabolism, medicine.disease, Good Health and Well Being, 030104 developmental biology, Gene Expression Regulation, Alanine transaminase, biology.protein, Insulin Resistance, Digestive Diseases, business, Genome-Wide Association Study
Abstract

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Published
2021

26. Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: Oral Presentations

Author

PB Munroe, Evangelos Evangelou, Barnes, Louise V. Wain, Raha Pazoki, J Ramirez, Ioanna Tzoulaki, MJ Caulfield, TL Edwards, HR Warren, Anil K. Giri, Jacklyn N. Hellwege, Paul Elliott, and Claudia P. Cabrera

Subjects
Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Abstracts Collection, Multi trait, Genome-Wide Association Analysis, Biology, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Published
2020

27. Urinary Sodium Excretion Enhances the Effect of Alcohol on Blood Pressure

Author

Xiyun Jiang, Mila D. Anasanti, Fotios Drenos, Alexandra I. Blakemore, and Raha Pazoki

Subjects
genetics of alcohol, urinary sodium, cardiovascular traits, nutrition, Health Information Management, Leadership and Management, Health Policy, Health Informatics
Abstract

Data Availability Statement: Not applicable. Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/healthcare10071296/s1, Table S1: UK Biobank data fields for blood pressure, physical and lifestyle variables used in the analysis, Table S2: Codes used to generate cardiovascular disease phenotypes in the analysis, Table S3: Genetic variants used to construct the genetic risk score for alcohol consumption, Table S4: Sex-specific effect of alcohol genetic risk on blood pressure and cardiovascular diseases, Table S5: Overview of association of urinary sodium with alcohol consumption and various outcomes. Copyright: © 2022 by the authors. Alcohol consumption is linked to urinary sodium excretion and both of these traits are linked to hypertension and cardiovascular diseases (CVDs). The interplay between alcohol consumption and sodium on hypertension, and cardiovascular diseases (CVDs) is not well-described. Here, we used genetically predicted alcohol consumption and explored the relationships between alcohol consumption, urinary sodium, hypertension, and CVDs. Methods: We performed a comparative analysis among 295,189 participants from the prospective cohort of the UK Biobank (baseline data collected between 2006 and 2010). We created a genetic risk score (GRS) using 105 published genetic variants in Europeans that were associated with alcohol consumption. We explored the relationships between GRS, alcohol consumption, urinary sodium, blood pressure traits, and incident CVD. We used linear and logistic regression and Cox proportional hazards (PH) models and Mendelian randomization in our analysis. Results: The median follow-up time for composite CVD and stroke were 6.1 years and 7.1 years respectively. Our analyses showed that high alcohol consumption is linked to low urinary sodium excretion. Our results showed that high alcohol GRS was associated with high blood pressure and higher risk of stroke and supported an interaction effect between alcohol GRS and urinary sodium on stage 2 hypertension (Pinteraction = 0.03) and CVD (Pinteraction = 0.03), i.e., in the presence of high urinary sodium excretion, the effect of alcohol GRS on blood pressure may be enhanced. Conclusions: Our results show that urinary sodium excretion may offset the risk posed by genetic risk of alcohol consumption. R.P. holds a fellowship supported by Rutherford Fund from Medical Research Council (MR/R0265051/1 and MR/R0265051/2). X.J. was supported by Rutherford Fund from Medical Research Council MR/R0265051/2. UKB genotyping was supported by the British Heart Foundation (grant SP/13/2/30111) for Large-scale comprehensive genotyping of UKB for cardiometabolic traits and diseases: UK CardioMetabolic Consortium.

Published
2022

28. The global effects of alcohol consumption on Gross Domestic Product in high- and low-income countries: a systematic review and meta-analysis

Author

Swettha Mahesarajah and Raha Pazoki

Abstract

Aims and objectivesThis study aims to measure the disease burden and the economic burden associated with alcohol consumption in both high- and low-income countries. To emphasise the necessity of making this issue a worldwide priority, the percentage of GDP attributable to alcohol-related costs will be stated.DesignSystematic review and meta-analysisData sourcesA systematic search concerning health and social costs was conducted primarily through PubMed and subsequent citation chaining of appropriate systematic reviews. Other electronic databases such as Google Scholar was also freely searched.Eligibility criteria for selecting studiesObservational studies examining alcohol-related harm, alcohol-related disease, and alcohol-related expenditure with all studies measuring alcohol-related harm using the alcohol-attributable fraction (AAF).Results9 cross-sectional studies were obtained assessing the consequences of alcohol on the respective country’s economy with all studies utilising a prevalence-based approach. 5 studies were eligible for a meta-analysis in the statistically programming software, R. The pooled estimate of the economic burden of alcohol in 5 countries equated to be 0.01% of GDP. Though inconsistencies in cost estimations resulted in an underestimation, our results provide evidence to suggest that alcohol negatively affects both individuals and society. The available literature on the topic of the economic impact of alcohol is inadequate; especially when investigating concerns in poorer regions of the world.ConclusionThough the current estimate of global GDP attributable to alcohol use is low, the evidence suggesting the global increase of alcohol consumption is paramount to avoid future calamities. Cooperative leadership from the World Health Organisation (WHO), International Monetary Fund, and the World Bank are requisite to control the harmful patterns of alcohol consumption seen across the globe.STRENGTHS AND LIMITATIONS OF THIS STUDYThis is the first systematic review assessing the detrimental consequences of alcohol on economic health with the inclusion of both lower-middle income and high-income countries.This study provides a pooled estimate of the global estimate of the percentage of GDP attributable to alcohol related costs using statistical package, R which has not been done before.The obtainment of research conducted in low-income countries proved to be difficult, and as a result no low-middle income countries were used when calculating the pooled estimate. Therefore, the accuracy of the provided estimate was decreased.

Published
2022

29. Estimated 24-Hour Urinary Sodium Excretion and Incident Cardiovascular Disease and Mortality Among 398 628 Individuals in UK Biobank

Author

Raha Pazoki, Abbas Dehghan, Deborah Schneider-Luftman, Paul Elliott, Evangelos Evangelou, Ioanna Tzoulaki, Bruce Neal, David C. Muller, and Cancer Research UK

Subjects
Male, medicine.medical_specialty, Urinary system, Blood Pressure, Coronary Disease, 030204 cardiovascular system & hematology, 1117 Public Health and Health Services, Excretion, 03 medical and health sciences, 0302 clinical medicine, Cause of Death, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Mortality, Sodium Chloride, Dietary, Correlation of Data, Prospective cohort study, 1102 Cardiorespiratory Medicine and Haematology, Stroke, risk, Biological Specimen Banks, business.industry, Sodium, Hazard ratio, 1103 Clinical Sciences, Middle Aged, medicine.disease, United Kingdom, cardiovascular diseases, Renal Elimination, Blood pressure, Cardiovascular System & Hematology, Heart Disease Risk Factors, Heart failure, Female, business
Abstract

We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40–69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01–1.10) and 0.96 (0.92–1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.

Published
2020

30. Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study

Author

Jana Nano, Raha Pazoki, Zayne Milena Roa-Díaz, Fotios Drenos, Pedro Marques-Vidal, Lyda Z. Rojas, Oscar H. Franco, Trudy Voortman, Eralda Asllanaj, Mohammad Arfan Ikram, Taulant Muka, Hasnat A Amin, and Epidemiology

Subjects
Age At Menopause, Blood Pressure, Hypertension, Mendelian Randomization Analysis, Menopause, Systolic Blood Pressure, medicine.medical_specialty, systolic blood pressure, hypertension, menopause, 610 Medicine & health, Genome-wide association study, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, 360 Social problems & social services, Internal medicine, Mendelian randomization, age at menopause, medicine, 030304 developmental biology, 0303 health sciences, business.industry, Confounding, blood pressure, Regression analysis, General Medicine, mendelian randomization analysis, medicine.disease, Blood pressure, Medicine, Observational study, business
Abstract

Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0, 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = −1.31, 95% CI −2.43, −0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP, the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.

Published
2021
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31. Alcohol consumption in the general population is associated with structural changes in multiple organ systems

Author

Paul M. Matthews, He Gao, Paul Elliott, Raha Pazoki, Evangelos Evangelou, Wenjia Bai, Hideaki Suzuki, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), Engineering & Physical Science Research Council (EPSRC), and UK DRI Ltd

Subjects
Male, global health, 030204 cardiovascular system & hematology, 0601 Biochemistry and Cell Biology, 0302 clinical medicine, Promotion (rank), Risk Factors, Epidemiology, Global health, Prospective Studies, Biology (General), Organ system, Aorta, media_common, education.field_of_study, Brain Diseases, General Neuroscience, imaging, General Medicine, Middle Aged, Medical research, Magnetic Resonance Imaging, Alcohol-Induced Disorders, Medicine, epidemiology, Female, Alcohol consumption, Research Article, Fatty Liver, Alcoholic, medicine.medical_specialty, Alcohol Drinking, QH301-705.5, Science, media_common.quotation_subject, alcohol consumption, brain, Population, heart, liver, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Predictive Value of Tests, None, medicine, Humans, education, Aged, General Immunology and Microbiology, business.industry, Cardiomyopathy, Alcoholic, United Kingdom, Epidemiology and Global Health, Family medicine, business, 030217 neurology & neurosurgery
Abstract

Background:Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample.Methods:We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol.Results:We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7 × 10−3 ± 0.76 × 10−3 per doubling of alcohol consumption, p=3.0 × 10−14). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption.Conclusions:Our results imply that there is not a ‘safe threshold’ below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.Funding:See acknowledgements.

Published
2021

32. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center

Subjects
Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Published
2019

33. Molecular Alterations Caused by Alcohol Consumption in the UK Biobank: A Mendelian Randomisation Study

Author

Felix O’Farrell, Xiyun Jiang, Shahad Aljifri, and Raha Pazoki

Subjects
UK Biobank, Nutrition and Dietetics, Alcohol Drinking, alcohol consumption, Mendelian randomisation, UK biobank, Phenome wide association studies, biomarker, phenome wide association studies, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, United Kingdom, Alcoholism, Humans, Biological Specimen Banks, Genome-Wide Association Study, Food Science
Abstract

Data Availability Statement: Not applicable. Acknowledgments: This study has been performed using the UK Biobank application 60549. Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu14142943/s1, Table S1: Genetic variants used in Mendelian randomisation analysis. Copyright: © 2022 by the authors. Alcohol consumption is associated with the development of cardiovascular diseases, cancer, and liver disease. The biological mechanisms are still largely unclear. Here, we aimed to use an agnostic approach to identify phenotypes mediating the effect of alcohol on various diseases. Methods: We performed an agnostic association analysis between alcohol consumption (red and white wine, beer/cider, fortified wine, and spirits) with over 7800 phenotypes from the UK biobank comprising 223,728 participants. We performed Mendelian randomisation analysis to infer causality. We additionally performed a Phenome-wide association analysis and a mediation analysis between alcohol consumption as exposure, phenotypes in a causal relationship with alcohol consumption as mediators, and various diseases as the outcome. Results: Of 45 phenotypes in association with alcohol consumption, 20 were in a causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; β = 9.44; 95% CI = 5.94, 12.93; Pfdr = 9.04 × 10−7), mean sphered cell volume (β = 0.189; 95% CI = 0.11, 0.27; Pfdr = 1.00 × 10−4), mean corpuscular volume (β = 0.271; 95% CI = 0.19, 0.35; Pfdr = 7.09 × 10−10) and mean corpuscular haemoglobin (β = 0.278; 95% CI = 0.19, 0.36; Pfdr = 1.60 × 10−6) demonstrated the strongest causal relationships. We also identified GGT and physical inactivity as mediators in the pathway between alcohol consumption, liver cirrhosis and alcohol dependence. Conclusion: Our study provides evidence of causality between alcohol consumption and 20 phenotypes and a mediation effect for physical activity on health consequences of alcohol consumption. Rutherford Fund from Medical Research Council (MR/R0265051/1 and MR/R0265051/2); Rutherford Fund from Medical Research Council MR/R0265051/2; UK Biobank genotyping was supported by the British Heart Foundation (grant SP/13/2/30111) for Large-scale comprehensive genotyping of UK biobank for cardiometabolic traits and diseases: UK CardioMetabolic Consortium.

Published
2022

34. Alcohol consumption is associated with structural changes in various organ systems: A population-based study in UK Biobank

Author

Paul Elliott, Hideaki Suzuki, Raha Pazoki, He Gao, Evangelos Evangelou, Wenjia Bai, and Paul M. Matthews

Subjects
education.field_of_study, business.industry, Population, Alcohol, Biobank, Excessive alcohol consumption, Population based study, chemistry.chemical_compound, chemistry, Environmental health, Liver fat, Medicine, business, education, Alcohol consumption, Organ system
Abstract

Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample. We assessed global effects of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta and liver of UK-Biobank participants who reported drinking alcohol. We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7×10−3±0.76×10−3 per doubling of alcohol consumption, P=3.0×10−14). Alcohol consumption also was associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption. Our results imply that there is not a “safe threshold” below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.

Published
2021

35. Genetic Predisposition to High Blood Pressure and Lifestyle Factors

Author

Evangelos Evangelou, Ioanna Tzoulaki, Mark J. Caulfield, Abbas Dehghan, Paul Elliott, He Gao, Helen R. Warren, and Raha Pazoki

Subjects
Male, Blood Pressure, 030204 cardiovascular system & hematology, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Physiology (medical), Environmental health, Genetic predisposition, Humans, Medicine, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, Life Style, Life style, business.industry, Follow up studies, Middle Aged, Blood pressure, Lifestyle factors, Genetic Loci, Hypertension, Cohort, Female, Diet, Healthy, Cardiology and Cardiovascular Medicine, business, Body mass index, Follow-Up Studies
Abstract

Background:High blood pressure (BP) is a major risk factor for cardiovascular diseases (CVDs), the leading cause of mortality worldwide. Both heritable and lifestyle risk factors contribute to elevated BP levels. We aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse BP genetic profile and its effect on CVD risk.Methods:We constructed a genetic risk score for high BP by using 314 published BP loci in 277 005 individuals without previous CVD from the UK Biobank study, a prospective cohort of individuals aged 40 to 69 years, with a median of 6.11 years of follow-up. We scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. We examined the association between tertiles of genetic risk and tertiles of lifestyle score with BP levels and incident CVD by using linear regression and Cox regression models, respectively.Results:Healthy lifestyle score was strongly associated with BP (P–320) for systolic and diastolic BP and CVD events regardless of the underlying BP genetic risk. Participants with a favorable in comparison with an unfavorable lifestyle (bottom versus top tertile lifestyle score) had 4.9, 4.3, and 4.1 mm Hg lower systolic BP in low, middle, and high genetic risk groups, respectively (Pfor interaction=0.0006). Similarly, favorable in comparison with unfavorable lifestyle showed 30%, 33%, and 31% lower risk of CVD among participants in low, middle, and high genetic risk groups, respectively (Pfor interaction=0.99).Conclusions:Our data further support population-wide efforts to lower BP in the population via lifestyle modification. The advantages and disadvantages of disclosing genetic predisposition to high BP for risk stratification needs careful evaluation.

Published
2018

36. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author

Barbara McKnight, Martina Müller-Nurasyid, Raha Pazoki, Michael W.T. Tanck, Thomas Engstrøm, Arthur A.M. Wilde, Man Li, Martin VanDenburgh, Marieke T. Blom, Reza Jabbari, Thomas Meitinger, Philippe Goyette, Anna Moes, Rebecca N. Mitchell, Christine M. Albert, Aravinda Chakravarti, Dan E. Arking, Jean-Claude Tardif, Rozenn N. Lemaitre, Foram N. Ashar, Pui-Yan Kwok, Frank D. Kolodgie, Jacob Tfelt-Hansen, Renu Virmani, Susan R. Heckbert, Angel C.Y. Mak, David S. Siscovick, Vinicius Tragante, Xavier Jouven, Hanno L. Tan, John D. Rioux, Mark Eijgelsheim, Ronald J. Prineas, Nona Sotoodehnia, Xiaoqing Zhao, Stefan A. Escher, Heikki V. Huikuri, Bruce M. Psaty, Charlotte Glinge, Albert Hofman, Oscar H. Franco, Florence Dumas, Bruno H. Stricker, M. Juhani Junttila, Folkert W. Asselbergs, Josef Coresh, Christopher J. O'Donnell, Paul W. Franks, Shih-Jen Hwang, Veikko Salomaa, Jan-Håkan Jansson, Stefan Kääb, Christopher Newton-Cheh, Joseph J. Maleszewski, Paul I.W. de Bakker, Jennifer A. Brody, Aki S. Havulinna, André G. Uitterlinden, Georg Ehret, Jerome I. Rotter, Thomas Lumley, Connie R. Bezzina, Marc K. Halushka, Sara L. Pulit, Epidemiology, Internal Medicine, Ehret, Georg Benedikt, Cardiology, Epidemiology and Data Science, APH - Methodology, ACS - Heart failure & arrhythmias, and APH - Health Behaviors & Chronic Diseases

Subjects
Male, Genome-wide association study, Coronary Artery Disease, Cardiorespiratory Medicine and Haematology, Arrhythmias, 030204 cardiovascular system & hematology, VARIANTS, Cardiovascular, Bioinformatics, Body Mass Index, Sudden cardiac death, Coronary artery disease, 0302 clinical medicine, Risk Factors, 2.1 Biological and endogenous factors, Medicine, 030212 general & internal medicine, Family history, Aetiology, Cardiac/genetics/physiopathology, reproductive and urinary physiology, POPULATION, 0303 health sciences, education.field_of_study, Coronary Artery Disease/genetics, ATHEROSCLEROSIS-RISK, DEATH, hemic and immune systems, Mendelian Randomization Analysis, Single Nucleotide, 3. Good health, Death, Heart Disease, MENDELIAN RANDOMIZATION, Medical genetics, Female, FIBRILLATION, medicine.symptom, Cardiology and Cardiovascular Medicine, Cardiac, Cardiac/etiology, medicine.medical_specialty, Clinical Sciences, Population, Single-nucleotide polymorphism, 610 Medicine & health, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Risk Assessment, Heart Conduction System/physiopathology, 03 medical and health sciences, Sex Factors, Sudden cardiac arrest, Clinical Research, Heart Conduction System, 360 Social problems & social services, RISK-FACTOR, Mendelian randomization, Genetics, Journal Article, Humans, INTERVAL, Polymorphism, Risk Assessment/methods, education, Heart Disease - Coronary Heart Disease, 030304 developmental biology, business.industry, Prevention, Human Genome, Arrhythmias, Cardiac, medicine.disease, Sudden, Genetic architecture, Good Health and Well Being, Death, Sudden, Cardiac, Cardiovascular System & Hematology, business
Abstract

BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.MethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.ResultsNo variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in highrisk populations and the general community.

Published
2018

37. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Chris Finan, Yoav Ben-Shlomo, Eric B. Larson, Tine Jess, Richard W Morris, Daniel I. Chasman, Fernando Pires Hartwig, Catherine Welch, Rodney J. Scott, Helen E. Speedy, Andrzej Pajak, Raha Pazoki, André G. Uitterlinden, Torben Hansen, Marc Sanson, Hakon Hakonarson, Claudia Langenberg, Joey Ward, John Wright, Dorothée Thuillier, Ben Kinnersley, Diederick E. Grobbee, Yvonne T. van der Schouw, Pieter Sonneveld, Michiel L. Bots, Harold Snieder, Karim Labreche, Dan M. Roden, Archie Campbell, Melissa C. Smart, Christine Power, Pim van der Harst, Amélie Bonnefond, Ingrid E. Christophersen, Riyaz S. Patel, Uwe Völker, Stephen Hancock, Niels Grarup, Dennis O. Mook-Kanamori, Mariza de Andrade, Caroline Dale, N. Charlotte Onland-Moret, David R. Crosslin, Meena Kumari, Erik Ingelsson, Michael V. Holmes, Spiros Denaxas, Sudha Seshadri, Kees Hovingh, Marcus Dörr, Paul M. Ridker, Stefan Coassin, Albert Hofman, Andrew N. Nicolaides, Oluf Pedersen, Philippe Froguel, Simonetta Guarrera, Murray H. Brilliant, Sara E. Dobbins, Salim Yusuf, Kari Hemminki, Erik P A Van Iperen, Abbas Dehghan, Jill P. Pell, Alexander Teumer, Peter W. Schofield, Aroon D. Hingorani, Dan Mason, Amand F. Schmidt, Rui Bebiano Da Providencia E Costa, James M. Allan, Leslie A. Lange, Niels Weinhold, Stefan Gustafsson, Jackie F. Price, Mika Kivimäki, Hynek Pikhart, Kirchner H. Lester, Lars Lind, Philip J. Law, Cara L. Carty, David Preiss, Richard S. Houlston, Robin Young, Tom W. Meade, Martin O'Donnell, Alexander P. Reiner, Ni Li, Oscar H. Franco, Zammy Fairhurst-Hunter, Ronan Roussel, Tim Christen, Ilja Demuth, David Carrell, Catherine A. McCarty, Juan P. Casas, Johann Willeit, Peter H. Whincup, Stela McLachlan, Adelaida Sanchez-Galvez, Hartmut Goldschmidt, Guillaume Paré, Harry Hemingway, Anubha Mahajan, Elisabeth Steinhagen-Thiessen, Elizabeth G. Holliday, Giuseppe Matullo, Henry Völzke, Ian Ford, Martin Bobak, Pedro Marques-Vidal, Bertrand Cariou, Bernardo L. Horta, Melissa L. Bondy, Goya Wanamethee, Naveed Sattar, Steve E. Humphries, Marylyn D. Ritchie, Kristina Norman, Carlotta Sacerdote, Giovanni Fiorito, Sebastian E. Baumeister, Amit Sud, Dennis Valentine, Andreas Engert, Juri Demuth, Rupert Faraway, Abdonas Tamosiunas, Andrie G. Panayiotou, Terrie Kitchner, Lars Bertram, Sandosh Padmanabhan, Sofia Malyutina, Anke H. Maitland-van der Zee, Alex J. Cornish, Joshua C. Denny, Jian'an Luan, Robert A. Scott, Daniel I. Swerdlow, John Attia, Karin Willeit, Gareth J. Morgan, Michael Chong, Ruben N. Eppinga, Elina Hyppönen, Ekaterina V. Baranova, Jackie A. Cooper, Ghazaleh Fatemifar, Niek Verweij, Max Moldovan, Brendan J. Keating, M. Abdullah Said, Markus M. Lerch, Christina M. Lill, Markus Hansson, Jemma C. Hopewell, Björn Nilsson, Folkert W. Asselbergs, Ruzena Kubinova, Molly Went, Nicholas J. Wareham, Stefan Kiechl, Yanchun Bao, Allan Linneberg, Matthias Simon, Epidemiology and Data Science, Pulmonology, Paediatric Pulmonology, APH - Personalized Medicine, AII - Inflammatory diseases, AII - Cancer immunology, CCA - Cancer biology and immunology, Ear, Nose and Throat, Schmidt, Amand F, Holmes, Michael V, Preiss, David, Swerdlow, Daniel I, Hypponen, Elina, Dehghan, Abbas, Schmidt, Amand F [0000-0003-1327-0424], Apollo - University of Cambridge Repository, Lifelines Cohort, ICBP Consortium, METASTROKE Consortium of the ISGC, PharmacoTherapy, -Epidemiology and -Economics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Schmidt, Amand F. [0000-0003-1327-0424], Epidemiology, and Hematology

Subjects
Oncology, lcsh:Diseases of the circulatory (Cardiovascular) system, Genetic association studies, Proprotein Convertase 9/genetics, Apolipoprotein B, Anticholesteremic Agents/adverse effects, Myocardial Infarction, Blood lipids, Genome-wide association study, 030204 cardiovascular system & hematology, Coronary artery disease, Gastroenterology, Medical and Health Sciences, Stroke/epidemiology, Brain Ischemia, 0302 clinical medicine, Risk Factors, Dyslipidemias/blood, Medicine, LDL-cholesterol, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Myocardial infarction, Mendelian randomisation, 1102 Cardiorespiratory Medicine and Haematology, Randomized Controlled Trials as Topic, Kardiologi, biology, Anticholesteremic Agents, PCSK9 Inhibitors, Single Nucleotide, 16. Peace & justice, LDL/blood, 3. Good health, Stroke, Cholesterol, Treatment Outcome, Cholesterol, LDL/blood, ICBP Consortium, Phenome-wide association scan, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Research Article, medicine.medical_specialty, Serine Proteinase Inhibitors, Down-Regulation, 610 Medicine & health, Single-nucleotide polymorphism, Placebo, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Internal medicine, Genetic variation, Myocardial Infarction/epidemiology, Humans, Serine Proteinase Inhibitors/adverse effects, Polymorphism, Dyslipidemias, Genetic association, Lifelines Cohort authors, METASTROKE Consortium of the ISGC, business.industry, PCSK9, Cholesterol, LDL, Odds ratio, medicine.disease, Cardiovascular System & Hematology, lcsh:RC666-701, biology.protein, Brain Ischemia/epidemiology, Clinical Medicine, business, Biomarkers, Biomarkers/blood, Genome-Wide Association Study
Abstract

BackgroundWe characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.MethodsPublished and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Fourteen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentrationResultsThe PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95%CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95%CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95%CI 0.57; 1.22) for the GS, compared to 0.85 (95%CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95%CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable.ConclusionsGenetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. Apparent discordance between genetic associations and trial outcome for T2DM might be explained lack by a of statistical precision, or differences in the nature and duration of genetic versus pharmacological perturbation of PCSK9.FundingThis research was funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456, FS/18/23/33512), UCL Hospitals NIHR Biomedical Research Centre, by the Rosetrees and Stoneygate Trusts.Condensed abstractEvidence on the long-term efficacy and safety of therapeutic inhibition of PCSK9 is lacking. To explore potential long-term effects of PCSK9 inhibition, we characterised the phenotypic consequence of LDL-cholesterol lowering variants at the PCSK9 locus. A PCSK9 gene score comprising 4 SNPs recapitulated the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and risk of myocardial infarction, and was associated with an increased risk of type 2 diabetes. No associations with safety outcomes such as cancer, COPD, Alzheimer’s disease or atrial fibrillation were identified. Our findings suggest PCSK9 inhibition may be safe and effective during prolonged use.

Published
2019

38. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Peter W. Schofield, Dan Rujescu, Gail Davies, Vidar M. Steen, Ahmad R. Hariri, Sara Hägg, Lars Nyberg, Dimitrios Avramopoulos, Nikolaos Smyrnis, Gerardo Heiss, Pamela DeRosse, Russell A. Poldrack, Jingyun Yang, Evangelos Evangelou, Katri Räikkönen, Fred W. Sabb, B. Gwen Windham, Aiden Corvin, Peter R. Schofield, Teemu Palviainen, André G. Uitterlinden, Anders Lundquist, Henry Brodaty, Aarno Palotie, Gary Donohoe, Elisabeth Widen, Teresa Lee, Cornelia M. van Duijn, Harry Campbell, Caroline Hayward, Rebecca F. Gottesman, Shuo Li, Steffi G. Riedel-Heller, M. Arfan Ikram, Sudha Seshadri, Jari Lahti, Joshua C. Bis, Panos Bitsios, Nikos C. Stefanis, Bettina Konte, Steven T. Turner, Edith Hofer, Vilmundur Gudnason, Michael Gill, P. Eline Slagboom, Ozren Polasek, Ida K. Karlsson, Christopher Oldmeadow, Michael Griswold, Ulman Lindenberger, Eric Boerwinkle, Saskia P. Hagenaars, Ingrid Melle, Alfredo Ramirez, Janie Corley, Rodney J. Scott, Sven J. van der Lee, Mika Kähönen, Alison D. Murray, Daniel R. Weinberger, Neil Pendleton, J. Wouter Jukema, Suvi P. Rovio, Wei Zhao, Muralidharan Sargurupremraj, Raha Pazoki, Matthias Schmid, Ina Giegling, Grant W. Montgomery, Daniel E. Gustavson, Jerome I. Rotter, Dan E. Arking, Oscar L. Lopez, David J. Stott, Julian N. Trollor, Chandra A. Reynolds, Tobias Luck, Andrea Christoforou, David J. Porteous, Kent D. Taylor, Simon R. Cox, Yasaman Saba, Matthew A. Scult, Astri J. Lundervold, Aicha Soumare, Antony Payton, Stella Trompet, W. David Hill, Shu-Chen Li, Robert M. Bilder, Eero Vuoksimaa, Jennifer A. Smith, Katherine E. Burdick, Deborah K. Attix, Sudheer Giddaluru, David C. Glahn, Edythe D. London, Stephanie Le Hellard, Terho Lehtimäki, Markus Leber, Katja Petrovic, James F. Wilson, Dwight Dickinson, Elizabeth T. Cirulli, Christophe Tzourio, Panos Roussos, Amelia A. Assareh, Markus Scholz, Alex Hatzimanolis, Tamara B. Harris, Stéphanie Debette, Alison Pattie, Thomas Espeseth, John M. Starr, William E R Ollier, Nicola J. Armstrong, Kjetil Sundet, Michael Wagner, Ian Ford, Simone Reppermund, Qiong Yang, Albert V. Smith, Nicole A. Kochan, Riccardo E. Marioni, Anu Loukola, Igor Rudan, Nicholas G. Martin, Jan Bressler, Tian Liu, K. Hoyan Wen, Natalie Terzikhan, Emma Knowles, Raymond Noordam, Joey W. Trampush, John Attia, Nancy L. Pedersen, Claudia L. Satizabal, Anne C. Böhmer, Chloe Fawns-Ritchie, Adele M. Taylor, Bruce M. Psaty, Paul Elliott, David R. Weir, Catharine R. Gale, Ioanna Tzoulaki, Leonie Weinhold, Anbupalam Thalamuthu, Anders M. Dale, Helena Schmidt, Annette M. Hartmann, Ole A. Andreassen, Ian J. Deary, Arno Villringer, Andrew M. McIntosh, Srdjan Djurovic, Najaf Amin, David C. Liewald, Nathan A. Gillespie, Ivar Reinvang, Thomas H. Mosley, Veronique Vitart, Michelle Luciano, Robert Karlsson, Lenore J. Launer, Eliza Congdon, Karen A. Mather, Marisa Koini, Tyrone D. Cannon, Elizabeth G. Holliday, Goran Papenberg, Reinhold Schmidt, Philippe Amouyel, Holger Wagner, Todd Lencz, Margaret J. Wright, Leo-Pekka Lyytikäinen, Emily Drabant Conley, David A. Bennett, William S. Kremen, M. Kamran Ikram, Catriona L. K. Barnes, Stella G. Giakoumaki, Scott D. Gordon, Johan G. Eriksson, Perminder S. Sachdev, Olli T. Raitakari, Judith A. Okely, Aristotle N. Voineskos, Max Lam, Sarah E. Harris, Luca Kleineidam, Jaakko Kaprio, Derek W. Morris, Sharon L.R. Kardia, Peter K. Joshi, Erin B. Ware, Lars Bertram, Philip L. De Jager, Anna C. Need, Abbas Dehghan, Jin Yu, Jessica D. Faul, N Freimer, Matthew C. Keller, John B.J. Kwok, Anil K. Malhotra, Will Longstreth, Hieab H.H. Adams, Richard J. Rose, Annette L. Fitzpatrick, Richard E. Straub, Christina M. Lill, David Ames, Patricia A. Boyle, David S. Knopman, He Gao, Narelle K. Hansell, Ornit Chiba-Falek, Danielle M. Dick, Stuart J. Ritchie, Ari Ahola-Olli, and Jeannette Simino

Subjects
0301 basic medicine, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, computer.software_genre, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Multidisciplinary, business.industry, Published Erratum, Cognition, General Chemistry, 021001 nanoscience & nanotechnology, 030104 developmental biology, Correction study, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lcsh:Q, Artificial intelligence, ddc:500, 0210 nano-technology, Psychology, business, computer, Natural language processing
Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019

39. New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Author

Jessica D. Faul, Ilja M. Nolte, Alexandra I. F. Blakemore, Raha Pazoki, Marjo-Riitta Järvelin, Andrew C. Heath, Adrian Rothenfluh, Nicholas G. Martin, Catharina A. Hartman, Paul Blakeley, Michael Boehnke, Paul M. Matthews, Dan E. Arking, Jennifer A. Smith, Yuri Milaneschi, James F. Wilson, Alena Stančáková, Laura J. Scott, Jie Yao, Paul Elliott, Sharon L.R. Kardia, Peter K. Joshi, Niki Dimou, Leo-Pekka Lyytikäinen, Tim D. Spector, Ozren Polasek, Pim van der Harst, Sylvane Desrivières, Bing Yu, Brenda W.J.H. Penninx, Katherine A. Kentistou, Michael Kühne, Mika Kähönen, Hideaki Suzuki, Ioanna Tzoulaki, Daniel Levy, Congying Chu, Johan G. Eriksson, Minna Männikkö, Markku Laakso, Anne U. Jackson, Sebastian E. Baumeister, Hans J. Grabe, Massimo Mangino, Albertine J. Oldehinkel, Evangelos Evangelou, Caroline Hayward, Niek Verweij, Penelope A. Lind, Lorenz Risch, Harold Snieder, Andrianos M. Yiorkas, Andrew R. Butts, David Conen, Toni-Kim Clarke, Harry Campbell, Fotios Koskeridis, Johanna Kuusisto, Alexis C. Wood, Karen L. Mohlke, Mia-Maria Perälä, Jerome I. Rotter, Gunter Schumann, Wei Zhao, Terho Lehtimäki, Ibrahim Karaman, Olli T. Raitakari, Rozenn N. Lemaitre, David J. Porteous, Michael R. Brown, Xiuqing Guo, Igor Rudan, Juha Auvinen, David R. Weir, Christopher P. Nelson, Traci M. Bartz, Peter S. Braund, Bruce M. Psaty, Alanna C. Morrison, Alexander Teumer, Nilesh J. Samani, Georg Homuth, Jennifer A. Brody, Joshua Elliott, John Whitfield, He Gao, Andrew M. McIntosh, Georgios Ntritsos, Samuli Tuominen, Sébastien Thériault, Chunyu Liu, Juha Veijola, Stefanie Aeschbacher, Jimmy D. Bell, Scott M. Ratliff, Jagadish Vangipurapu, Qiang Luo, Jari Lahti, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Academic Medical Center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, Imperial College Healthcare NHS Trust- BRC Funding, Health Data Research Uk, National Institute for Health Research, Medical Research Council (MRC), and UK DRI Ltd

Subjects
Male, LOCI, Social Sciences, Genome-wide association study, physiopathology [Brain], VARIANTS, genetics [Mental Disorders], Cardiovascular, Oral and gastrointestinal, genetics [Genes], Behavioral Neuroscience, Alcohol Use and Health, Substance Misuse, 0302 clinical medicine, ddc:150, PARKINSONS-DISEASE, DEPENDENCE, Epidemiology, Psychology, 2.1 Biological and endogenous factors, risk factors, genetics [Schizophrenia], genetics, genetics [Genetic Predisposition to Disease], Aetiology, 610 Medicine & health, Cancer, Genetics, RISK, 0303 health sciences, Psychology, Biological, Psychology, Experimental, Mental Disorders, Brain, Single Nucleotide, Middle Aged, Serious Mental Illness, Biobank, Magnetic Resonance Imaging, Multidisciplinary Sciences, Stroke, physiology [Genes], Alcoholism, Mental Health, Schizophrenia, Meta-analysis, genetics [Polymorphism, Single Nucleotide], Science & Technology - Other Topics, Female, Life Sciences & Biomedicine, Biotechnology, EXPRESSION, Adult, medicine.medical_specialty, Social Psychology, Alcohol Drinking, Quantitative Trait Loci, genetics [White People], Experimental and Cognitive Psychology, Neuroimaging, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Aged, European Continental Ancestry Group, Genes, Genome-Wide Association Study, GENOME-WIDE ASSOCIATION, Polymorphism, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, genetics [Quantitative Trait Loci], Human Genome, Neurosciences, CONSUMPTION, medicine.disease, Genetic architecture, Brain Disorders, Good Health and Well Being, genetics [Alcoholism], genetics [Alcohol Drinking], Neurosciences & Neurology, HIGH-DENSITY-LIPOPROTEIN, 030217 neurology & neurosurgery
Abstract

H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. I.K. was supported by the EU PhenoMeNal project (Horizon 2020, grant no. 654241) and the UK Dementia Research Institute, which is supported by the MRC, the Alzheimer’s Society and Alzheimer’s Research UK. S. Thériault was supported by the Canadian Institutes of Health Research and Université Laval (Quebec City, Canada). L.R. was supported by Forschungs- und Förder-Stiftung INOVA, Vaduz, Liechtenstein. D.C. holds a McMaster University Department of Medicine Mid-Career Research Award. M.B. is supported by NIH grant R01-DK062370. P.v.d.H. was supported by ICIN-NHI and Marie Skłodowska-Curie GF (call: H2020-MSCA-IF-2014; Project ID: 661395). C.H. was supported by a core MRC grant to the MRCHGU QTL in Health and Disease research programme. N.V. was supported by Marie Skłodowska-Curie GF (grant no. 661395) and ICIN-NHI. Q.L. is partially supported by the National Natural Sciences Foundation of China (No. 81873909), Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01) and ZJLab. P.E. acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141), the Medical Research Council (MRC) and Public Health England (PHE) Centre for Environment and Health (MR/L01341X/1) and Health Data Research (HDR) UK. P.E. is supported by a UK Dementia Research Institute (DRI) professorship, UK DRI at Imperial College London, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology; LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders; grant no. 695313), ERANID (Understanding the interplay between cultural, biological and subjective factors in drug use pathways; PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics; MR/N027558/1), the FP7 projects IMAGEMEND (grant no. 602450; IMAging GEnetics for MENtal Disorders) and MATRICS (grant no. 603016), the Innovative Medicine Initiative Project EU-AIMS (grant. no115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions; MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; and Forschungsnetz AERIAL 01EE1406A and 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2 and SFB 940/2), the Medical Research Foundation and Medical Research Council (MR/R00465X/1), the Human Brain Project (HBP SGA 2). Further support was provided by grants from ANR (project AF12-NEUR0008-01-WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1); and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence.

Published
2019

40. Additional file 2: of Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand, Holmes, Michael, Preiss, David, Swerdlow, Daniel, Denaxas, Spiros, Ghazaleh Fatemifar, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Zammy Fairhurst-Hunter, Hartwig, Fernando, Horta, Bernardo, Hypponen, Elina, Power, Christine, Moldovan, Max, Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Goya Wanamethee, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie, Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Andrie Panayiotou, N. Onland-Moret, Schouw, Yvonne, Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas, Langenberg, Claudia, Scott, Robert, Jian’An Luan, Bobak, Martin, Malyutina, Sofia, K, Andrzej PajÄ, Ruzena Kubinova, Abdonas Tamosiunas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve, Brilliant, Murray, Kitchner, Terrie, Hakon Hakonarson, Carrell, David, McCarty, Catherine, Kirchner Lester, Larson, Eric, Crosslin, David, Mariza Andrade, Roden, Dan, Denny, Joshua, Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O’Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Harst, Pim, M. Said, Eppinga, Ruben, Verweij, Niek, Snieder, Harold, Christen, Tim, D. Mook-Kanamori, Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Raha Pazoki, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, DĂśrr, Marcus, Lerch, Markus, VĂślker, Uwe, VĂślzke, Henry, Ward, Joey, Pell, Jill, Meade, Tom, Christophersen, Ingrid, Zee, Anke Maitland-Van Der, Baranova, Ekaterina, Young, Robin, Ford, Ian, Campbell, Archie, Sandosh Padmanabhan, Bots, Michiel, Grobbee, Diederick, Froguel, Philippe, DorothĂŠe Thuillier, Roussel, Ronan, AmĂŠlie Bonnefond, Cariou, Bertrand, Smart, Melissa, Yanchun Bao, Kumari, Meena, Anubha Mahajan, Hopewell, Jemma, Seshadri, Sudha, Dale, Caroline, Costa, Rui, Ridker, Paul, Chasman, Daniel, Reiner, Alex, Ritchie, Marylyn, Lange, Leslie, Cornish, Alex, Dobbins, Sara, Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, BjĂśrn Nilsson, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert, Riyaz Patel, Keating, Brendan, Sattar, Naveed, Houlston, Richard, Casas, Juan, and Aroon Hingorani

Abstract

Supplemental figures and study acknowledgments. (PDF 154 kb)

Published
2019
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41. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author

Michael R. Brown, Christian Gieger, André G. Uitterlinden, Diana van Heemst, Alison D. Murray, Stephen B. Kritchevsky, Timo A. Lakka, Karen Schwander, Federica Laguzzi, Stephen S. Rich, Rajkumar Dorajoo, Yun Ju Sung, Xiaofeng Zhu, Hugues Aschard, Jing Hua Zhao, Gregory P. Wilson, Kenneth Rice, Barbara Sternfeld, Kent D. Taylor, Paul Elliott, Ei-Ei Khaing Nang, Ilja M. Nolte, Heather M. Stringham, Bruce M. Psaty, Heming Wang, Tangchun Wu, Caroline Hayward, Vilmundur Gudnason, Fernando Pires Hartwig, Paolo Gasparini, Jingjing Liang, Neil Risch, Albertine J. Oldehinkel, Ani Manichaikul, Tibor V. Varga, Michael Y. Tsai, Niek Verweij, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Xiuqing Guo, Traci M. Bartz, Nicholette D. Palmer, Woon-Puay Koh, Rozenn N. Lemaitre, Caizheng Yu, Mike A. Nalls, Mariaelisa Graff, Eric Boerwinkle, Dabeeru C. Rao, Thomas Meitinger, Virginia Fisher, Mario Sims, Charles Kooperberg, Carl D. Langefeld, Jaakko Tuomilehto, Reedik Mägi, Wei Zhao, Wanqing Wen, Donna K. Arnett, Ervin R. Fox, Lynda M. Rose, Maris Alver, Ayse Demirkan, Solomon K. Musani, Dennis O. Mook-Kanamori, Andres Metspalu, Jerome I. Rotter, Barry I. Freedman, Jiang He, Hermina Jakupović, Steven C. Hunt, Marco Brumat, Maria Pina Concas, Rob M. van Dam, Rico Rueedi, Jonathan Marten, Chi Charles Gu, Tõnu Esko, Peter Vollenweider, Zoltán Kutalik, Olli T. Raitakari, Ya X. Wang, Yong-Bing Xiang, Pamela J. Schreiner, Antonietta Robino, Tanika N. Kelly, Igor Rudan, Mathilde Boissel, Claudia Langenberg, Yii-Der Ida Chen, Anne U. Jackson, Lawrence F. Bielak, Brenda W.J.H. Penninx, Brigitte Kühnel, Christopher P. Nelson, Konstantin Strauch, Albert V. Smith, Daniel I. Chasman, Jasmin Divers, Lisa R. Yanek, M. Arfan Ikram, Melissa A. Richard, Nilesh J. Samani, Lisa de las Fuentes, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Yongmei Liu, Peter J. van der Most, Fang-Chi Hsu, Jeffrey R. O'Connell, Alexandre C. Pereira, Raymond Noordam, Changwei Li, Jie Yao, Trudy Voortman, Zhe Wang, Thomas H. Mosley, Diane M. Becker, Charles N. Rotimi, Sami Heikkinen, Archie Campbell, John M. C. Connell, Lenore J. Launer, Hua Tang, Rainer Rauramaa, Ruth J. F. Loos, Pirjo Komulainen, Amy R. Bentley, Patrik Wennberg, Chew-Kiat Heng, Kari E. North, Salman M. Tajuddin, Renée de Mutsert, David J. Porteous, Susan Redline, Sarah E. Harris, Tamara B. Harris, Raha Pazoki, Mickaël Canouil, Robert A. Scott, Jingzhong Ding, Mary F. Feitosa, Jost B. Jonas, José Eduardo Krieger, John M. Starr, Karin Leander, Jennifer A. Smith, Paul W. Franks, Charles B. Eaton, Sharon L.R. Kardia, E. Shyong Tai, Jill M. Norris, Annette Peters, Chiamaka Vivian Nwuba, Jianjun Liu, Stella Aslibekyan, Nora Franceschini, Kurt Lohman, Myriam Fornage, Dina Vojinovic, Erin B. Ware, Xiaoyin Li, Najaf Amin, Johanna Kuusisto, M. Yldau van der Ende, Cora E. Lewis, Lynne E. Wagenknecht, Jennifer G. Robinson, Franco Giulianini, Ulf de Faire, Yechiel Friedlander, Nicholas J. Wareham, Meian He, George J. Papanicolau, Nancy L. Pedersen, Bernardo L. Horta, Karen L. Mohlke, Kelley Pettee Gabriel, Minjung Kho, Michele K. Evans, Ozren Polasek, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Ioanna Ntalla, Cornelia M. van Duijn, L. Adrienne Cupples, Yuri Milaneschi, Stephen Sidney, Alan B. Zonderman, Leo-Pekka Lyytikäinen, Mohsen Ghanbari, Harold Snieder, Donald W. Bowden, Aldi T. Kraja, Alaitz Poveda, Terho Lehtimäki, Paul S. de Vries, Dongfeng Gu, Sotoodehnia Nona, Thomas W. Winkler, Muhammad Riaz, Ian J. Deary, Fumihiko Takeuchi, Pim van der Harst, Alisa K. Manning, Michael A. Province, Andrea R. V. R. Horimoto, David R. Weir, Wei Zheng, Alanna C. Morrison, Marzyeh Amini, Jian-Min Yuan, W. James Gauderman, Paul M. Ridker, Melanie Waldenberger, Chuan Gao, Xiao-Ou Shu, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, Tamar Sofer, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, IT University of Copenhagen, Icahn School of Medicine at Mount Sinai [New York] (MSSM), National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Regensburg, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Queen Mary University of London (QMUL), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), University of Washington [Seattle], The present work was largely supported by a grant from the US National Heart, Lung,and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305)., Kilpeläinen, Tuomas O., Bentley, Amy R., Noordam, Raymond, Sung, Yun Ju, Schwander, Karen, Winkler, Thomas W., Jakupović, Hermina, Chasman, Daniel I., Manning, Alisa, Ntalla, Ioanna, Aschard, Hugue, Brown, Michael R., de las Fuentes, Lisa, Franceschini, Nora, Guo, Xiuqing, Vojinovic, Dina, Aslibekyan, Stella, Feitosa, Mary F., Kho, Minjung, Musani, Solomon K., Richard, Melissa, Wang, Heming, Wang, Zhe, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Li, Changwei, Lohman, Kurt K., Marten, Jonathan, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Evangelou, Evangelo, Gao, Chuan, Graff, Mariaelisa, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Zhao, Jing Hua, Kraja, Aldi T., Kühnel, Brigitte, Laguzzi, Federica, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Rueedi, Rico, Stringham, Heather M., Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Verweij, Niek, Ware, Erin B., Wen, Wanqing, Li, Xiaoyin, Yanek, Lisa R., Amin, Najaf, Arnett, Donna K., Boerwinkle, Eric, Brumat, Marco, Cade, Brian, Canouil, Mickaël, Chen, Yii-Der Ida, Concas, Maria Pina, Connell, John, de Mutsert, Renée, de Silva, H. Janaka, de Vries, Paul S., Demirkan, Ayşe, Ding, Jingzhong, Eaton, Charles B., Faul, Jessica D., Friedlander, Yechiel, Gabriel, Kelley P., Ghanbari, Mohsen, Giulianini, Franco, Gu, Chi Charle, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven C., Ikram, M. Arfan, Jonas, Jost B., Koh, Woon-Puay, Komulainen, Pirjo, Krieger, Jose E., Kritchevsky, Stephen B., Kutalik, Zoltán, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lemaitre, Rozenn N., Lewis, Cora E., Liang, Jingjing, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Navis, Gerjan, Rots, Marianne, Swertz, Morri, Wolffenbuttel, Bruce H. R., Wijmenga, Cisca, Liu, Jianjun, Mägi, Reedik, Manichaikul, Ani, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Mohlke, Karen L., Mosley, Thomas H., Murray, Alison D., Nalls, Mike A., Nang, Ei-Ei Khaing, Nelson, Christopher P., Nona, Sotoodehnia, Norris, Jill M., Nwuba, Chiamaka Vivian, O’Connell, Jeff, Palmer, Nicholette D., Papanicolau, George J., Pazoki, Raha, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Poveda, Alaitz, Raitakari, Olli T., Rich, Stephen S., Risch, Neil, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Schreiner, Pamela J., Scott, Robert A., Sidney, Stephen S., Sims, Mario, Smith, Jennifer A., Snieder, Harold, Sofer, Tamar, Starr, John M., Sternfeld, Barbara, Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Tsai, Michael Y., Tuomilehto, Jaakko, Uitterlinden, André G., van der Ende, M. Yldau, van Heemst, Diana, Voortman, Trudy, Waldenberger, Melanie, Wennberg, Patrik, Wilson, Gregory, Xiang, Yong-Bing, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., de Faire, Ulf, Deary, Ian J., Elliott, Paul, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Kato, Norihiro, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Samani, Nilesh J., Shu, Xiao-Ou, van der Harst, Pim, Van Vliet-Ostaptchouk, Jana V., Vollenweider, Peter, Wagenknecht, Lynne E., Wang, Ya X., Wareham, Nicholas J., Weir, David R., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Evans, Michele K., Franks, Paul W., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Liu, Yongmei, North, Kari E., Pereira, Alexandre C., Ridker, Paul M., Tai, E. Shyong, van Dam, Rob M., Fox, Ervin R., Kardia, Sharon L. R., Liu, Ching-Ti, Mook-Kanamori, Dennis O., Province, Michael A., Redline, Susan, van Duijn, Cornelia M., Rotter, Jerome I., Kooperberg, Charles B., Gauderman, W. Jame, Psaty, Bruce M., Rice, Kenneth, Munroe, Patricia B., Fornage, Myriam, Cupples, L. Adrienne, Rotimi, Charles N., Morrison, Alanna C., Rao, Dabeeru C., Loos, Ruth J. F., Bentley, Amy R [0000-0002-0827-9101], Jakupović, Hermina [0000-0001-9667-9406], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0003-0907-2548], de Las Fuentes, Lisa [0000-0002-4689-325X], Richard, Melissa [0000-0003-0129-9860], Liu, Ching-Ti [0000-0002-0703-0742], Rice, Kenneth [0000-0002-3071-7278], Munroe, Patricia B [0000-0002-4176-2947], Loos, Ruth JF [0000-0002-8532-5087], Apollo - University of Cambridge Repository, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, IT University of Copenhagen (ITU), Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Value, Affordability and Sustainability (VALUE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Navis, G., Rots, M., Swertz, M., Wolffenbuttel, BHR, and Wijmenga, C.

Subjects
Genetics and Molecular Biology (all), Male, Genome-wide association study, 02 engineering and technology, Biochemistry, MESH: Genotype, MESH: Nerve Tissue Proteins, lcsh:Science, MESH: Lipid Metabolism, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Asian Continental Ancestry Group, Kólesteról, Hispanic or Latino, MESH: Transcription Factors, MESH: European Continental Ancestry Group, Lipids, ddc, 3. Good health, REVEAL, Cholesterol, MESH: Young Adult, Science & Technology - Other Topics, MESH: Membrane Proteins, MESH: Cholesterol, HDL, Hispanic Americans, 0210 nano-technology, Erfðarannsóknir, MESH: Cholesterol, LDL, MESH: Triglycerides, Genotype, Genetic Loci, Lipid Metabolism, Science, European Continental Ancestry Group, LIM-Homeodomain Proteins, Locus (genetics), EXERCISE, Adolescent, Adult, African Continental Ancestry Group/genetics, Aged, Asian Continental Ancestry Group/genetics, Brazil, Calcium-Binding Proteins/genetics, Cholesterol/blood, Cholesterol, HDL/blood, Cholesterol, HDL/genetics, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, European Continental Ancestry Group/genetics, Exercise, Female, Genetic Loci/genetics, Genome-Wide Association Study, Hispanic Americans/genetics, Humans, LIM-Homeodomain Proteins/genetics, Lipid Metabolism/genetics, Lipids/blood, Lipids/genetics, Membrane Proteins/genetics, Microtubule-Associated Proteins/genetics, Middle Aged, Muscle Proteins/genetics, Nerve Tissue Proteins/genetics, Transcription Factors/genetics, Triglycerides/blood, Triglycerides/genetics, Young Adult, General Biochemistry, Genetics and Molecular Biology, Article, White People, CARBOXYLASE, 03 medical and health sciences, Physics and Astronomy (all), MESH: Muscle Proteins, Asian People, Lifelines Cohort Study, SNP, METAANALYSIS, Ancestry, MESH: Adolescent, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Science & Technology, Calcium-Binding Proteins, MESH: Adult, MESH: Microtubule-Associated Proteins, 030104 developmental biology, chemistry, MESH: Genome-Wide Association Study, lcsh:Q, MESH: African Continental Ancestry Group, Chemistry (all), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Brazil, MESH: Female, Transcription Factors, 0301 basic medicine, General Physics and Astronomy, Blood lipids, Muscle Proteins, MESH: Calcium-Binding Proteins, chemistry.chemical_compound, MESH: Aged, 80 and over, MESH: Cholesterol, WIDE ASSOCIATION, African Continental Ancestry Group, Genetics, MESH: Aged, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, 021001 nanoscience & nanotechnology, Multidisciplinary Sciences, lipids (amino acids, peptides, and proteins), Medical Genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Microtubule-Associated Proteins, Asian Continental Ancestry Group, Black People, Nerve Tissue Proteins, Biology, MESH: Genetic Loci, MD Multidisciplinary, Triglycerides, Medicinsk genetik, MESH: LIM-Homeodomain Proteins, Triglyceride, MESH: Hispanic Americans, Cholesterol, HDL, Genome-wide analyses, Membrane Proteins, Lipid metabolism, General Chemistry, Cholesterol, LDL, Arfgengi, MESH: Lipids, MESH: Male, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Exercise, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

Publisher's version (útgefin grein), Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels., The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.

Published
2018

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

Author

Mary Cushman, John M. Starr, Min-Lee Yang, Wei Zhou, Ursula M. Schick, Vinna Clavo, Bella Hu, Oluf Pedersen, Tarunveer S. Ahluwalia, John D. Eicher, Santhi K. Ganesh, Albert V. Smith, Abbas Dehghan, Rebecca D. Jackson, Ian J. Deary, Mika Kähönen, Megan L. Grove, Jennifer A. Brody, Judy Wang, Amanda M Rosa Di Sant, Lenore J. Launer, Stephen S. Rich, Jiansong Wang, David C. Liewald, Paul I.W. de Bakker, Jerome I. Rotter, Leo-Pekka Lyytikäinen, Ruth J. F. Loos, Leonard I. Zon, Bruce M. Psaty, Nora Franceschini, Erwin P. Bottinger, Ming-Huei Chen, Paul L. Auer, James G. Wilson, Raha Pazoki, Nathan Pankratz, Russell P. Tracy, Vilmundur Gudnason, André G. Uitterlinden, Mike A. Nalls, Kristina L. Hunker, Frank J. A. van Rooij, Eric Boerwinkle, Kent D. Taylor, Albert Hofman, Yan Zhang, Mattijs E. Numans, Yong Huo, Yi Zhou, Folkert W. Asselbergs, James S. Floyd, Richard L. Proia, Yingchang Lu, Terho Lehtimäki, Liguang Dong, Riccardo E. Marioni, Jette Bork-Jensen, Jia Jia, Tamara B. Harris, Vy M. Nguyen, Fernando Rivadeneira, Oscar H. Franco, Yongmei Liu, Niels Grarup, Andrew D. Johnson, L. Adrienne Cupples, Ani Manichaikul, Elliott J. Hagedorn, Xiaoling Zhang, Maarten Leusink, Torben Hansen, Ingrid B. Borecki, Maria L. Allende, Betina Heinsbek Thuesen, Allan Linneberg, Olli T. Raitakari, Christopher J. O'Donnell, Mary F. Feitosa, Melissa E. Garcia, Alexander P. Reiner, Epidemiology, and Internal Medicine

Subjects
Male, 0301 basic medicine, Erythrocytes, Quantitative Trait Loci, Population, Genome-wide association study, Quantitative trait locus, Hematocrit, Biology, Article, Mice, 03 medical and health sciences, White blood cell, Genotype, Ethnicity, Journal Article, Genetics, medicine, Animals, Humans, Exome, education, Zebrafish, Medicine(all), education.field_of_study, medicine.diagnostic_test, ta1184, ta3121, 3. Good health, Receptors, Lysosphingolipid, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Immunology, Erythrocyte Count, Absolute neutrophil count, Female, Genome-Wide Association Study
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

43. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Author

Anne-Claire Vergnaud, Nauder Faraday, Tim Kacprowski, Lisa R. Yanek, Oscar H. Franco, Yongmei Liu, Andreas Greinacher, Gina M. Peloso, Cristen J. Willer, Leslie A. Lange, Eric S. Torstenson, Reedik Mägi, Jeanette Erdmann, Ethan M. Lange, Deborah A. Nickerson, Henry Völzke, David R. Crosslin, Gunnar Engström, Albert V. Smith, André G. Uitterlinden, Salman M. Tajuddin, W. David Hill, Diane M. Becker, Paul Elliot, Caterina Vacchi-Suzzi, Linda M. Polfus, Traci M. Bartz, Nathalie Chami, Abbas Dehghan, Mike A. Nalls, John D. Eicher, Leo-Pekka Lyytikäinen, Evelin Mihailov, Uwe Völker, Caroline Hayward, Ioanna Tzoulaki, Myriam Fornage, Marju Orho-Melander, Mary Cushman, Lars Wallentin, Terho Lehtimäki, Ayush Giri, Laura M. Raffield, Lewis C. Becker, Yingchang Lu, Emma Raitoharju, Sekar Kathiresan, Simon de Denus, Ruth J. F. Loos, James S. Floyd, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Lenore J. Launer, Andrew D. Johnson, Andrew J. Slater, Jean-Claude Tardif, Raha Pazoki, Evangelos Evangelou, Kenneth Rice, Harvey D. White, Marie-Pierre Dubé, Frank J. A. van Rooij, Akihiro Nomura, Tamara B. Harris, Vilmundur Gudnason, Gonçalo R. Abecasis, Alan B. Zonderman, Guillaume Lettre, Todd L. Edwards, Amber A. Burt, Ani Manichaikul, Heribert Schunkert, Ming-Huei Chen, Ian J. Deary, Michelle L. O'Donoghue, Jennifer A. Brody, Russell P. Tracy, Tõnu Esko, Mika Kähönen, Panos Deloukas, Eric Boerwinkle, Rasika A. Mathias, Dajiang J. Liu, Jin Li, Santhi K. Ganesh, David C. Liewald, Paul L. Auer, Digna R. Velez Edwards, Erwin P. Bottinger, Nina Mononen, Claudia Schurmann, Michele K. Evans, John M. Starr, Thomas Thiele, Jussi Hernesniemi, Jerome I. Rotter, Rakale C. Quarells, He Gao, Kjell Nikus, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Ursula M. Schick, Andres Metspalu, Melissa A. Richard, Neil A. Zakai, Olle Melander, John D. Rioux, Olli T. Raitakari, Alexander P. Reiner, Joel N. Hirschhorn, Nilesh J. Samani, Epidemiology, Internal Medicine, Home Office, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Blood Platelets, Male, CARDIoGRAM Exome Consortium, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Myocardial Infarction Genetics Consortium, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Platelet, Exome, Genetics(clinical), Mean platelet volume, Allele frequency, Genotyping, Genetics (clinical), Genetics & Heredity, Platelet Count, ta1184, Genetic Variation, Global Lipids Genetics Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, FCER1A, Genetic architecture, 030104 developmental biology, Hemostasis, Immunology, Female, Mean Platelet Volume, Genome-Wide Association Study
Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Published
2016

44. Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis

Author

Raha Pazoki, Nora Franceschini, James S. Floyd, Guillaume Lettre, Fernando Rivadeneira, Abbas Dehghan, Leo-Pekka Lyytikäinen, Albert Hofman, Ming-Huei Chen, Eric Boerwinkle, Jill M. Johnsen, Mart Kals, Xiaoling Zhang, Lewis C. Becker, Jennifer A. Brody, Dennis O. Mook-Kanamori, Lu Chen, James G. Wilson, Rajiv K. Khajuria, Vijay G. Sankaran, Nathan Pankratz, Lisa R. Yanek, Leslie A. Lange, Mika Kähönen, Linda M. Polfus, Traci M. Bartz, Nena Matijevic, Oscar H. Franco, Donna M. Muzny, Keolu Fox, Richard A. Gibbs, Narayanan Veeraraghavan, Tõnu Esko, Aoi Wakabayashi, Gina M. Peloso, André G. Uitterlinden, Paul L. Auer, Frank J. A. van Rooij, Kenneth Rice, Santhi K. Ganesh, Terho Lehtimäki, Klaudia Walter, Ruifang Li-Gao, Ginger A. Metcalf, Jie Huang, Stephen S. Rich, Cornelia M. van Duijn, Nicole Soranzo, Bruce M. Psaty, Robert B. Wallace, Ursula M. Schick, Andres Metspalu, Olli T. Raitakari, Christopher J. O'Donnell, Alexander P. Reiner, Andrew D. Johnson, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Blood Platelets, Megakaryocyte differentiation, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Biology, Blood cell, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Report, medicine, Genetics, CRISPR, Humans, splice, Exome, Genetics(clinical), Progenitor cell, Genetics (clinical), Exome sequencing, Gene Editing, Platelet Count, Alternative splicing, Correction, ta3121, Hematopoietic Stem Cells, Human genetics, 3. Good health, Hematopoiesis, Repressor Proteins, Haematopoiesis, Alternative Splicing, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, CRISPR-Cas Systems, Megakaryocytes
Abstract

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis.

Published
2016

45. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Author

Yingchang Lu, Lisa R. Yanek, Evangelos Evangelou, Andreas Greinacher, Leslie A. Lange, Albert Hofman, Rakale C. Quarells, Christopher J. O'Donnell, Simon de Denus, Marcus Dörr, Tamara B. Harris, Mary Cushman, Lars Wallentin, Digna R. Velez Edwards, Michelle L. O'Donoghue, Deborah A. Nickerson, Lisa Bastarache, Caterina Vacchi-Suzzi, Harvey D. White, Rasika A. Mathias, Jin Li, Santhi K. Ganesh, Leo-Pekka Lyytikäinen, Kjell Nikus, Ayush Giri, Paul Elliott, John M. Starr, Ruth J. F. Loos, Vilmundur Gudnason, Ioanna Tzoulaki, Myriam Fornage, Joshua C. Denny, Alan B. Zonderman, Caroline Hayward, Lewis C. Becker, Raha Pazoki, Guillaume Lettre, Lenore J. Launer, Ursula M. Schick, Michele K. Evans, Andrew J. Slater, Diane M. Becker, Jean-Claude Tardif, Ethan M. Lange, John D. Eicher, He Gao, James S. Floyd, Eric Boerwinkle, Paul L. Auer, Nathalie Chami, Frank J. A. van Rooij, Claudia Schurmann, Nele Friedrich, Kent D. Taylor, Andres Metspalu, Todd L. Edwards, Anne-Claire Vergnaud, Yongmei Liu, W. David Hill, Nauder Faraday, Terho Lehtimäki, Amber A. Burt, Jerome I. Rotter, Albert V. Smith, Tõnu Esko, Traci M. Bartz, Tim Kacprowski, Mike A. Nalls, Alexander P. Reiner, Ani Manichaikul, Ian J. Deary, Eric S. Torstenson, Laura M. Raffield, David C. Liewald, Ming-Huei Chen, Erwin P. Bottinger, Reedik Mägi, Andrew D. Johnson, Melissa A. Richard, Neil A. Zakai, John D. Rioux, Mika Kähönen, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Joel N. Hirschhorn, Salman M. Tajuddin, Linda M. Polfus, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Abbas Dehghan, Evelin Mihailov, David R. Crosslin, André G. Uitterlinden, Georg Homuth, Jennifer A. Brody, Gastroenterology & Hepatology, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Quality Control, Myeloid, 1.1 Normal biological development and functioning, Genome-wide association study, Biology, Autoimmune Disease, Medical and Health Sciences, Article, 03 medical and health sciences, Underpinning research, White blood cell, medicine, Leukocytes, Genetics, Humans, 2.1 Biological and endogenous factors, Genetics(clinical), Exome, Aetiology, Genetics (clinical), Genetic association, Genetics & Heredity, Medical And Health Sciences, Neutrophil clearance, Hematopoietic stem cell differentiation, Inflammatory and immune system, Human Genome, Genetic Pleiotropy, Hematology, Biological Sciences, Acquired immune system, Stem Cell Research, 3. Good health, Blood Cell Count, 030104 developmental biology, medicine.anatomical_structure, Immune System Diseases, Genetic Loci, Immunology, Stem Cell Research - Nonembryonic - Non-Human, Genome-Wide Association Study
Abstract

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Published
2016

46. Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Author

Marcus E. Kleber, Lu Chen, Farmaki A-E., Tom R. Gaunt, C.M. van Duijn, Gianluigi Zaza, Charles Kooperberg, Abbas Dehghan, Oscar H. Franco, Jian'an Luan, Matthew T. Maurano, Mattia Frontini, Nicole Soranzo, Giovanni Malerba, George Dedoussis, Tao Jiang, Heather Elding, Michela Traglia, Raha Pazoki, Robert A. Scott, Maria Sabater-Lleal, Mattias Frånberg, J L Min, Daniela Toniolo, Valentina Iotchkova, Paul L. Auer, Adam S. Butterworth, E. C. M. van Leeuwen, Daniel Mead, Christopher S. Franklin, Anders Hamsten, Yasin Memari, André G. Uitterlinden, William J. Astle, Lorraine Southam, Claudia Langenberg, Jie Huang, Massimiliano Cocca, Fernando Rivadeneira, Alexander P. Reiner, Patrick Deelen, John A. Morris, Giovanni Gambaro, Ioanna Ntalla, Aaron Isaacs, Genevieve Lachance, Winfried März, N J Timpson, Perry Jrb., Kalliope Panoutsopoulou, Najaf Amin, Hugh Watkins, Albert Hofman, John C. Chambers, Lude Franke, Eleftheria Zeggini, Weihua Zhang, Shin S-Y., Caterina Barbieri, Deepti Jain, Bengt Sennblad, Angela Matchan, Jaspal S. Kooner, Klaudia Walter, Morris A. Swertz, Paolo Gasparini, and F van Dijk

Subjects
Cardiometabolic risk, Genetics & Heredity, Science & Technology, Published Erratum, MEDLINE, Computational biology, Biology, 06 Biological Sciences, Genetics, UK10K Consortium, Life Sciences & Biomedicine, Imputation (genetics), 11 Medical and Health Sciences, Developmental Biology
Abstract

Correction to: Nature Genetics https://doi.org/10.1038/ng.3668, published online 26 September 2016. In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.

Published
2018

47. Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Author

Raha Pazoki, Michael R. Brown, Albertine J. Oldehinkel, Evangelos Evangelou, Bruce M. Psaty, Caroline Hayward, Penelope A. Lind, Harry Campbell, Sylvane Desrivières, Leo-Pekka Lyytikäinen, Harold Snieder, Niek Verweij, Igor Rudan, Rozenn N. Lemaitre, Andrianos M. Yiorkas, David Conen, Ozren Polasek, Mia-Maria Perälä, Jennifer A. Smith, Christopher P. Nelson, Wei Zhao, Ilja M. Nolte, Michael Kühne, Mika Kähönen, Jessica D. Faul, Sharon L.R. Kardia, Peter K. Joshi, Ibrahim Karaman, Paul M. Matthews, Adrian Rothenfluh, Jari Lahti, Alexandra I. F. Blakemore, John Whitfield, Alexander Teumer, James F. Wilson, Alena Stančáková, Marjo-Riitta Järvelin, David R. Weir, Peter S. Braund, Andrew M. McIntosh, Scott M. Ratliff, Nicholas G. Martin, Hideaki Suzuki, Georgios Ntritsos, Niki Dimou, Bing Yu, Andrew R. Butts, Alanna C. Morrison, Gunter Schumann, Michael Boehnke, Paul Elliott, Samuli Tuominen, Paul Blakeley, Xiuqing Guo, Massimo Mangino, Yuri Milaneschi, Brenda W.J.H. Penninx, Daniel Levy, Juha Auvinen, Jie Yao, Hans J. Grabe, David J. Porteous, Laura J. Scott, Lorenz Risch, Katherine A. Kentistou, Jagadish Vangipurapu, Stefanie Aeschbacher, Terho Lehtimäki, Markku Laakso, Jimmy D. Bell, Fotios Koskeridis, Anne U. Jackson, Karen L. Mohlke, Catharina A. Hartman, Ioanna Tzoulaki, Sebastian E. Baumeister, Dan E. Arking, Alexis C. Wood, Sébastien Thériault, Johanna Kuusisto, Pim van der Harst, Chunyu Liu, Juha Veijola, Georg Homuth, Jennifer A. Brody, Traci M. Bartz, Andrew C. Heath, He Gao, Toni-Kim Clarke, Jerome I. Rotter, Tim D. Spector, Congying Chu, Johan G. Eriksson, Minna Männikkö, Olli T. Raitakari, Nilesh J. Samani, and Joshua Elliott

Subjects
Genetics, 0303 health sciences, Genome-wide association study, Biology, medicine.disease, Excessive alcohol consumption, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Trait, medicine, Functional significance, Functional studies, Alcohol consumption, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.

Published
2018
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48. Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort

Author

Raha Pazoki, Marc Chadeau Hyam, Oliver Robinson, Paolo Vineis, Matthew M. Lewis, Giovanni Fiorito, Ioanna Tzoulaki, Paul Elliott, Ibrahim Karaman, He Gao, Marjo-Riitta Järvelin, Andy Heard, Rui Pinto, Silvia Polidoro, and Matthias Wielscher

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Psychological risk factors, Primary care, Chronological age, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Metabolomics, Ageing, Internal medicine, Cohort, DNA methylation, medicine, Epigenetics, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Markers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p

Published
2018
Full Text
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49. Methods for Polygenic Traits

Author

Raha, Pazoki

Subjects
Multifactorial Inheritance, Quantitative Trait, Heritable, Quantitative Trait Loci, Genetic Variation, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Genome-Wide Association Study, Randomized Controlled Trials as Topic
Abstract

An important aspect of public health is disease prediction and health promotion through better targeting of preventive strategies. Well-targeted preventive strategies will eventually decrease burden of diseases and thus precise prediction plays a crucial role in public health. Many investigators put efforts into finding models that improve prediction using known risk factors of diseases. Recently with the overwhelming load of genetic loci discovered for complex diseases through genome-wide association studies (GWAS), much of attention has been focused on the role of these genetic loci to improve prediction models. Genetic loci in solo explain little variance of diseases. It is thus necessary to create new genetic parameters that combine the effect of as many genetic loci as possible. Such new parameters aim to better distinguish individuals who will develop a disease from those who will not. In this chapter, various polygenic methods that use multiple genetic loci to directly or indirectly improve precision of genetic prediction are discussed.

Published
2018

50. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)

Published
2018

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