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1. Associations of autozygosity with a broad range of human phenotypes

Author

David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson

Subjects
Science
Abstract

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Published
2019
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2. Distinction between the effects of parental and fetal genomes on fetal growth

Author

Daniel F. Gudbjartsson, Vinicius Tragante, Kari Stefansson, Hilma Holm, Gudmar Thorleifsson, Emil L. Sigurdsson, Gudmundur Thorgeirsson, Rafn Benediktsson, Rosa B. Thorolfsdottir, Erna V. Ivarsdottir, Thora Steingrimsdottir, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Kristjan E. Hjorleifsson, David O. Arnar, Gardar Sveinbjornsson, Michael L. Frigge, Valgerdur Steinthorsdottir, Lilja Stefansdottir, Thorhildur Juliusdottir, Jon K. Sigurdsson, and Anna Helgadottir

Subjects
Adult, Blood Glucose, Male, Offspring, Birth weight, Iceland, Blood Pressure, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome, Fetal Development, Genetics, Birth Weight, Humans, Allele, Genetic association, Fetus, Models, Genetic, Haplotype, Infant, Newborn, Body Height, Haplotypes, Cardiovascular Diseases, Female, Genome-Wide Association Study
Abstract

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome. Genome-wide association analyses using parental and offspring genotypes provide insights into fetal and maternal genetic effects on fetal growth. The results show that maternal and fetal genomes influence birth weight through distinct mechanisms.

Published
2021

3. Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

Author

Bjorn R. Ludviksson, Daniel F. Gudbjartsson, Vinicius Tragante, Pall T. Onundarson, Arnaldur Gylfason, Thorarinn Gislason, Olafur A. Stefansson, Olof Sigurdardottir, Stefania Benonisdottir, Gudmundur L. Norddahl, Arna B Agustsdottir, Fannar Theodors, Bjarni V. Halldorsson, Patrick Sulem, Lilja Stefansdottir, Gardar Sveinbjornsson, Erna V. Ivarsdottir, Thorunn A. Olafsdottir, Unnur Thorsteinsdottir, Gisli Masson, Gudmar Thorleifsson, Gudmundur I. Eyjolfsson, Steinunn Guðmundsdóttir, Thorhildur Juliusdottir, David Gislason, Ingileif Jonsdottir, Jon K. Sigurdsson, Kristjan Norland, Kristbjorg Bjarnadottir, Kari Stefansson, Unnur S. Bjornsdottir, Gisli H. Halldorsson, Anna M. Kristinsdottir, Dora Ludviksdottir, Isleifur Olafsson, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræðideild (HR), Department of Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Tæknisvið (HR), School of Technology (RU), Háskóli Íslands, University of Iceland, Háskólinn í Reykjavík, and Reykjavik University

Subjects
0301 basic medicine, T-Lymphocytes, Iceland, Receptor, Transforming Growth Factor-beta Type I, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Genome-wide association studies, Pathogenesis, Leukocyte Count, Missense mutation, lcsh:Science, 3' Untranslated Regions, Multidisciplinary, Gen, 021001 nanoscience & nanotechnology, Phenotype, Astmi, 3. Good health, medicine.anatomical_structure, Airway Remodeling, 0210 nano-technology, Erfðarannsóknir, T cell, Science, Quantitative Trait Loci, T cells, Ki-1 Antigen, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immunogenetics, medicine, Humans, Genetic Predisposition to Disease, Loss function, Asthma, business.industry, General Chemistry, medicine.disease, United Kingdom, respiratory tract diseases, Eosinophils, MicroRNAs, Meta-analysis, Genarannsóknir, 030104 developmental biology, Expression quantitative trait loci, Immunology, lcsh:Q, Gene expression, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3‘ UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis., We thank the individuals who participated in this study and the staff at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities. Further to all our colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK biobank Resource under Application Number ‘24711’.

Published
2020

4. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Author

Christian Erikstrup, Jon K. Sigurdsson, Dragana Vuckovic, Isleifur Olafsson, Daniel F. Gudbjartsson, Vinicius Tragante, Steven Bell, Stephen Kaptoge, Andreas S. Rigas, Snaedis Kristmundsdottir, Khoa Manh Dinh, Hreinn Stefansson, Helene M. Paarup, Anna Ramond, Kristinn Juliusson, Hannes P. Eggertsson, Pall T. Onundarson, Erik Sørensen, Gudmundur Runarsson, Parsa Akbari, Tao Jiang, Søren Brunak, David J. Roberts, Willem H. Ouwehand, Asmundur Oddsson, Gisli H. Halldorsson, Adam S. Butterworth, James E Peters, Brynjar Vidarsson, Hilma Holm, Magnus I Magnusson, Kari Stefansson, Joanna M. M. Howson, Lise Wegner Thørner, Angela M. Wood, Karina Banasik, Sigrun H. Lund, Henrik Hjalgrim, Olof Sigurdardottir, David Westergaard, Emanuele Di Angelantonio, Unnur Thorsteinsdottir, Henrik Ullum, John Danesh, Gudmar Thorleifsson, Egil Ferkingstad, Michael L. Frigge, Patrick Sulem, Ingileif Jonsdottir, Thomas Hansen, Ole Birger Pedersen, Magnus K. Magnusson, David B. Rye, Dirk S. Paul, Gyda Bjornsdottir, Praveen Surendran, Elias Allara, William J. Astle, Kaspar René Nielsen, Nicole Soranzo, Kristoffer Sølvsten Burgdorf, and United Kingdom Research and Innovation

Subjects
Life Sciences & Biomedicine - Other Topics, 0301 basic medicine, Denmark, Iceland, Medicine (miscellaneous), Transferrin/metabolism, Genome-wide association study, Anemia, Iron-Deficiency/blood, 0302 clinical medicine, Total iron-binding capacity, Risk Factors, Genetics research, Homeostasis, Biology (General), Genetics, education.field_of_study, medicine.diagnostic_test, biology, Anemia, Iron-Deficiency, Transferrin, Iron deficiency, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, TMPRSS6, Iron Overload, Genotype, QH301-705.5, Iron, Population, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Humans, education, Iron/blood, Biology, Science & Technology, Transferrin saturation, Ferritins/blood, DBDS Genomic Consortium, Genetic Variation, medicine.disease, United Kingdom, Ferritin, Iron Overload/blood, 030104 developmental biology, Iron-deficiency anemia, Genetic Loci, Ferritins, biology.protein, Biomarkers/blood, Biomarkers, Genome-Wide Association Study
Abstract

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation., Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women.

Published
2021

5. Genetic insight into sick sinus syndrome

Author

Jon K. Sigurdsson, Gudmundur Thorgeirsson, Ingileif Jonsdottir, Søren Brunak, Mette Nyegaard, Bjarni Torfason, Henrik Ullum, Hildur M Aegisdottir, Gudmundur L. Norddahl, Stefan Jonsson, Hilma Holm, Lilja Stefansdottir, Christian Torp-Pedersen, Ben Michael Brumpton, Asmundur Oddsson, Daniel F. Gudbjartsson, Vinicius Tragante, Kristoffer Sølvsten Burgdorf, Kari Stefansson, Erna V. Ivarsdottir, Stefania Benonisdottir, Kristjan E. Hjorleifsson, Cristen J. Willer, Kristian Hveem, David O. Arnar, Gardar Sveinbjornsson, Sridharan Rajamani, Rosa B. Thorolfsdottir, Karina Banasik, Ole Birger Pedersen, Solveig Gretarsdottir, Atli S Valgardsson, David Westergaard, Erik Sørensen, Gudmar Thorleifsson, Peter Weeke, Unnur Thorsteinsdottir, Olafur B. Davidsson, Gisli H. Halldorsson, Michael L. Frigge, Anna Helgadottir, Wei Zhou, Patrick Sulem, Henning Bundgaard, and Kaspar René Nielsen

Subjects
Pacemaker, Artificial, KERATIN-8 MUTATIONS, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Electrocardiography, Sick Sinus Syndrome/genetics, 0302 clinical medicine, Atrial Fibrillation, SEQUENCE VARIANTS, Missense mutation, GWAS, AcademicSubjects/MED00200, Precision Medicine, Sick Sinus Syndrome, MYOSIN HEAVY-CHAIN, 0303 health sciences, Mendelian Randomization Analysis, RARE VARIANTS, Atrial Fibrillation/genetics, NODE DYSFUNCTION, Cardiology and Cardiovascular Medicine, Sick sinus syndrome, GANGLIONATED PLEXUS ABLATION, NAV1.8 Voltage-Gated Sodium Channel, 03 medical and health sciences, Clinical Research, Mendelian randomization, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, PULMONARY VEIN ISOLATION, Triglycerides, 030304 developmental biology, INTERMEDIATE-FILAMENTS, KRT8, business.industry, Keratin-8, Odds ratio, medicine.disease, Atrial fibrillation, Human genetics, SSS, Diabetes Mellitus, Type 2, ATRIAL-FIBRILLATION, business, Genome-Wide Association Study
Abstract

Aims The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10−20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS., Graphical Abstract Summary of genetic insight into the pathogenesis of SSS and the role of risk factors in its development. Variants at six loci (named by corresponding gene names) were identified through GWAS and their unique phenotypic associations provide insight into distinct pathways underlying SSS. Investigation of the role of risk factors in SSS development supported a causal role for AF and heart rate and provided convincing evidence against causality for BMI, cholesterol (HDL and non-HDL), triglycerides and T2D. Mendelian randomization did not support causality for CAD, ischaemic stroke, heart failure, PR interval or QRS duration (not shown in figure). Red and blue arrows represent positive and negative associations, respectively.

Published
2021

6. Genetic variants associated with platelet count are predictive of human disease and physiological markers

Author

Lilja Stefansdottir, Arni Jon Geirsson, Sigurdur Y. Kristinsson, Daniel F. Gudbjartsson, Vinicius Tragante, Brynjar Vidarsson, Gunnar B Ragnarsson, Anna Helgadottir, Solvi Rognvaldsson, Gudmundur Geirsson, Magnus K. Magnusson, Pall T. Onundarson, Gudmundur Thorgeirsson, Sigrun Reykdal, Kari Stefansson, Thorunn Rafnar, Isleifur Olafsson, Julius Gudmundsson, Evgenia Mikaelsdottir, Gerdur Grondal, Ingileif Jonsdottir, Hilma Holm, Kristjan Norland, Emil L. Sigurdsson, Saedis Saevarsdottir, Páll Melsted, Jon K. Sigurdsson, Olof Sigurdardottir, Gisli H. Halldorsson, Sigrun H. Lund, Unnur Thorsteinsdottir, Gudmar Thorleifsson, and Ingibjorg J. Gudmundsdottir

Subjects
Male, QH301-705.5, Quantitative Trait Loci, Medicine (miscellaneous), Genome-wide association study, Disease, Quantitative trait locus, Bioinformatics, Quantitative trait, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Article, medicine, Humans, Platelet, Biology (General), Ankylosing spondylitis, business.industry, Platelet Count, Genetic Variation, Hyperplasia, medicine.disease, Phenotype, Hemostasis, Rheumatoid arthritis, Female, Gene expression, General Agricultural and Biological Sciences, business, Biomarkers
Abstract

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease., Evgenia Mikaelsdottir et al. report a study of variants associated with platelet count among European individuals where they identify 577 associations. They also report a genetic overlap between platelet count and human diseases, including myeloproliferative neoplasms, rheumatoid arthritis, and hypertension, as well as a genetic overlap between platelet count and various physiological markers.

Published
2020

7. Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis

Author

Hildigunnur Katrinardottir, Daniel F. Gudbjartsson, Vinicius Tragante, Jona Saemundsdottir, Aslaug Jonasdottir, Anna Helgadottir, Brynjar O. Jensson, Stefania Benonisdottir, Isleifur Olafsson, Pall T. Onundarson, Jon K. Sigurdsson, Olafur B. Davidsson, Thorunn Rafnar, Stefan Jonsson, Unnur Thorsteinsdottir, Bjarni Gunnarsson, Gisli H. Halldorsson, Reynir L. Gudmundsson, Lilja Stefansdottir, Adalbjorg Jonasdottir, Egil Ferkingstad, Amy L. Lee, Gudmar Thorleifsson, Gudjon R. Oskarsson, Erna V. Ivarsdottir, Anna M. Kristinsdottir, Magnus K. Magnusson, Asmundur Oddsson, Patrick Sulem, Gudmundur L. Norddahl, Kari Stefansson, Florian Zink, Ragnar P. Kristjansson, Gardar Sveinbjornsson, Hilma Holm, Folkert W. Asselbergs, Gudny A. Arnadottir, Gisli Masson, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
medicine.medical_specialty, Blóðrannsóknir, Regulator, Iceland, Medicine (miscellaneous), Locus (genetics), Pedigree chart, Biology, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Hemoglobins, 0302 clinical medicine, Loss of Function Mutation, Internal medicine, Databases, Genetic, Genetics research, medicine, Missense mutation, Humans, Erythropoiesis, Iron Regulatory Protein 1, Hemoglobin, Genome-wide, lcsh:QH301-705.5, ACO1, 030304 developmental biology, Genetic association, 0303 health sciences, Gen, Rare variants, United Kingdom, Endocrinology, lcsh:Biology (General), Gain of Function Mutation, General Agricultural and Biological Sciences, Erfðarannsóknir, 030217 neurology & neurosurgery, Homeostasis, Biomarkers, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = −1.61 SD, CI95 = [−1.98, −1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10−14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration., We thank the individuals who participated in this study and whose contributions made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK Biobank Resource under application number 24711. F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre.

Published
2020

8. Genome-wide association identifies seven loci for pelvic organ prolapse in Iceland and the UK Biobank

Author

Gudmar Thorleifsson, Unnur Styrkarsdottir, Asgeir Sigurdsson, Daniel F. Gudbjartsson, Vinicius Tragante, Olafur A. Stefansson, Asmundur Oddsson, Kari Stefansson, Hilma Holm, Helga Medek, I. Jonsdottir, Michael L. Frigge, Orri Ingthorsson, Gisli H. Halldorsson, Hannes P. Eggertsson, Lilja Stefansdottir, Valgerdur Steinthorsdottir, Sigrun H. Lund, Julius Gudmundsson, Thorunn Rafnar, Unnur Thorsteinsdottir, Páll Melsted, Valur Gudmundsson, Jon K. Sigurdsson, Thorhildur Ólafsdóttir, Patrick Sulem, Kristín Jónsdóttir, Bjarni V. Halldorsson, Karl Olafsson, Ragnar P. Kristjansson, Folkert W. Asselbergs, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræðideild (HR), Department of Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Tæknisvið (HR), School of Technology (RU), Háskóli Íslands, University of Iceland, Háskólinn í Reykjavík, and Reykjavik University

Subjects
0301 basic medicine, genetic structures, Iceland, Uterus, Endometriosis, Medicine (miscellaneous), Genome-wide association study, Comorbidity, Genome-wide association studies, Body Mass Index, 0302 clinical medicine, Gene Frequency, Risk Factors, Uterine Prolapse, Wnt4 Protein, lcsh:QH301-705.5, Extracellular Matrix Proteins, Genome-wide association, 030219 obstetrics & reproductive medicine, 3. Good health, Phenotype, medicine.anatomical_structure, Leiomyoma, Female, Erfðarannsóknir, General Agricultural and Biological Sciences, psychological phenomena and processes, Reproductive signs and symptoms, medicine.medical_specialty, Connective tissue, Pathophysiology, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Risk Assessment, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Gynecology, Leg, urogenital system, business.industry, Grindargliðnun, medicine.disease, United Kingdom, Pelvic organ prolapse, body regions, Minor allele frequency, 030104 developmental biology, Genes, lcsh:Biology (General), Genetic Loci, Connective tissue metabolism, Case-Control Studies, Etiology, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P 5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP., This research has been conducted using the UK Biobank Resource under Application Number 24898 and 24711. We thank the individuals who participated in the study and whose contribution made this work possible. Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre.

Published
2020

9. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Dilbar Najmutdinova, Firuza Nishanova, Tatyana Hegay, John P. Kemp, Anna Helgadottir, Lucilla Poston, Saedis Saevarsdottir, Ralph McGinnis, Lilja Stefansdottir, Yr Frisbaek, Hrefna Johannsdottir, Olafur A. Stefansson, Thorunn A. Olafsdottir, Markus Perola, Scott Shooter, Frank Geller, Mads Melbye, Reynir Tómas Geirsson, Lill Trogstad, Thorhildur Juliusdottir, Kari Stefansson, Jonas Bybjerg-Grauholm, Eleonora Staines-Urias, Nodira Zakhidova, Daniel F. Gudbjartsson, Vinicius Tragante, João Fadista, Galina Berezina, Damilya Salimbayeva, Zosia Miedzybrodska, Katja Kivinen, James J. Walker, Kari Klungsøyr, Anna F. Dominiczak, Maria Carolina Borges, Fiona Broughton Pipkin, Nigel Simpson, Quaker E. Harmon, Per Magnus, Ashley Moffett, Tamara Aripova, Gordon Prescott, Sigrun Hjartardottir, Noor Kalsheker, Karina Meden Sørensen, Nicholas Williams, Hannele Laivuori, David M. Hougaard, Gulnara Svyatova, Debbie A Lawlor, Stephanie M. Engel, Gudmar Thorleifsson, Wai K. Lee, Paula J. Scaife, Christopher S. Franklin, Bjarke Feenstra, Irina Colgiu, Ann-Charlotte Iversen, Abdumadjit Kasimov, Jon K. Sigurdsson, Liv Cecilie Vestrheim Thomsen, Unnur Thorsteinsdottir, Line Skotte, Linda Morgan, Juan P Casas, Michael L. Frigge, Vivien A. Dolby, Frank Dudbridge, Valgerdur Steinthorsdottir, Suzannah Bumpstead, Kirsi M Auro, Ingileif Jonsdottir, Tiina Jääskeläinen, Heather A. Boyd, Solveig Gretarsdottir, Pregnancy and Genes, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital Area, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, HUS Children and Adolescents, Lastentautien yksikkö, Clinicum, Children's Hospital, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Tampere University, Department of Gynaecology and Obstetrics, Clinical Medicine, University of Helsinki, Research Programs Unit, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, HUS Gynecology and Obstetrics, University of Helsinki, HUS Children and Adolescents, University of Helsinki, STEMM - Stem Cells and Metabolism Research Program, Steinthorsdottir, Valgerdur [0000-0003-1846-6274], McGinnis, Ralph [0000-0003-4540-9857], Williams, Nicholas O [0000-0003-3989-9167], Berezina, Galina [0000-0002-5442-4461], Bybjerg-Grauholm, Jonas [0000-0003-1705-4008], Dudbridge, Frank [0000-0002-8817-8908], Franklin, Christopher S [0000-0003-3893-0759], Geller, Frank [0000-0002-9238-3269], Gudbjartsson, Daniel F [0000-0002-5222-9857], Hougaard, David Michael [0000-0001-5928-3517], Helgadottir, Anna [0000-0002-1806-2467], Jääskeläinen, Tiina [0000-0002-1202-0936], Jonsdottir, Ingileif [0000-0001-8339-150X], Kemp, John P [0000-0002-9105-2249], Kivinen, Katja [0000-0002-1135-7625], Melbye, Mads [0000-0001-8264-6785], Moffett, Ashley [0000-0002-8388-9073], Pipkin, Fiona Broughton [0000-0002-6209-5987], Prescott, Gordon [0000-0002-9156-2361], Saevarsdottir, Saedis [0000-0001-9392-6184], Skotte, Line [0000-0002-7398-1271], Stefansson, Olafur A [0000-0002-9663-3018], Simpson, Nigel AB [0000-0002-0758-7583], Dominiczak, Anna F [0000-0003-4913-3608], Walker, James J [0000-0002-8922-083X], Iversen, Ann-Charlotte [0000-0001-7726-7684], Feenstra, Bjarke [0000-0003-1478-649X], Lawlor, Deborah A [0000-0002-6793-2262], Boyd, Heather Allison [0000-0001-6849-9985], Laivuori, Hannele [0000-0003-3212-7826], Svyatova, Gulnara [0000-0001-5092-3143], Stefansson, Kari [0000-0003-1676-864X], Morgan, Linda [0000-0002-2995-4081], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Gestational hypertension, Multifactorial Inheritance, Reproductive disorders, A990, Datasets as Topic, General Physics and Astronomy, Blood Pressure, Genome-wide association study, VARIANTS, Genome-wide association studies, 0302 clinical medicine, Pre-Eclampsia, 3123 Gynaecology and paediatrics, Medicine, Prospective Studies, 030212 general & internal medicine, reproductive and urinary physiology, 2. Zero hunger, RISK, Multidisciplinary, biology, Obstetrics, Middle Aged, MEDICAL BIRTH REGISTRY, female genital diseases and pregnancy complications, 3. Good health, Europe, PREGNANCY, CARDIOVASCULAR-DISEASE, Hypertension, embryonic structures, Asia, Central, Female, Adult, medicine.medical_specialty, Fibroblast Growth Factor 5, Science, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Article, General Biochemistry, Genetics and Molecular Biology, Preeclampsia, 03 medical and health sciences, Fibroblast growth factor-5, Genetic predisposition, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, FETAL, METAANALYSIS, Adaptor Proteins, Signal Transducing, Aged, Pregnancy, business.industry, Case-control study, Hypertension, Pregnancy-Induced, General Chemistry, medicine.disease, MDS1 and EVI1 Complex Locus Protein, BODY-MASS INDEX, 030104 developmental biology, Genetic Loci, Case-Control Studies, COHORT PROFILE, biology.gene, business, Body mass index, Genome-Wide Association Study
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia., Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020

10. Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA

Author

Sigurjon A. Gudjonsson, Kari Stefansson, Gisli H. Halldorsson, Julius Gudmundsson, Gudmundur Geirsson, Thorunn Rafnar, Isleifur Olafsson, Thorvaldur Jonsson, Unnur Thorsteinsdottir, Olafur A. Stefansson, Eirikur Jonsson, Gudmundur I. Eyjolfsson, Bjarni A. Agnarsson, Daniel F. Gudbjartsson, Vinicius Tragante, Rosa B. Barkardottir, Rafn Hilmarsson, Gudmar Thorleifsson, Lilja Stefansdottir, Hilma Holm, Gisli Masson, Helgi J Isaksson, Folkert W. Asselbergs, Olof Sigurdardottir, Michael L. Frigge, Patrick Sulem, Simon N. Stacey, Jon K. Sigurdsson, Faculty of Medicine (UI), Læknadeild (HÍ), Biomedical Center (UI), Lífvísindasetur (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), and University of Iceland (UI)

Subjects
Male, 0301 basic medicine, Multifactorial Inheritance, Iceland, Prostatic Hyperplasia, General Physics and Astronomy, Genome-wide association study, urologic and male genital diseases, Histones, 0302 clinical medicine, Risk Factors, Non-U.S. Gov't, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, Research Support, Non-U.S. Gov't, Acetylation, Hyperplasia, humanities, 3. Good health, Prostate-specific antigen, Phenotype, 030220 oncology & carcinogenesis, medicine.medical_specialty, Science, Quantitative Trait Loci, Urology, Blöðruhálskirtilskrabbamein, Research Support, Genetic correlation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Lower Urinary Tract Symptoms, Meta-Analysis as Topic, Lower urinary tract symptoms, Genetics, Journal Article, medicine, Erfðafræði, Humans, Genetic Predisposition to Disease, Krabbamein, Aged, business.industry, Lysine, Computational Biology, Rannsóknir, General Chemistry, Prostate-Specific Antigen, medicine.disease, United Kingdom, 030104 developmental biology, Mutation, Polygenic risk score, lcsh:Q, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein) Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r g = 0.77 (P = 2.6 × 10 −11 ), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10 −55 ). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels., We thank the individuals that participated in the study and whose contribution made this work possible. This research has been conducted using the UK Biobank Resource under Application Number 24711. Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the cancer patients.

Published
2018

11. Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis

Author

Eiríkur Steingrímsson, Reynir L. Gudmundsson, Thorunn Rafnar, Ingileif Jonsdottir, Helgi Jonsson, Jon K. Sigurdsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Lilja Stefansdottir, Sara Sigurbjörnsdóttir, Unnur Styrkarsdottir, Stefan Jonsson, Gisli Masson, Thorvaldur Ingvarsson, Gudmundur L. Norddahl, Gyda Bjornsdottir, Florian Zink, Olafur A. Stefansson, Patrick Sulem, Gardar Sveinbjornsson, Kristbjorg Bjarnadottir, Asgeir Sigurdsson, Kristinn Juliusson, Kristjan Norland, Asmundur Oddsson, Kari Stefansson, Gudmar Thorleifsson, Gisli H. Halldorsson, and Sigrun H. Lund

Subjects
030203 arthritis & rheumatology, 0301 basic medicine, medicine.medical_specialty, Case-control study, Genome-wide association study, Odds ratio, Osteoarthritis, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Meta-analysis, Internal medicine, Genotype, Genetics, medicine, Missense mutation, Allele frequency
Abstract

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10-12, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10-11, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10-10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL1 (rs117018441, P = 1.8 × 10-25, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.

Published
2018

12. FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease

Author

Erna V. Ivarsdottir, Lars Klareskog, Saedis Saevarsdottir, Thorunn Rafnar, Lars Alfredsson, Hallgrimur Gudjonsson, Bjorn Gudbjornsson, Gisli H. Halldorsson, Thorunn A. Olafsdottir, Edda L. Styrmisdottir, Julius Gudmundsson, Gudmundur L. Norddahl, Bjorn R. Ludviksson, Leonid Padyukov, Sigrun H. Lund, Kristbjorg Gunnarsdottir, Haukur Hjaltason, Johan Askling, Patrick Sulem, Kristjan Steinsson, Arni Jon Geirsson, Daniel F. Gudbjartsson, Vinicius Tragante, Ari Johannesson, Páll Melsted, I. Jonsdottir, Helga Kristjansdottir, Gerdur M. Grondal, Asgeir Sigurdsson, Rafn Benediktsson, Bardur Sigurgeirsson, Kjartan B. Orvar, Pall T. Onundarson, Gudmar Thorleifsson, Jon K. Sigurdsson, Ingrid Kockum, Thorhildur Juliusdottir, Tomas Olsson, Asgeir O. Arnthorsson, Unnur Thorsteinsdottir, Kristbjorg Bjarnadottir, Kari Stefansson, Ragnar Bjarnason, Gisli Masson, Thorvardur Jon Love, and Astradur B. Hreidarsson

Subjects
0301 basic medicine, Myeloid, Databases, Factual, Iceland, Genome-wide association study, medicine.disease_cause, Ligands, Coeliac disease, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Loss of Function Mutation, medicine, Rheumatoid factor, Humans, Genetic Predisposition to Disease, Alleles, Germ-Line Mutation, Autoimmune disease, Mutation, Multidisciplinary, Thyroiditis, Autoimmune, medicine.disease, Introns, United Kingdom, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, fms-Like Tyrosine Kinase 3, Codon, Nonsense, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Immunology, RNA Splice Sites, Genome-Wide Association Study
Abstract

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2–7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10−24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10−4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10−4) and coeliac disease (OR = 1.62, P = 1.20 × 10−4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10−3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation. A predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of FLT3 ligand, leading to increased risk of autoimmune thyroid disease.

Published
2019

13. Associations of autozygosity with a broad range of human phenotypes

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - 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M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019

14. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Author

Simon N. Stacey, Reynir Tómas Geirsson, Asgeir Thoroddsen, Gardar Sveinbjornsson, Gudny A. Arnadottir, Gisli Masson, Unnur Styrkarsdottir, Bjarni V. Halldorsson, Andres Ingason, Gudmar Thorleifsson, Anna Salvarsdottir, Patrick Sulem, Ragnheidur Arnadottir, Daniel F. Gudbjartsson, Vinicius Tragante, Jon G. Jonasson, Elisabet A. Helgadottir, Unnur Thorsteinsdottir, Karl Olafsson, Olafur B. Davidsson, Katrin Kristjansdottir, Michael L. Frigge, Ragnar P. Kristjansson, Thorunn Rafnar, Folkert W. Asselbergs, Valgerdur Steinthorsdottir, Florian Zink, Bjarni Gunnarsson, Gisli H. Halldorsson, Valur Gudmundsson, Lilja Stefansdottir, Jon K. Sigurdsson, Julius Gudmundsson, Olafur A. Stefansson, Orri Ingthorsson, Asmundur Oddsson, Kari Stefansson, Læknadeild (HÍ), Faculty of Medicine (UI), School of Science and Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Tækni- og verkfræðideild (HR), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskólinn í Reykjavík, Reykjavik University, Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, General Physics and Astronomy, Genome-wide association study, Identifies 2, Bioinformatics, Breast cancer, Brjóstakrabbamein, Genamengi, Beinþéttni, European Continental Ancestry Group/genetics, lcsh:Science, Non-U.S. Gov't, education.field_of_study, Multidisciplinary, Uterine leiomyoma, Leiomyoma, Research Support, Non-U.S. Gov't, Eitlar, musculoskeletal system, Leiomyoma/genetics, female genital diseases and pregnancy complications, 3. Good health, surgical procedures, operative, Uterine Neoplasms, Steinefni, Female, Science, Population, Endometriosis, Biology, Research Support, White People, Article, General Biochemistry, Genetics and Molecular Biology, Sequence variants, 03 medical and health sciences, Krabbameinsrannsóknir, medicine, Bone mineral density, Journal Article, Humans, Uterine Neoplasms/genetics, Hvítblæði, education, neoplasms, Genetic association, Krabbamein, Genome association, Risk loci, Telomere length, Case-control study, Cancer, General Chemistry, Epithelial ovarian cancer, medicine.disease, body regions, 030104 developmental biology, Eggjastokkar, Case-Control Studies, lcsh:Q, Chronic lymphocytic leukemia, Susceptibility loci, Endometriosis/genetics, Genome-Wide Association Study, Meta-Analysis
Abstract

We thank the individuals who participated in the study and whose contribution made this work possible. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the cancer patients. T.R., B.G., P.S., B.V.H., G.T, and K.S. designed the study and interpreted the results. A.S, A.T., E.A.H., K.K., O.I., V.G., R.T.G., R.A., J.G.J., and K.O. carried out the subject ascertainment, recruitment, and collection of clinical data. U.S., V.S., S.N.S., J.G., G.A.A., A.O., F.Z., G.H., R.P.K., O.B.D., G.M., V.T., F.W.A., and U.T. collected, processed, and analyzed the genotype and phenotype data. O.A.S. performed the functional annotations. A.I., M.L.F., L.S., J.K.S., G.S., D.F.G., B.G., and B.V.H., performed the statistical and bioinformatics analyses. T.R., B.G., O.A.S, G.T., and K.S., drafted the manuscript. All authors contributed to the final version of the paper., Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth., This research has been conducted using the UK Biobank Resource under Application Number ‘24711’.

Published
2018

15. Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin

Author

Gisli Masson, Hrefna Johannsdottir, Julius Gudmundsson, Jona Saemundsdottir, Helgi J Isaksson, Fridbjorn Sigurdsson, Hronn Hardardottir, Gudridur H Olafsdottir, Luba M. Pardo, Daniel F. Gudbjartsson, Hannes Helgason, Jon G. Jonasson, Simon N. Stacey, L.A. Kiemeney, Laufey Tryggvadottir, Martin Lacko, Thorkell Gudjonsson, Thorunn Rafnar, Asgeir Sigurdsson, Steinn Jonsson, Jon K. Sigurdsson, Tessel E. Galesloot, Wilbert H.M. Peters, Gunnar B Ragnarsson, Tamar Nijsten, Gudbjorg R Sigurjonsdottir, Kristin Thorisdottir, Kristin Alexiusdottir, Dawn C. Allain, Unnur Thorsteinsdottir, Sita H. Vermeulen, Kari Stefansson, Jón Ólafsson, Patrick Sulem, André G. Uitterlinden, Amanda E. Toland, Gisli H. Halldorsson, Oskar T. Johannsson, Stefan T Sigurdsson, Gudmar Thorleifsson, Bardur Sigurgeirsson, Tomas Gudbjartsson, Dermatology, and Internal Medicine

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Skin Neoplasms, Genotype, Genes, BRCA2, Population, Iceland, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Odds Ratio, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Lung cancer, education, Alleles, Netherlands, BRCA2 Protein, education.field_of_study, business.industry, Epithelial Cells, Articles, Odds ratio, medicine.disease, Small Cell Lung Carcinoma, United States, 030104 developmental biology, Organ Specificity, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Mutation, Carcinoma, Squamous Cell, Carcinogens, Ovarian cancer, business
Abstract

Contains fulltext : 195644.pdf (Publisher’s version ) (Closed access) Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.

Published
2018

16. Sequence variant at 4q25 near PITX2 associates with appendicitis

Author

Thorvaldur Jonsson, Olafur B. Davidsson, Stefania Benonisdottir, Jon K. Sigurdsson, Brynjar O. Jensson, Lambertus A. Kiemeney, Hilma Holm, Gudmar Thorleifsson, Ragnar P. Kristjansson, Stefan Jonsson, Snaevar Sigurdsson, Ingileif Jonsdottir, Thorunn Rafnar, Unnur Thorsteinsdottir, Tessel E. Galesloot, Kristin Alexiusdottir, Daniel F. Gudbjartsson, Katja K.H. Aben, Asmundur Oddsson, Kari Stefansson, G. Bragi Walters, Patrick Sulem, David O. Arnar, Gudny A. Arnadottir, Gudmundur Thorgeirsson, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, medicine.medical_specialty, Pathology, Genotype, Science, Áhættuþættir, Botnlangabólga, Genome-wide association studies, Article, 03 medical and health sciences, Internal medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, In patient, Alleles, Sequence (medicine), Homeodomain Proteins, Multidisciplinary, PITX2, business.industry, Computational Biology, Genetic Variation, Molecular Sequence Annotation, Atrial fibrillation, Acute surgery, medicine.disease, Appendicitis, 030104 developmental biology, Increased risk, Risk factors, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Medicine, Chromosomes, Human, Pair 4, business, Erfðarannsóknir, Genome-Wide Association Study, Transcription Factors
Abstract

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10−11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Published
2017

17. Epigenetic and genetic components of height regulation

Author

Gudny A. Arnadottir, Thorunn Rafnar, Hannes Helgason, Michael L. Frigge, Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Patrick Sulem, Lucas D. Ward, Stefania Benonisdottir, Paul D. Iordache, Ragnar P. Kristjansson, Augustine Kong, Gisli Masson, Sigurjon A. Gudjonsson, G. Bragi Walters, Arna Oskarsdottir, Kristjan F. Alexandersson, Hilma Holm, Olafur B. Davidsson, Jon K. Sigurdsson, Gerald Sulem, Laufey Tryggvadottir, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Asmundur Oddsson, Kari Stefansson, Brynjar O. Jensson, and Agnar Helgason

Subjects
Adult, 0301 basic medicine, Genotype, Science, Iceland, General Physics and Astronomy, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Humans, Epigenetics, Allele, Genetic Association Studies, Sequence (medicine), Epigenesis, Genetics, Multidisciplinary, Models, Genetic, Genetic Variation, General Chemistry, Body Height, female genital diseases and pregnancy complications, Adult height, 030104 developmental biology, Genetic Loci, Trait, 030217 neurology & neurosurgery
Abstract

Adult height is a highly heritable trait. Here we identified 31.6 million sequence variants by whole-genome sequencing of 8,453 Icelanders and tested them for association with adult height by imputing them into 88,835 Icelanders. Here we discovered 13 novel height associations by testing four different models including parent-of-origin (|β|=0.4–10.6 cm). The minor alleles of three parent-of-origin signals associate with less height only when inherited from the father and are located within imprinted regions (IGF2-H19 and DLK1-MEG3). We also examined the association of these sequence variants in a set of 12,645 Icelanders with birth length measurements. Two of the novel variants, (IGF2-H19 and TET1), show significant association with both adult height and birth length, indicating a role in early growth regulation. Among the parent-of-origin signals, we observed opposing parental effects raising questions about underlying mechanisms. These findings demonstrate that common variations affect human growth by parental imprinting., Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.

Published
2016

18. A genome-wide association study yields five novel thyroid cancer risk loci

Author

Thorvaldur Jonsson, Hannes Helgason, Huiling He, Isleifur Olafsson, Gudmundur I. Eyjolfsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Jon G. Jonasson, Enrique Prats, Julius Gudmundsson, Lilja Stefansdottir, Hrefna Johannsdottir, Gisli Masson, Li Xu, Theo S. Plantinga, Lambertus A. Kiemeney, Thorunn Rafnar, Hoskuldur Kristvinsson, Jose I. Mayordomo, Jon Hrafnkelsson, Esperanza Aguillo, Gisli H. Halldorsson, Ana de Juan, Matthew D. Ringel, Olof Sigurdardottir, Erich M. Sturgis, Leigha Senter, Sandya Liyanarachchi, Romana T. Netea-Maier, Sigurjon A. Gudjonsson, Albert de la Chapelle, Fernando Rivera, Jon K. Sigurdsson, Gudmar Thorleifsson, Almudena García-Castaño, Simon N. Stacey, Angeles Panadero, Kari Stefansson, Patrick Sulem, Hannes Hjartarson, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Male, Thyroid Gland, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Gene Frequency, Risk Factors, Genotype, Missense mutation, Chromosomes, Human, Thyroid cancer, Cancer genetics, Genetics, Multidisciplinary, Thyroid, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Thyroid Cancer, Papillary, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Adult, medicine.medical_specialty, endocrine system, Science, Biology, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], General Biochemistry, Genetics and Molecular Biology, White People, Article, 03 medical and health sciences, Asian People, Molecular genetics, medicine, Erfðafræði, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Allele, Krabbamein, Whole Genome Sequencing, Case-control study, General Chemistry, Rannsóknir, medicine.disease, Carcinoma, Papillary, Pituitary Hormones, 030104 developmental biology, Genetic Loci, Case-Control Studies, Genomic Structural Variation, Genome-Wide Association Study
Abstract

The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with Pcombined, We thank the patients whose contribution made this work possible. The study was supported in part by grants from the National Institutes of Health: CA16058 (to the Ohio State University Comprehensive Cancer Center) and CA168505 (to M.D.R. and A.d.l.C.). This work was supported in part by The University of Texas MD Anderson Cancer Center start-up funds (to E.M.S.); an American Thyroid Association research grant (to E.M.S.), National Institutes of Health (NIH) grant U01 DE019765-01 (to E.M.S.); and Cancer Center Support Grant CA016672 to the University of Texas MD Anderson Cancer Center. This study makes use of data generated by the Genome of the Netherlands Project (GoNL). A full list of the investigators is available from http://www.nlgenome.nl. Funding for the GoNL project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated 9 July 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). This study also makes use of data generated by the GTEx Consortium and we are grateful for early stage sharing of RNA-seq and genotypic data. The following acknowledgement refers to the GTEx data: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820 and MH101825), the University of North Carolina—Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810) and the University of Pennsylvania (MH101822).

Published
2016

19. Major Hemorrhage as a Complication of Cough Fracture

Author

Stefan Hjalmarsson, Tryggvi Asmundsson, Bjarni Torfason, Gudmundur S. Jonsson, and Jon K. Sigurdsson

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Anesthesia, Cough fracture, medicine, Hemorrhage as a complication, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, business, Surgery
Published
1993

20. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

Author

Anita Haugan, Sigrun Hjartardottir, Gulnara Svyatova, Hannele Laivuori, Ralph McGinnis, Scott Shooter, Per Magnus, James J. Walker, Linda M. Morgan, Susan E. Hiby, Unnur Thorsteinsdottir, Tiina Jääskeläinen, Nigel Simpson, Debbie A Lawlor, Vivien A. Dolby, Reynir Tómas Geirsson, Valgerdur Steinthorsdottir, Juan P. Casas, Lill Trogstad, Eleonora Staines-Urias, Ann-Charlotte Iversen, Dilbar Najmutdinova, Stephanie M. Engel, Nodira Zakhidova, John P. Kemp, Kari Stefansson, Håkon K. Gjessing, Anna F. Dominiczak, Fiona Broughton Pipkin, Lucy Hildyard, Gudmar Thorleifsson, Noor Kalsheker, Lilja Stefansdottir, Eero Kajantie, Ashley Moffett, Sandosh Padmanabhan, Frank Dudbridge, Suzannah Bumpstead, Jon K. Sigurdsson, Liv Cecilie Vestrheim Thomsen, Nicholas Williams, Gabriela Silva, Sally Chappell, and Wai K. Lee

Subjects
0301 basic medicine, Genotype, Offspring, Population, Genome-wide association study, Locus (genetics), 030204 cardiovascular system & hematology, Biology, Pregnancy Proteins, Bioinformatics, Polymorphism, Single Nucleotide, Preeclampsia, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Fetus, Pre-Eclampsia, Pregnancy, Genetics, medicine, Humans, Genetic Predisposition to Disease, education, reproductive and urinary physiology, Genetic association, education.field_of_study, Vascular Endothelial Growth Factor Receptor-1, Genome, Human, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, embryonic structures, Female, Follow-Up Studies, Genome-Wide Association Study
Abstract

Ralph McGinnis, Valgerdur Steinthorsdottir, Linda Morgan and colleagues perform a genome-wide association study in the offspring of preeclampsia pregnancies and identify variants in the fetal genome near FLT1 that are associated with risk of preeclampsia. FLT1 is known to encode an isoform of placental origin implicated in the pathology of preeclampsia, providing biological support for the association of this locus with preeclampsia risk. Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death1. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility2. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets3,4. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10−11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia5. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

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21. Genetic variants associated with platelet count are predictive of human disease and physiological markers

Author

Evgenia Mikaelsdottir, Gudmar Thorleifsson, Lilja Stefansdottir, Gisli Halldorsson, Jon K. Sigurdsson, Sigrun H. Lund, Vinicius Tragante, Pall Melsted, Solvi Rognvaldsson, Kristjan Norland, Anna Helgadottir, Magnus K. Magnusson, Gunnar B. Ragnarsson, Sigurdur Y. Kristinsson, Sigrun Reykdal, Brynjar Vidarsson, Ingibjorg J. Gudmundsdottir, Isleifur Olafsson, Pall T. Onundarson, Olof Sigurdardottir, Emil L. Sigurdsson, Gerdur Grondal, Arni J. Geirsson, Gudmundur Geirsson, Julius Gudmundsson, Hilma Holm, Saedis Saevarsdottir, Ingileif Jonsdottir, Gudmundur Thorgeirsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Thorunn Rafnar, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Evgenia Mikaelsdottir et al. report a study of variants associated with platelet count among European individuals where they identify 577 associations. They also report a genetic overlap between platelet count and human diseases, including myeloproliferative neoplasms, rheumatoid arthritis, and hypertension, as well as a genetic overlap between platelet count and various physiological markers.

Published
2021
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22. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Author

Steven Bell, Andreas S. Rigas, Magnus K. Magnusson, Egil Ferkingstad, Elias Allara, Gyda Bjornsdottir, Anna Ramond, Erik Sørensen, Gisli H. Halldorsson, Dirk S. Paul, Kristoffer S. Burgdorf, Hannes P. Eggertsson, Joanna M. M. Howson, Lise W. Thørner, Snaedis Kristmundsdottir, William J. Astle, Christian Erikstrup, Jon K. Sigurdsson, Dragana Vuckovic, Khoa M. Dinh, Vinicius Tragante, Praveen Surendran, Ole B. Pedersen, Brynjar Vidarsson, Tao Jiang, Helene M. Paarup, Pall T. Onundarson, Parsa Akbari, Kaspar R. Nielsen, Sigrun H. Lund, Kristinn Juliusson, Magnus I. Magnusson, Michael L. Frigge, Asmundur Oddsson, Isleifur Olafsson, Stephen Kaptoge, Henrik Hjalgrim, Gudmundur Runarsson, Angela M. Wood, Ingileif Jonsdottir, Thomas F. Hansen, Olof Sigurdardottir, Hreinn Stefansson, David Rye, DBDS Genomic Consortium, James E. Peters, David Westergaard, Hilma Holm, Nicole Soranzo, Karina Banasik, Gudmar Thorleifsson, Willem H. Ouwehand, Unnur Thorsteinsdottir, David J. Roberts, Patrick Sulem, Adam S. Butterworth, Daniel F. Gudbjartsson, John Danesh, Søren Brunak, Emanuele Di Angelantonio, Henrik Ullum, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women.

Published
2021
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23. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Valgerdur Steinthorsdottir, Ralph McGinnis, Nicholas O. Williams, Lilja Stefansdottir, Gudmar Thorleifsson, Scott Shooter, João Fadista, Jon K. Sigurdsson, Kirsi M. Auro, Galina Berezina, Maria-Carolina Borges, Suzannah Bumpstead, Jonas Bybjerg-Grauholm, Irina Colgiu, Vivien A. Dolby, Frank Dudbridge, Stephanie M. Engel, Christopher S. Franklin, Michael L. Frigge, Yr Frisbaek, Reynir T. Geirsson, Frank Geller, Solveig Gretarsdottir, Daniel F. Gudbjartsson, Quaker Harmon, David Michael Hougaard, Tatyana Hegay, Anna Helgadottir, Sigrun Hjartardottir, Tiina Jääskeläinen, Hrefna Johannsdottir, Ingileif Jonsdottir, Thorhildur Juliusdottir, Noor Kalsheker, Abdumadjit Kasimov, John P. Kemp, Katja Kivinen, Kari Klungsøyr, Wai K. Lee, Mads Melbye, Zosia Miedzybrodska, Ashley Moffett, Dilbar Najmutdinova, Firuza Nishanova, Thorunn Olafsdottir, Markus Perola, Fiona Broughton Pipkin, Lucilla Poston, Gordon Prescott, Saedis Saevarsdottir, Damilya Salimbayeva, Paula Juliet Scaife, Line Skotte, Eleonora Staines-Urias, Olafur A. Stefansson, Karina Meden Sørensen, Liv Cecilie Vestrheim Thomsen, Vinicius Tragante, Lill Trogstad, Nigel A. B. Simpson, FINNPEC Consortium, GOPEC Consortium, Tamara Aripova, Juan P. Casas, Anna F. Dominiczak, James J. Walker, Unnur Thorsteinsdottir, Ann-Charlotte Iversen, Bjarke Feenstra, Deborah A. Lawlor, Heather Allison Boyd, Per Magnus, Hannele Laivuori, Nodira Zakhidova, Gulnara Svyatova, Kari Stefansson, and Linda Morgan

Subjects
Science
Abstract

Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020
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24. Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

Author

Thorunn A. Olafsdottir, Fannar Theodors, Kristbjorg Bjarnadottir, Unnur Steina Bjornsdottir, Arna B. Agustsdottir, Olafur A. Stefansson, Erna V. Ivarsdottir, Jon K. Sigurdsson, Stefania Benonisdottir, Gudmundur I. Eyjolfsson, David Gislason, Thorarinn Gislason, Steinunn Guðmundsdóttir, Arnaldur Gylfason, Bjarni V. Halldorsson, Gisli H. Halldorsson, Thorhildur Juliusdottir, Anna M. Kristinsdottir, Dora Ludviksdottir, Bjorn R. Ludviksson, Gisli Masson, Kristjan Norland, Pall T. Onundarson, Isleifur Olafsson, Olof Sigurdardottir, Lilja Stefansdottir, Gardar Sveinbjornsson, Vinicius Tragante, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur L. Norddahl, Ingileif Jonsdottir, and Kari Stefansson

Subjects
Science
Abstract

Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.

Published
2020
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25. Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA

Author

Julius Gudmundsson, Jon K. Sigurdsson, Lilja Stefansdottir, Bjarni A. Agnarsson, Helgi J. Isaksson, Olafur A. Stefansson, Sigurjon A. Gudjonsson, Daniel F. Gudbjartsson, Gisli Masson, Michael L. Frigge, Simon N. Stacey, Patrick Sulem, Gisli H. Halldorsson, Vinicius Tragante, Hilma Holm, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Thorvaldur Jonsson, Eirikur Jonsson, Rosa B. Barkardottir, Rafn Hilmarsson, Folkert W. Asselbergs, Gudmundur Geirsson, Unnur Thorsteinsdottir, Thorunn Rafnar, Gudmar Thorleifsson, and Kari Stefansson

Subjects
Science
Abstract

Elderly males are often affected by benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS), but their link to prostate cancer risk is not well defined. Here, a genome-wide association study of BPH/LUTS patients from Iceland and the UK found 23 significant variants at 14 loci, and 15 of these variants associate with prostate specific antigen, which is linked to prostate cancer risk.

Published
2018
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26. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Author

Thorunn Rafnar, Bjarni Gunnarsson, Olafur A. Stefansson, Patrick Sulem, Andres Ingason, Michael L. Frigge, Lilja Stefansdottir, Jon K. Sigurdsson, Vinicius Tragante, Valgerdur Steinthorsdottir, Unnur Styrkarsdottir, Simon N. Stacey, Julius Gudmundsson, Gudny A. Arnadottir, Asmundur Oddsson, Florian Zink, Gisli Halldorsson, Gardar Sveinbjornsson, Ragnar P. Kristjansson, Olafur B. Davidsson, Anna Salvarsdottir, Asgeir Thoroddsen, Elisabet A. Helgadottir, Katrin Kristjansdottir, Orri Ingthorsson, Valur Gudmundsson, Reynir T. Geirsson, Ragnheidur Arnadottir, Daniel F. Gudbjartsson, Gisli Masson, Folkert W. Asselbergs, Jon G. Jonasson, Karl Olafsson, Unnur Thorsteinsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, and Kari Stefansson

Subjects
Science
Abstract

Uterine leiomyomas are common benign tumors. Here, a meta-analysis of two European leiomyoma GWAS uncovers 21 leiomyoma risk variants at 16 loci, providing evidence of genetic overlap between leiomyoma and various benign and malignant tumors and highlighting the role of estrogen in tumor growth.

Published
2018
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27. Sequence variant at 4q25 near PITX2 associates with appendicitis

Author

Ragnar P. Kristjansson, Stefania Benonisdottir, Asmundur Oddsson, Tessel E. Galesloot, Gudmar Thorleifsson, Katja K. Aben, Olafur B. Davidsson, Stefan Jonsson, Gudny A. Arnadottir, Brynjar O. Jensson, G. Bragi Walters, Jon K. Sigurdsson, Snaevar Sigurdsson, Hilma Holm, David O. Arnar, Gudmundur Thorgeirsson, Kristin Alexiusdottir, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Lambertus A. Kiemeney, Thorvaldur Jonsson, Daniel F. Gudbjartsson, Thorunn Rafnar, Patrick Sulem, and Kari Stefansson

Subjects
Medicine, Science
Abstract

Abstract Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10−11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Published
2017
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28. A genome-wide association study yields five novel thyroid cancer risk loci

Author

Julius Gudmundsson, Gudmar Thorleifsson, Jon K. Sigurdsson, Lilja Stefansdottir, Jon G. Jonasson, Sigurjon A. Gudjonsson, Daniel F. Gudbjartsson, Gisli Masson, Hrefna Johannsdottir, Gisli H. Halldorsson, Simon N. Stacey, Hannes Helgason, Patrick Sulem, Leigha Senter, Huiling He, Sandya Liyanarachchi, Matthew D. Ringel, Esperanza Aguillo, Angeles Panadero, Enrique Prats, Almudena Garcia-Castaño, Ana De Juan, Fernando Rivera, Li Xu, Lambertus A. Kiemeney, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Hoskuldur Kristvinsson, Romana T. Netea-Maier, Thorvaldur Jonsson, Jose I. Mayordomo, Theo S. Plantinga, Hannes Hjartarson, Jon Hrafnkelsson, Erich M. Sturgis, Unnur Thorsteinsdottir, Thorunn Rafnar, Albert de la Chapelle, and Kari Stefansson

Subjects
Science
Abstract

Non-medullary thyroid cancers include papillary and follicular subtypes, and are the most common type of thyroid cancer. Here, the authors extend previous work by performing a large genome-wide association study and find five novel loci associated with this disease.

Published
2017
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29. Epigenetic and genetic components of height regulation

Author

Stefania Benonisdottir, Asmundur Oddsson, Agnar Helgason, Ragnar P. Kristjansson, Gardar Sveinbjornsson, Arna Oskarsdottir, Gudmar Thorleifsson, Olafur B. Davidsson, Gudny A. Arnadottir, Gerald Sulem, Brynjar O. Jensson, Hilma Holm, Kristjan F. Alexandersson, Laufey Tryggvadottir, G. Bragi Walters, Sigurjon A. Gudjonsson, Lucas D. Ward, Jon K. Sigurdsson, Paul D. Iordache, Michael L. Frigge, Thorunn Rafnar, Augustine Kong, Gisli Masson, Hannes Helgason, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Patrick Sulem, and Kari Stefansson

Subjects
Science
Abstract

Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.

Published
2016
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