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1. 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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2. Sequence variants with large effects on cardiac electrophysiology and disease

Author: Kristjan Norland, Gardar Sveinbjornsson, Rosa B. Thorolfsdottir, Olafur B. Davidsson, Vinicius Tragante, Sridharan Rajamani, Anna Helgadottir, Solveig Gretarsdottir, Jessica van Setten, Folkert W. Asselbergs, Jon Th. Sverrisson, Sigurdur S. Stephensen, Gylfi Oskarsson, Emil L. Sigurdsson, Karl Andersen, Ragnar Danielsen, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, David O. Arnar, Patrick Sulem, Hilma Holm, Daniel F. Gudbjartsson, and Kari Stefansson
Subjects: Science
Abstract: Aberrant morphology of the QRS complex in an electrocardiogram can be associated with cardiac morbidity and mortality. Here, the authors perform genome-wide association studies for ten measures of the QRS complex in 81,192 individuals and find 86 previously unreported loci that associate with at least one parameter.
Published: 2019
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3. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease

Author: Egil Ferkingstad, Asmundur Oddsson, Solveig Gretarsdottir, Stefania Benonisdottir, Gudmar Thorleifsson, Aimee M. Deaton, Stefan Jonsson, Olafur A. Stefansson, Gudmundur L. Norddahl, Florian Zink, Gudny A. Arnadottir, Bjarni Gunnarsson, Gisli H. Halldorsson, Anna Helgadottir, Brynjar O. Jensson, Ragnar P. Kristjansson, Gardar Sveinbjornsson, David A. Sverrisson, Gisli Masson, Isleifur Olafsson, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Hilma Holm, Ingileif Jonsdottir, Sigurdur Olafsson, Thora Steingrimsdottir, Thorunn Rafnar, Einar S. Bjornsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Patrick Sulem, and Kari Stefansson
Subjects: Science
Abstract: Genome-wide association studies have so far identified eight risk loci for gallstone disease. Here, the authors perform meta-analysis in cohorts from Iceland and the UK which reveals further 21 common and low-frequency risk variants that highlight the role of bile acid homeostasis in gallstone disease.
Published: 2018
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4. Genome-wide analysis yields new loci associating with aortic valve stenosis

Author: Anna Helgadottir, Gudmar Thorleifsson, Solveig Gretarsdottir, Olafur A. Stefansson, Vinicius Tragante, Rosa B. Thorolfsdottir, Ingileif Jonsdottir, Thorsteinn Bjornsson, Valgerdur Steinthorsdottir, Niek Verweij, Jonas B. Nielsen, Wei Zhou, Lasse Folkersen, Andreas Martinsson, Mahyar Heydarpour, Siddharth Prakash, Gylfi Oskarsson, Tomas Gudbjartsson, Arnar Geirsson, Isleifur Olafsson, Emil L. Sigurdsson, Peter Almgren, Olle Melander, Anders Franco-Cereceda, Anders Hamsten, Lars Fritsche, Maoxuan Lin, Bo Yang, Whitney Hornsby, Dongchuan Guo, Chad M. Brummett, Gonçalo Abecasis, Michael Mathis, Dianna Milewicz, Simon C. Body, Per Eriksson, Cristen J. Willer, Kristian Hveem, Christopher Newton-Cheh, J. Gustav Smith, Ragnar Danielsen, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hilma Holm, and Kari Stefansson
Subjects: Science
Abstract: Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.
Published: 2018
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5. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Author: Femke N. G. van ’t Hof, Ynte M. Ruigrok, Cue Hyunkyu Lee, Stephan Ripke, Graig Anderson, Mariza de Andrade, Annette F. Baas, Jan D. Blankensteijn, Erwin P. Böttinger, Matthew J. Bown, Joseph Broderick, Philippe Bijlenga, David S. Carrell, Dana C. Crawford, David R. Crosslin, Christian Ebeling, Johan G. Eriksson, Myriam Fornage, Tatiana Foroud, Mikael von und zu Fraunberg, Christoph M. Friedrich, Emília I. Gaál, Omri Gottesman, Dong‐Chuan Guo, Seamus C. Harrison, Juha Hernesniemi, Albert Hofman, Ituro Inoue, Juha E. Jääskeläinen, Gregory T. Jones, Lambertus A. L. M. Kiemeney, Riku Kivisaari, Nerissa Ko, Seppo Koskinen, Michiaki Kubo, Iftikhar J. Kullo, Helena Kuivaniemi, Mitja I. Kurki, Aki Laakso, Dongbing Lai, Suzanne M. Leal, Hanna Lehto, Scott A. LeMaire, Siew‐Kee Low, Jennifer Malinowski, Catherine A. McCarty, Dianna M. Milewicz, Thomas H. Mosley, Yusuke Nakamura, Hirofumi Nakaoka, Mika Niemelä, Jennifer Pacheco, Peggy L. Peissig, Joanna Pera, Laura Rasmussen‐Torvik, Marylyn D. Ritchie, Fernando Rivadeneira, Andre M. van Rij, Regie Lyn P. Santos‐Cortez, Athanasios Saratzis, Agnieszka Slowik, Atsushi Takahashi, Gerard Tromp, André G. Uitterlinden, Shefali S. Verma, Sita H. Vermeulen, Gao T. Wang, Buhm Han, Gabriël J. E. Rinkel, Paul I. W. de Bakker, Ana Verissimo, Benjamin J. Wright, Suzannah Bumpstead, Solveig Gretarsdottir, Stephen A. Badger, Anne H. Child, Rachel E. Clough, Gillian Cockerill, Hany Hafez, D. Julian A. Scott, Simon Futers, Soroush Sohrabi, Alberto Smith, Matthew M. Thompson, Frank M. van Bockxmeer, Stefan E. Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Joep A. W. Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A. Kiemeney, Jutta Palmen, Andrew J. Smith, Jes S. Lindholt, Declan T. Bradley, Matthew Waltham, Sarah Edkins, Rhian Gwilliam, Sarah E. Hunt, Simon Potter, Jonathan Golledge, Per Eriksson, Paul E. Norman, Janet T. Powell, Kari Stefansson, John R. Thompson, Steve E. Humphries, Robert D. Sayers, Panos Deloukas, Nilesh J. Samani, L. Victoria Phillip, Geraldine B. Hill, Michael J. A. Williams, Ian A. Thomson, Jo Krysa, Gerard T. Wilkins, Tony R. Merriman, Thodor M. Vasudevan, David R. Lewis, Ross D. Blair, and Andrew A. Hill
Subjects: abdominal aortic aneurysm, genome wide association study, intracranial aneurysm, thoracic aortic aneurysm, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: BackgroundIntracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and ResultsWe performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). ConclusionsAlthough there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
Published: 2016
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6. A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease.

Author: Solveig Gretarsdottir, Hannes Helgason, Anna Helgadottir, Asgeir Sigurdsson, Gudmar Thorleifsson, Audur Magnusdottir, Asmundur Oddsson, Valgerdur Steinthorsdottir, Thorunn Rafnar, Jacqueline de Graaf, Maryam S Daneshpour, Mehdi Hedayati, Fereidoun Azizi, Niels Grarup, Torben Jørgensen, Henrik Vestergaard, Torben Hansen, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Lambertus A Kiemeney, Oluf Pedersen, Patrick Sulem, Gudmundur Thorgeirsson, Daniel F Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, and Kari Stefansson
Subjects: Genetics, QH426-470
Abstract: Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻⁸⁰ and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻⁸ and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.
Published: 2015
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7. The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

Author: Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H M Draisma, Janina S Ried, Natalie R van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P Nelson, Natalia V Rivera, Kati Kristiansson, Huei-Yi Shen, Aki S Havulinna, Abbas Dehghan, Louise A Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tõnu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C Karssen, Johannes Kettunen, Wolfgang Koenig, Kari Kuulasmaa, Tiina Laatikainen, Jaana Laitinen, Cecilia Lindgren, Valeriya Lyssenko, Esa Läärä, Nigel W Rayner, Satu Männistö, Anneli Pouta, Wolfgang Rathmann, Fernando Rivadeneira, Aimo Ruokonen, Markku J Savolainen, Eric J G Sijbrands, Kerrin S Small, Jan H Smit, Valgerdur Steinthorsdottir, Ann-Christine Syvänen, Anja Taanila, Martin D Tobin, Andre G Uitterlinden, Sara M Willems, Gonneke Willemsen, Jacqueline Witteman, Markus Perola, Alun Evans, Jean Ferrières, Jarmo Virtamo, Frank Kee, David-Alexandre Tregouet, Dominique Arveiler, Philippe Amouyel, Marco M Ferrario, Paolo Brambilla, Alistair S Hall, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, John B Whitfield, Antti Jula, Paul Knekt, Ben Oostra, Cornelia M van Duijn, Brenda W J H Penninx, George Davey Smith, Jaakko Kaprio, Nilesh J Samani, Christian Gieger, Annette Peters, H Erich Wichmann, Dorret I Boomsma, Eco J C de Geus, TiinaMaija Tuomi, Chris Power, Christopher J Hammond, Tim D Spector, Lars Lind, Marju Orho-Melander, Colin Neil Alexander Palmer, Andrew D Morris, Leif Groop, Marjo-Riitta Järvelin, Veikko Salomaa, Erkki Vartiainen, Albert Hofman, Samuli Ripatti, Andres Metspalu, Unnur Thorsteinsdottir, Kari Stefansson, Nancy L Pedersen, Mark I McCarthy, Erik Ingelsson, Inga Prokopenko, and European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
Subjects: Medicine
Abstract: BackgroundThe association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and findingsWe used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).ConclusionsWe provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Published: 2013
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8. European bone mineral density loci are also associated with BMD in East-Asian populations.

Author: Unnur Styrkarsdottir, Bjarni V Halldorsson, Daniel F Gudbjartsson, Nelson L S Tang, Jung-Min Koh, Su-mei Xiao, Timothy C Y Kwok, Ghi Su Kim, Juliana C N Chan, Stacey Cherny, Seung Hun Lee, Anthony Kwok, Suzanne Ho, Solveig Gretarsdottir, Jelena Pop Kostic, Stefan Th Palsson, Gunnar Sigurdsson, Pak C Sham, Beom-Jun Kim, Annie W C Kung, Shin-Yoon Kim, Jean Woo, Ping-C Leung, Augustine Kong, Unnur Thorsteinsdottir, and Kari Stefansson
Subjects: Medicine, Science
Abstract: Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10(-9)), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10(-5)), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10(-5)), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10(-5)), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.
Published: 2010
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9. A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries.

Author: Astridur Palsdottir, Agnar Helgason, Snaebjorn Palsson, Hans Tomas Bjornsson, Birkir Thor Bragason, Solveig Gretarsdottir, Unnur Thorsteinsdottir, Elias Olafsson, and Kari Stefansson
Subjects: Genetics, QH426-470
Abstract: Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.
Published: 2008
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10. Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism

Author: Jonas Ghouse, Vinicius Tragante, Gustav Ahlberg, Søren A. Rand, Jakob B. Jespersen, Eva Birgitte Leinøe, Christoffer Rasmus Vissing, Linea Trudsø, Ingileif Jonsdottir, Karina Banasik, Søren Brunak, Sisse R. Ostrowski, Ole B. Pedersen, Erik Sørensen, Christian Erikstrup, Mie Topholm Bruun, Kaspar Rene Nielsen, Lars Køber, Alex H. Christensen, Kasper Iversen, David Jones, Kirk U. Knowlton, Lincoln Nadauld, Gisli H. Halldorsson, Egil Ferkingstad, Isleifur Olafsson, Solveig Gretarsdottir, Pall T. Onundarson, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Daniel F. Gudbjartsson, Kari Stefansson, Hilma Holm, Morten Salling Olesen, and Henning Bundgaard
Subjects: Genetics
Abstract: We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).
Published: 2023

11. Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland

Author: Emil L. Sigurðsson, Unnur Thorsteinsdottir, Valgerður Steinthórsdóttir, Davíð O. Arnar, Karl Andersen, Ásgeir Sigurðsson, G. Thorleifsson, Magnús Baldvinsson, Patrick Sulem, Stefan E Matthiasson, Kari Stefansson, G Sveinbjörnsson, Aslaug Jonasdottir, Ólöf Sigurðardóttir, Ragnar Bjarnason, Aðalbjörg Jónasdóttir, Ingileif Jonsdottir, Thórarinn Guðnason, Eythór Björnsson, Bjorn L. Thorarinsson, Isleifur Olafsson, Solveig Gretarsdottir, Ragnar Danielsen, Brynjar Viðarsson, Snaedis Kristmundsdottir, Daníel F. Guðbjartsson, Hakon Jonsson, Anna Helgadottir, Bjarni V. Halldorsson, Guðmundur Thorgeirsson, and Hilma Holm
Subjects: Scale (ratio), Familial hypercholesterolemia, Monogenic disease, lipids, Hyperlipoproteinemia Type II, medicine, Prevalence, Humans, genetics, Registries, Lipoprotein cholesterol, Genetics, hypercholesterolemia, business.industry, genetic screening, Cholesterol, LDL, medicine.disease, Mutation (genetic algorithm), ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, mutation, Cardiology and Cardiovascular Medicine, business, Clinical and Population Studies
Abstract: Supplemental Digital Content is available in the text., Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of
Published: 2021

12. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
Subjects: Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022

13. 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

14. Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

Author: Daniel F. Gudbjartsson, Vinicius Tragante, Einar Bjornsson, Alex Hørby Christensen, Erik Sørensen, Ole Birger Pedersen, Solveig Gretarsdottir, Folkert W. Asselbergs, Eythór Björnsson, Søren Brunak, Mette Nyegaard, Olof Sigurdardottir, Ingileif Jonsdottir, Lars Køber, Thomas Hansen, Kari Stefansson, Gardar Sveinbjornsson, Bjorn L. Thorarinsson, Ragnar Danielsen, Gudmundur Thorgeirsson, Brynjar O. Jensson, David O Arnar, Gudmundur I. Eyjolfssson, Stefan E Matthiasson, Henrik Ullum, Valgerdur Steinthorsdottir, Olafur Th Magnusson, Kristjan F. Alexandersson, Hilma Holm, Thora Steingrimsdottir, Christian Erikstrup, Hreinn Stefansson, Anna Helgadottir, Patrick Sulem, Henning Bundgaard, Isleifur Olafsson, Christian Torp-Pedersen, Finnur F. Eiriksson, Karina Banasik, Margret Thorsteinsdottir, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Egil Ferkingstad, 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, Coronary Artery Disease, 030204 cardiovascular system & hematology, Intestinal absorption, Absorption, Coronary artery disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Basic Science, Internal medicine, Genetic variation, Genetics, Medicine, Humans, AcademicSubjects/MED00200, 030212 general & internal medicine, Genetic variability, Kransæðasjúkdómar, business.industry, Cholesterol, Phytosterol, Kólesteról, Phytosterols, ABCG5/8, Odds ratio, medicine.disease, Dietary cholesterol, Lipids, Sterols, Endocrinology, chemistry, lipids (amino acids, peptides, and proteins), Erfðarannsóknir, Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: Publisher's version (útgefin grein), Aims: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. Methods and results: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4). Conclusions: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis., This work was supported by deCODE genetics/Amgen. S.B. is supported by the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). F.W.A. is supported by University College London Hospital National Institute for Health Research Biomedical Research Centre (BRC288A).
Published: 2020

15. 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

16. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease

Author: Unnur Thorsteinsdottir, Aimee M. Deaton, Isleifur Olafsson, Egil Ferkingstad, Asmundur Oddsson, Kari Stefansson, Brynjar O. Jensson, Gisli Masson, Gudmundur I. Eyjolfsson, Sigurdur Olafsson, Einar Bjornsson, Thora Steingrimsdottir, Thorunn Rafnar, Gudmar Thorleifsson, Solveig Gretarsdottir, Florian Zink, David A. Sverrisson, Bjarni Gunnarsson, Gisli H. Halldorsson, Gardar Sveinbjornsson, Stefania Benonisdottir, Hilma Holm, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Olafur A. Stefansson, Gudmundur L. Norddahl, Ragnar P. Kristjansson, Stefan Jonsson, Olof Sigurdardottir, Gudny A. Arnadottir, Patrick Sulem, Anna Helgadottir, Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), and University of Iceland (UI)
Subjects: 0301 basic medicine, General Physics and Astronomy, Genome-wide association study, Gallstones, Disease, Genome-wide association studies, Gastroenterology, 0302 clinical medicine, Cholelithiasis, Gall bladder, Missense mutation, lcsh:Science, Enterohepatic circulation, Multidisciplinary, Symporters, Bile acid, biology, Medical genetics, 3. Good health, Hepatocyte Nuclear Factor 4, 030220 oncology & carcinogenesis, medicine.medical_specialty, læknisfr, medicine.drug_class, Science, Mutation, Missense, Organic Anion Transporters, Sodium-Dependent, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, medicine, Humans, Erfðafræði, SLC10A2, Gallsteinar, business.industry, Rannsóknir, General Chemistry, medicine.disease, Gallblaðra, 030104 developmental biology, alpha 1-Antitrypsin, biology.protein, lcsh:Q, business, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genomewide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25–1.49], P = 2.1 × 10–12, MAF = 1%; Val98Ile: OR = 1.15 [1.10–1.20], P = 1.8 × 10–10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease., We thank the individuals who participated in this study and whose contribution 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 data.
Published: 2018

17. Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Author: Unnur Thorsteinsdottir, Sridharan Rajamani, Páll Melsted, Erna V. Ivarsdottir, Jonas B. Nielsen, Jon Thor Sverrisson, David O Arnar, Maja-Lisa Løchen, Cristen J. Willer, Atli S Valgardsson, Oddgeir L. Holmen, Terje R. Pedersen, Daniel F. Gudbjartsson, Vinicius Tragante, Olafur B. Davidsson, Gardar Sveinbjornsson, Hilma Holm, Gisli H. Halldorsson, Ingileif Jonsdottir, Patrick Sulem, Marc S. Sabatine, Bjarni Torfason, Anna Helgadottir, Stefan Jonsson, Bjarni V. Halldorsson, Dan M. Roden, Solveig Gretarsdottir, Kristian Hveem, Gudmundur L. Norddahl, Ragnar P. Kristjansson, Folkert W. Asselbergs, Rosa B. Thorolfsdottir, Kari Stefansson, Gudmar Thorleifsson, and Dawood Darbar
Subjects: 0301 basic medicine, Medicine (miscellaneous), Genome-wide association study, 030204 cardiovascular system & hematology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Journal Article, Missense mutation, splice, Gene, lcsh:QH301-705.5, Sequence (medicine), Genetic association, Genetics, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Atrial fibrillation, medicine.disease, Exon skipping, 3. Good health, 030104 developmental biology, lcsh:Biology (General), VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, General Agricultural and Biological Sciences
Abstract: Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
Published: 2018

18. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease

Author: Kari Stefansson, Unnur Thorsteinsdottir, Isleifur Olafsson, Hilma Holm, Solveig Gretarsdottir, Olof Sigurdardottir, Patrick Sulem, Gudny A. Arnadottir, Gudmar Thorleifsson, Gudmundur I. Eyjolfsson, Anna Helgadottir, Gudmundur Thorgeirsson, Brynjar O. Jensson, Daniel F. Gudbjartsson, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), and University of Iceland (UI)
Subjects: 0301 basic medicine, medicine.medical_specialty, Coronary arteriosclerosis, Population, Iceland, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, Stökkbreytingar, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, HDL cholesterol, Internal medicine, medicine, Erfðafræði, Humans, Scavenger receptor, Allele, education, education.field_of_study, Gen, Kransæðasjúkdómar, Cholesterol, business.industry, Cholesterol, HDL, Kólesteról, SR-BI, Scavenger Receptors, Class B, medicine.disease, SCARB1, 030104 developmental biology, Endocrinology, Liver, chemistry, Mutation, Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: Publisher's version (útgefin grein)., Aims Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland. Methods and results Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10 -7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10 -6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10 -4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10 -18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD. Conclusion Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk., The authors thank all the individuals who participated in this study and whose contribution 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. Funding This work was supported by deCODE genetics/Amgen.
Published: 2018

19. A Missense Variant in PLEC Increases Risk of Atrial Fibrillation

Author: Anna Helgadottir, Hilma Holm, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Audur Magnusdottir, Sridharan Rajamani, Dawood Darbar, Stefania Benonisdottir, Marc S. Sabatine, Solveig Gretarsdottir, Terje R. Pedersen, Dan M. Roden, Ingileif Jonsdottir, Patrick Sulem, Rosa B. Thorolfsdottir, Kari Stefansson, David O. Arnar, Gardar Sveinbjornsson, and Olafur B. Davidsson
Subjects: Risk, Sarcomeres, 0301 basic medicine, Myosin Light Chains, Population, Mutation, Missense, Genome-wide association study, Electrocardiography, 03 medical and health sciences, Atrial Fibrillation, Humans, Medicine, Missense mutation, education, Gene, Genetic association, Genetics, education.field_of_study, business.industry, Atrial fibrillation, Odds ratio, medicine.disease, 030104 developmental biology, Genomic Structural Variation, Plectin, MYH6, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: Background Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. Objectives The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. Methods The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. Results The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10−18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10−10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. Conclusions The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.
Published: 2017

20. Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Author: Geir Selbæk, Daniel F. Gudbjartsson, Ina S. Almdahl, John Loughlin, Patrick Sulem, Asmundur Oddson, Unnur Thorsteinsdottir, Gudmundur L. Norddahl, Gisli Masson, Maryam S. Daneshpour, Jose I. Mayordomo, Helgi Jonsson, Lambertus A. Kiemeney, Thorunn Rafnar, Peter S. Braund, Solveig Gretarsdottir, Amanda Villalvilla, Jung Min Koh, Farhad Hosseinpanah, Anne Brækhus, Hannes Helgason, Nilesh J. Samani, Augustine Kong, Asgeir Sigurdsson, Unnur Styrkarsdottir, Hrefna Johannsdottir, Tormod Fladby, Louise N. Reynard, Hreinn Stefansson, Olafur Th Magnusson, Agnar Helgason, Gisli H. Halldorsson, Nelson L.S. Tang, Audur Magnusdottir, Florian Zink, Thorvaldur Ingvarsson, L. Stefan Lohmander, Gardar Sveinbjornsson, Arna B Agustsdottir, Ingileif Jonsdottir, Kari Stefansson, Anna Helgadottir, Aslaug Jonasdottir, Gerald Sulem, Corrine K. Welt, Claus Christiansen, Fereidoun Azizi, and Ole A. Andreassen
Subjects: 0301 basic medicine, Genotype, Arthroplasty, Replacement, Hip, Population, Iceland, Mutation, Missense, Gene Expression, Genome-wide association study, Kaplan-Meier Estimate, Biology, Cartilage Oligomeric Matrix Protein, Polymorphism, Single Nucleotide, Hip replacement (animal), Osteoarthritis, Hip, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, Genetics, Missense mutation, Humans, Genetic Predisposition to Disease, education, Frameshift Mutation, Allele frequency, Gene, Cells, Cultured, 030203 arthritis & rheumatology, Hip surgery, education.field_of_study, Extracellular Matrix Proteins, Genome, Human, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, 030104 developmental biology, Codon, Nonsense, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genome-Wide Association Study
Abstract: Contains fulltext : 174179.pdf (Publisher’s version ) (Closed access) We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 x 10-12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 x 10-18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.
Published: 2017

21. A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease

Author: Hannes Helgason, Gisli H. Halldorsson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Adalbjorg Jonasdottir, Margret Asgeirsdottir, Asmundur Oddsson, Kari Stefansson, Eythór Björnsson, Hilma Holm, Ragnar P. Kristjansson, Olafur Th Magnusson, Florian Zink, Dorine W. Swinkels, Isleifur Olafsson, Asgeir Sigurdsson, Olof Sigurdardottir, Arnaldur Gylfason, Gisli Masson, Anna Helgadottir, Aslaug Jonasdottir, Patrick Sulem, Birte Kehr, Daniel F. Gudbjartsson, Solveig Gretarsdottir, Gudmundur I. Eyjolfsson, Gudmundur Thorgeirsson, and Lambertus A. Kiemeney
Subjects: 0301 basic medicine, Adult, Male, DNA Copy Number Variations, Lipoproteins, Iceland, Blood lipids, Coronary Artery Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Risk Factors, Genetics, Odds Ratio, Humans, Allele, Molecular Biology, Gene, Allele frequency, Genetics (clinical), Alleles, Genetic Association Studies, biology, Base Sequence, Haptoglobins, Cholesterol, Haptoglobin, Haplotype, Genetic Variation, General Medicine, Molecular biology, Lipids, Minor allele frequency, 030104 developmental biology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], chemistry, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Mutation, biology.protein, Female, RNA Splice Sites
Abstract: Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.
Published: 2017

22. Sequence variants with large effects on cardiac electrophysiology and disease

Author: Patrick Sulem, Sigurdur S. Stephensen, David O Arnar, Emil L. Sigurdsson, Gylfi Oskarsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Sridharan Rajamani, Gudmundur Thorgeirsson, Kari Stefansson, Kristjan Norland, Daniel F. Gudbjartsson, Vinicius Tragante, Anna Helgadottir, Karl Andersen, Solveig Gretarsdottir, Olafur B. Davidsson, Jessica van Setten, Gardar Sveinbjornsson, Folkert W. Asselbergs, Ragnar Danielsen, Hilma Holm, Jon Th. Sverrisson, Læknadeild (HÍ), Faculty of Medicine (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: Male, 0301 basic medicine, Chemistry(all), Iceland, General Physics and Astronomy, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, Quantitative trait, Biochemistry, Genome-wide association studies, Electrocardiography, 0302 clinical medicine, Atrial Fibrillation, Tachycardia, Supraventricular, Blóðrásarsjúkdómar, lcsh:Science, Multidisciplinary, Cardiac electrophysiology, Heart, Atrial fibrillation, 3. Good health, Megindlegar rannsóknir, cardiovascular system, Cardiology, Female, Erfðarannsóknir, circulatory and respiratory physiology, medicine.medical_specialty, Science, Physics and Astronomy(all), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, QRS complex, Internal medicine, Cardiac conduction, medicine, Humans, cardiovascular diseases, Heart Failure, Biochemistry, Genetics and Molecular Biology(all), business.industry, Genetic Variation, Proteins, Cardiovascular genetics, General Chemistry, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Heart failure, Hjartasjúkdómar, lcsh:Q, Supraventricular tachycardia, business, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease., We thank all study subjects for their valuable participation as well as our colleagues who contributed to data collection, sample handling and genotyping. This research was conducted using the UK Biobank Resource under Application Number 24711.
Published: 2019

23. Serum magnesium and calcium levels in relation to ischemic stroke Mendelian randomization study

Author: Susanna C. Larsson, Matthew Traylor, Stephen Burgess, Giorgio B. Boncoraglio, Christina Jern, Karl Michaëlsson, Hugh S. Markus, Rainer Malik, Ganesh Chauhan, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, raci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, Berr, Claudine, Unit of Cardiovascular and Nutritional Epidemiology [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Institute of Environmental Medicine [Stockholm, Sweden], Stroke Research Group [London, UK] (Department of Brain Repair and Rehabilitation), University of London - UCL [London, UK], MRC Biostatistics Unit [Cambridge, UK], University of Cambridge [UK] (CAM), Department of Public Health and Primary Care [Cambridge, UK] (Institute of Public Health), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Section of Clinical Immunology [Uppsala, Sweden] (Department of Immunology, Genetics and Pathology), Uppsala University, Department of Surgical Sciences [Uppsala, Sweden], This work was supported by the Swedish Research Council for Health, Working Life and Welfare (Forte) and the Swedish Research Council. Hugh Markus is supported by an NIHR Senior Investigator award. His and Matthew Traylor’s work is supported by infrastructural support from the Cambridge University Hospitals Trust NIHR Biomedical Research Centre., MEGASTROKE project of the International Stroke Genetics Consortium : Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HH, Ago T, Almgren P, Amouyel P, Ay H, Bartz RM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PI, DeStefano AL, Hoed MD, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CL, Tanislav C, Tatlisumak T, Taylor KD, Thijs VN, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Amin N, Aparicio HS, Arnett DK, Attia J, Beiser AS, Berr C, Buring JE, Bustamante M, Caso V, Cheng YC, Choi SH, Chowhan A, Cullell N, Dartigues JF, Delavaran H, Delgado P, Dörr M, Engström G, Ford I, Gurpreet WS, Hamsten A, Heitsch L, Hozawa A, Ibanez L, Ilinca A, Ingelsson M, Iwasaki M, Jackson RD, Jood K, Jousilahti P, Kaffashian S, Kalra L, Kamouchi M, Kitazono T, Kjartansson O, Kloss M, Koudstaal PJ, Krupinski J, Labovitz DL, Laurie CC, Levi CR, Li L, Lind L, Lindgren CM, Lioutas V, Liu YM, Lopez OL, Makoto H, Martinez-Majander N, Matsuda K, Minegishi N, Montaner J, Morris AP, Muiño E, Müller-Nurasyid M, Norrving B, Ogishima S, Parati EA, Peddareddygari LR, Pedersen NL, Pera J, Perola M, Pezzini A, Pileggi S, Rabionet R, Riba-Llena I, Ribasés M, Romero JR, Roquer J, Rudd AG, Sarin AP, Sarju R, Sarnowski C, Sasaki M, Satizabal CL, Satoh M, Sattar N, Sawada N, Sibolt G, Sigurdsson Á, Smith A, Sobue K, Soriano-Tárraga C, Stanne T, Stine OC, Stott DJ, Strauch K, Takai T, Tanaka H, Tanno K, Teumer A, Tomppo L, Torres-Aguila NP, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Völzke H, Wakai K, Weir D, Williams SR, Wolfe CD, Wong Q, Xu H, Yamaji T, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JM, Kamatani Y, Debette S, Dichgans M., Larsson, Susanna C [0000-0003-0118-0341], Apollo - University of Cambridge Repository, and Neurology
Subjects: medicine.medical_specialty, Neurology, Heredity, Neurologi, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Calcium, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Internal medicine, Mendelian randomization, Medicine, Humans, Magnesium, 030212 general & internal medicine, Stroke, Herència (Biologia), Genètica humana, business.industry, Neurosciences, Mendelian Randomization Analysis, Odds ratio, medicine.disease, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], Intracranial Embolism, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Neurovetenskaper
Abstract: Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019

24. Genetic Variability in the Uptake of Dietary Sterols Affects the Risk of Coronary Artery Disease

Author: Gudmundur Thorgeirsson, Patrick Sulem, Finnur F. Eiriksson, Bjorn L. Thorarinsson, Eythór Björnsson, Olafur Th Magnusson, Anna Helgadottir, Isleifur Olafsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Ragnar Danielsen, Stefan E Matthiasson, Gudmundur I. Eyjolfssson, Thora Steingrimsdottir, Einar Bjornsson, Folkert W. Asselbergs, Olof Sigurdardottir, Solveig Gretarsdottir, Kari Stefansson, Daniel F. Gudbjartsson, Vinicius Tragante, Margret Thorsteinsdottir, Gudmar Thorleifsson, Kristjan F. Alexandersson, Hilma Holm, David O. Arnar, and Gardar Sveinbjornsson
Subjects: biology, Cholesterol, business.industry, ABCG8, Bioinformatics, medicine.disease, Biobank, Sterol, Intestinal absorption, Coronary artery disease, chemistry.chemical_compound, chemistry, ABCG5, biology.protein, Medicine, lipids (amino acids, peptides, and proteins), Genetic variability, business
Abstract: Background: The ATP-binding cassette (ABC) G5 and G8 transporters, encoded by the ABCG5 and ABCG8 (ABCG5/8) genes, have a key role in controlling intestinal absorption of cholesterol and other sterols, and in promoting their hepatobiliary secretion. Here, we use novel rare ABCG5/8 variants, together with common variants, to explore whether variability in sterol absorption impacts the risk of coronary artery disease (CAD). Methods: We examined 41 ABCG5/8 coding variants for association with non-high density lipoprotein (non-HDL) cholesterol in data from Iceland and the Global Lipid Genetics Consortium (N up to 472,392 combined). We tested variants for association with CAD in up to 67,130 cases and 700,075 controls from Iceland and the UK Biobank. Findings: We identified several rare ABCG5/8 coding variants with substantial impact on circulating levels of non-HDL cholesterol, and demonstrate that heterozygous carriers are at increased risk of CAD and other related diseases. Consistent with causal effects of other sterols such as phytosterols, on atherosclerotic disease we demonstrate that the degree of CAD risk conferred by both common and rare ABCG5/8 variants is greater than predicted based on their effect on non-HDL cholesterol levels. Interpretation: Our data highlight intestinal absorption as an important mechanism in the regulation of non-HDL /LDL cholesterol levels and CAD risk. Further, the results support the notion that other sterols such as phytosterols contribute to the pathogenesis of CAD. Funding Statement: The study was funded by deCODE genetics/Amgen Inc. Declaration of Interests: The authors who are affiliated with deCODE genetics/AMGEN, declare competing financial interests as employees. The remaining authors declare no competing financial interests. Ethics Approval Statement: The study was approved by The Icelandic Data Protection Authority and the National Bioethics Committee of Iceland (approvals no. VSNb201508003/03.01, VSNb2015010033/03.12 and VSNb2014100020/03.12 with amendments). All participating subjects donating biological samples signed informed consents. Personal identities of the participants and biological samples were encrypted with a third-party system approved and monitored by the Icelandic Data Protection Authority.
Published: 2019

25. Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes

Author: Unnur Thorsteinsdottir, Olafur S. Indridason, I. Jonsdottir, Rafn Benediktsson, Arnaldur Gylfason, Thorarinn Gudnason, Fridbert Jonasson, Isleifur Olafsson, Kari Stefansson, Daniel F. Gudbjartsson, Snaedis Kristmundsdottir, Gudmundur I. Eyjolfsson, Ragnar Danielsen, Hilma Holm, Anna Helgadottir, Adalbjorg Jonasdottir, Hannes P. Eggertsson, Jona Saemundsdottir, Valgerdur Steinthorsdottir, Gudmundur L. Norddahl, Olof Sigurdardottir, Gudmar Thorleifsson, Runolfur Palsson, Aslaug Jonasdottir, Bjarni V. Halldorsson, Gudmundur Thorgeirsson, Patrick Sulem, Stefan E Matthiasson, Solveig Gretarsdottir, Astradur B. Hreidarsson, Eythór Björnsson, Einar M. Valdimarsson, Læknadeild (HÍ), Faculty of Medicine (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Science and Engineering (RU), Tækni- og verkfræðideild (HR), Háskóli Íslands (HÍ), University of Iceland (UI), Reykjavik University (RU), and Háskólinn í Reykjavík (HR)
Subjects: medicine.medical_specialty, Apolipoprotein B, DNA Copy Number Variations, Iceland, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, Sykursýki, 03 medical and health sciences, 0302 clinical medicine, Lp(a), Kringles, Risk Factors, Diabetes mellitus, Internal medicine, medicine, Genetics, Mendelian randomization, Erfðafræði, Humans, Protein Isoforms, 030212 general & internal medicine, Blóðrásarsjúkdómar, Risk factor, biology, Gen, business.industry, Kransæðasjúkdómar, Lipoprotein(a), Mendelian Randomization Analysis, medicine.disease, Molecular Weight, Endocrinology, Diabetes Mellitus, Type 2, Heart failure, Case-Control Studies, biology.protein, Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: Publisher's version (útgefin grein), Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). Objectives: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. Methods: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. Results: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. Conclusions: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.
Published: 2018

26. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta

Author: Gudmundur L. Norddahl, Ragnar Danielsen, Sverrir I. Gunnarsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Rosa B. Thorolfsdottir, Berglind Adalsteinsdottir, Hilma Holm, Thorsteinn Bjornsson, Engilbert Sigurdsson, Tomas Gudbjartsson, Gardar Sveinbjornsson, Kari Stefansson, Ingileif Jonsdottir, Solveig Gretarsdottir, Patrick Sulem, Anna Helgadottir, David O Arnar, Hrodmar Helgason, Audur Magnusdottir, Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), and University of Iceland (UI)
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, Iceland, Genome-wide association study, 030204 cardiovascular system & hematology, 0302 clinical medicine, Bicuspid aortic valve, MYH6, Medicine, Missense mutation, Child, Aorta, education.field_of_study, Congenital Heart Disease, Sarcomere, Pedigree, Child, Preschool, Cardiology, Female, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Adolescent, Population, Coarctation of the aorta, Mutation, Missense, Aortic Coarctation, Sick sinus syndrome, 03 medical and health sciences, Young Adult, Clinical Research, Internal medicine, Genetics, Humans, Erfðafræði, Genetic Predisposition to Disease, education, Retrospective Studies, Myosin Heavy Chains, business.industry, Infant, Newborn, Infant, Odds ratio, DNA, medicine.disease, 030104 developmental biology, Asymptomatic Diseases, Hjartasjúkdómar, business, Cardiac Myosins, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Aims Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA. Methods and results We performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing. We found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio = 44.2, P = 5.0-10-22), encoding the lphaheavy chain subunit of cardiac myosin, an essential sarcomere protein. Approximately 20% of individuals with CoA in Iceland carry this mutation. We show that p.Arg721Trp also associates with other CHDs, in particular bicuspid aortic valve. We have previously reported broad effects of p.Arg721Trp on cardiac electrical function and strong association with sick sinus syndrome and atrial fibrillation. Conclusion Through a population approach, we found that a rare missense mutation p.Arg721Trp in the sarcomere gene MYH6 has a strong effect on the risk of CoA and explains a substantial fraction of the Icelanders with CoA. This is the first mutation associated with non-familial or sporadic form of CoA at a population level. The p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity and emphasizes the importance of sarcomere integrity for cardiac development and function. © 2018. Published by Oxford University Press on behalf of the European Society of Cardiology., deCODE genetics/Amgen, Inc. The study was approved by the Icelandic Data Protection Authority and the National Bioethics Committee of Iceland. Study approval numbers were VSN-15-053, VSN-15-016, VSN-15-056, VSN-15-058, VSN-15-114, VSN-15-057, and 10-009-S1. Written informed consent was obtained from all study participants. The study complies with the declaration of Helsinki.
Published: 2018

27. Coding variants in

Author: Rosa B, Thorolfsdottir, Gardar, Sveinbjornsson, Patrick, Sulem, Jonas B, Nielsen, Stefan, Jonsson, Gisli H, Halldorsson, Pall, Melsted, Erna V, Ivarsdottir, Olafur B, Davidsson, Ragnar P, Kristjansson, Gudmar, Thorleifsson, Anna, Helgadottir, Solveig, Gretarsdottir, Gudmundur, Norddahl, Sridharan, Rajamani, Bjarni, Torfason, Atli S, Valgardsson, Jon T, Sverrisson, Vinicius, Tragante, Oddgeir L, Holmen, Folkert W, Asselbergs, Dan M, Roden, Dawood, Darbar, Terje R, Pedersen, Marc S, Sabatine, Cristen J, Willer, Maja-Lisa, Løchen, Bjarni V, Halldorsson, Ingileif, Jonsdottir, Kristian, Hveem, David O, Arnar, Unnur, Thorsteinsdottir, Daniel F, Gudbjartsson, Hilma, Holm, and Kari, Stefansson
Abstract: Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in
Published: 2018

28. Mutations in RPL3L and MYZAP increase risk of atrial fibrillation

Author: Gudmundur L. Norddahl, Ragnar P. Kristjansson, Marc S. Sabatine, G Sveinbjörnsson, Sridharan Rajamani, Folkert W. Asselbergs, Anna Helgadottir, Ingileif Jonsdottir, Rosa B. Thorolfsdottir, Bjarni V. Halldorsson, Kari Stefansson, Erna V. Ivarsdottir, Atli S Valgardsson, Páll Melsted, David O. Arnar, Terje R. Pedersen, Olafur B. Davidsson, Maja-Lisa Løchen, Tragante, Solveig Gretarsdottir, Bjarni Torfason, Dawood Darbar, G. Thorleifsson, Unnur Thorsteinsdottir, Dan M. Roden, Hilma Holm, Gisli H. Halldorsson, Stefan Jonsson, Jon Thor Sverrisson, Patrick Sulem, and Daniel F. Gudbjartsson
Subjects: Genetics, 0303 health sciences, Mutation, Atrial fibrillation, 030204 cardiovascular system & hematology, Ribosomal RNA, Biology, medicine.disease_cause, medicine.disease, Exon skipping, Right ventricular cardiomyopathy, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Ribosomal protein, medicine, Missense mutation, splice, 030304 developmental biology
Abstract: We performed a meta-analysis of genome-wide association studies on atrial fibrillation (AF) among 14,710 cases and 373,897 controls from Iceland and 14,792 cases and 393,863 controls from the UK Biobank, focusing on low frequency coding and splice mutations, with follow-up in samples from Norway and the US. We observed associations with two missense (OR=1.19 for both) and one splice-donor mutation (OR=1.52) in RPL3L, encoding a ribosomal protein primarily expressed in skeletal muscle and heart. Analysis of 167 RNA samples from the right atrium revealed that the splice donor mutation in RPL3L results in exon skipping. AF is the first disease associated with RPL3L and RPL3L is the first ribosomal gene implicated in AF. This finding is consistent with tissue specialization of ribosomal function. We also found an association with a missense variant in MYZAP (OR=1.37), encoding a component of the intercalated discs of cardiomyocytes, the organelle harbouring most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
Published: 2017

29. A rare missense mutation inMYH6confers high risk of coarctation of the aorta

Author: Daniel F. Gudbjartsson, Engilbert Sigurdsson, Gardar Sveinbjornsson, Gudmundur L. Norddahl, Solveig Gretarsdottir, Tomas Gudbjartsson, Thorsteinn Bjornsson, Unnur Thorsteinsdottir, David O Arnar, Ingileif Jonsdottir, Berglind Adalsteinsdottir, Kari Stefansson, Patrick Sulem, Hrodmar Helgason, Audur Magnusdottir, Rosa B. Thorolfsdottir, Anna Helgadottir, Ragnar Danielsen, Hilma Holm, and Sverrir I. Gunnarsson
Subjects: Genetics, medicine.medical_specialty, Coarctation of the aorta, Atrial fibrillation, Genome-wide association study, Odds ratio, Biology, medicine.disease, Sick sinus syndrome, Bicuspid aortic valve, Internal medicine, medicine, Cardiology, Missense mutation, MYH6
Abstract: Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment1. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp inMYH6(odds ratio (OR) = 44.2,P= 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF)2. These findings suggest that p.Arg721Trp inMYH6causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development and function.
Published: 2017

30. Genetic Variation at 16q24.2 is associated with small vessel stroke

Author: Matthew, Traylor, Rainer, Malik, Mike A, Nalls, Ioana, Cotlarciuc, Farid, Radmanesh, Gudmar, Thorleifsson, Ken B, Hanscombe, Carl, Langefeld, Danish, Saleheen, Natalia S, Rost, Idil, Yet, Tim D, Spector, Jordana T, Bell, Eilis, Hannon, Jonathan, Mill, Ganesh, Chauhan, Stephanie, Debette, Joshua C, Bis, W T, Longstreth, M Arfan, Ikram, Lenore J, Launer, Sudha, Seshadri, Monica Anne, Hamilton-Bruce, Jordi, Jimenez-Conde, John W, Cole, Reinhold, Schmidt, Agnieszka, Słowik, Robin, Lemmens, Arne, Lindgren, Olle, Melander, Raji P, Grewal, Ralph L, Sacco, Tatjana, Rundek, Kathryn, Rexrode, Donna K, Arnett, Julie A, Johnson, Oscar R, Benavente, Sylvia, Wasssertheil-Smoller, Jin-Moo, Lee, Sara L, Pulit, Quenna, Wong, Stephen S, Rich, Paul I W, de Bakker, Patrick F, McArdle, Daniel, Woo, Christopher D, Anderson, Huichun, Xu, Laura, Heitsch, Myriam, Fornage, Christina, Jern, Kari, Stefansson, Unnur, Thorsteinsdottir, Solveig, Gretarsdottir, Cathryn M, Lewis, Pankaj, Sharma, Cathie L M, Sudlow, Peter M, Rothwell, Giorgio B, Boncoraglio, Vincent, Thijs, Chris, Levi, James F, Meschia, Jonathan, Rosand, Steven J, Kittner, Braxton D, Mitchell, Martin, Dichgans, Bradford B, Worrall, Hugh S, Markus, Epidemiology, and Radiology & Nuclear Medicine
Subjects: Adult, Aged, 80 and over, Male, Genetic Variation, Zinc Fingers, Middle Aged, Stroke, Genetic Loci, Cerebral Small Vessel Diseases, Stroke, Lacunar, Humans, Female, Chromosomes, Human, Pair 16, Research Articles, Aged, Genome-Wide Association Study, Research Article
Abstract: Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6). Interpretation: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394.
Published: 2017

31. Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Author: Sefanja Achterberg, Matthew Traylor, Agniesczka Slowik, Steven J. Kittner, Gudmar Thorleifsson, Steve Bevan, Rainer Malik, Robert Clarke, Martin Farrall, Michèle M. Sale, Jemma C. Hopewell, Martin Dichgans, Lars Rönnblom, Giorgio B. Boncoraglio, M. Arfan Ikram, Myriam Fornage, Johanna K. Sandling, Andre Franke, Sudha Seshadri, Björn M. Hansen, Bradford B. Worrall, Christopher Levi, Bo Norrving, Joshua C. Bis, Bruce M. Psaty, Pankaj Sharma, An Goris, Hugh S. Markus, Peter M. Rothwell, Cathie Sudlow, Guillame Pare, Arne Lindgren, James F. Meschia, Jonathan Rosand, Laura L. Kilarski, Paul I.W. de Bakker, Vincent Thijs, Joan Montaner, William J. Devan, Kari Stefanson, Cisca Wijmenga, L. Jaap Kappelle, Elizabeth G. Holliday, Braxton D. Mitchell, Unnar Thorsteinsdottir, Ale Algra, Matthew Walters, Solveig Gretarsdottir, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Risk, medicine.medical_specialty, Neurology, Genotype, INTRACEREBRAL HEMORRHAGE, LOCI, RATIONALE, Single-nucleotide polymorphism, Genome-wide association study, VARIANTS, Bioinformatics, Polymorphism, Single Nucleotide, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, DESIGN, Internal medicine, IMPUTATION, Humans, Medicine, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Cerebral Hemorrhage, 030304 developmental biology, Intracerebral hemorrhage, 0303 health sciences, Chromosomes, Human, Pair 12, business.industry, Odds ratio, ALLELES, medicine.disease, 3. Good health, Stroke, C431 Medical Genetics, Meta-analysis, RISK-FACTORS, Cardiology, Neurology (clinical), BURDEN, business, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract: Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico “look-up” of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07–1.13], p = 7.12 × 10−11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90–1.17], p = 0.695). Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
Published: 2014

32. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Author: Daniel F. Gudbjartsson, Gisli Masson, Riyaz S. Patel, Nilesh J. Samani, Alistair S. Hall, Torben Hansen, Andre M. van Rij, Christopher P. Nelson, Svati H. Shah, William E. Kraus, Isleifur Olafsson, Audur Magnusdottir, Mogens Fenger, Gregory T. Jones, Arna B Agustsdottir, Paul Nioi, Gudmundur I. Eyjolfsson, Asgeir Sigurdsson, Ulrik Abildgaard, Thorunn Rafnar, Peter Riis Hansen, Daniel J. Rader, Hannes Helgason, Gudmundur L. Norddahl, Dorine W. Swinkels, Patrick Sulem, Tessel E. Galesloot, Torsten Lauritzen, Unnur Thorsteinsdottir, Kari Stefansson, Henrik Vestergaard, Hilma Holm, Muredach P. Reilly, Anna Helgadottir, Lambertus A. Kiemeney, Olof Sigurdardottir, Allan Linneberg, Nele Friedrich, Arshed A. Quyyumi, Peter S. Braund, Allan I Levey, Aslaug Jonasdottir, Michael J.A. Williams, Niels Grarup, Gudmundur Thorgeirsson, Valgerdur Steinthorsdottir, Torben Jørgensen, Nikolaj T. Krarup, Oluf Pedersen, Gudmar Thorleifsson, Salim S. Hayek, Solveig Gretarsdottir, Ingileif Jonsdottir, and Anders Galløe
Subjects: 0301 basic medicine, Male, LIVER, Myocardial Infarction/genetics, Myocardial Infarction, Iceland, Asialoglycoprotein Receptor, Coronary Artery Disease, Haploinsufficiency, Kaplan-Meier Estimate, Genome, Coronary artery disease, chemistry.chemical_compound, Myocardial infarction, European Continental Ancestry Group/genetics, FAMILIAL HYPERCHOLESTEROLEMIA, Genetics, Aged, 80 and over, PLASMA, CHOLESTEROL, Coronary Artery Disease/genetics, General Medicine, Middle Aged, RECEPTORS, Cholesterol, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Adult, Risk, Sequence analysis, European Continental Ancestry Group, Molecular Sequence Data, Biology, Cholesterol/blood, White People, 03 medical and health sciences, medicine, LOCUS, Humans, Genetic Predisposition to Disease, ASIALOGLYCOPROTEIN, SIALIC-ACID, Aged, AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA, Asialoglycoprotein Receptor/genetics, Base Sequence, Intron, Sequence Analysis, DNA, medicine.disease, GLYCOPROTEINS, 030104 developmental biology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], chemistry, Lipoprotein
Abstract: BACKGROUNDSeveral sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.METHODSWe sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.RESULTSWe found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P = 1.0x10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0x10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P = 1.8x10(-3)).CONCLUSIONSASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)
Published: 2016

33. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. Scott, Mika Kähönen, Peter Schwarz, Psychiatry, EMGO - Mental health, Pattaro, Cristian, Teumer, Alexander, Gorski, Mathia, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthia, Foster, Meredith, Yang, Qiong, Chen, Ming Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abba, D'Adamo, ADAMO PIO, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., Van Der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andre, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, Van Duijn, Cornelia M., Saint Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Dougla, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H. Erich, Campbell, Harry, Schmidt, Helena, Wallaschofski, Henri, Völzke, Henry, Brenner, Hermann, Kroemer, Heyo K., Kramer, Holly, Lin, Honghuang, Leach, I. Mateo, Ford, Ian, Guessous, Idri, Rudan, Igor, Prokopenko, Inga, Borecki, Ingrid, Heid, Iris M., Kolcic, Ivana, Persico, Ivana, Jukema, J. Wouter, Wilson, James F., Felix, Janine F., Divers, Jasmin, Lambert, Jean Charle, Stafford, Jeanette M., Gaspoz, Jean Michel, Smith, Jennifer A., Faul, Jessica D., Wang, Jie Jin, Ding, Jingzhong, Hirschhorn, Joel N., Attia, John, Whitfield, John B., Chalmers, John, Viikari, Jorma, Coresh, Josef, Denny, Joshua C., Karjalainen, Juha, Fernandes, Jyotika K., Endlich, Karlhan, Butterbach, Katja, Keene, Keith L., Lohman, Kurt, Portas, Laura, Launer, Lenore J., Lyytikäinen, Leo Pekka, Yengo, Loic, Franke, Lude, Ferrucci, Luigi, Rose, Lynda M., Kedenko, Lyudmyla, Rao, Madhumathi, Struchalin, Maksim, Kleber, Marcus E., Cavalieri, Margherita, Haun, Margot, Cornelis, Marilyn C., Ciullo, Marina, Pirastu, Mario, De Andrade, Mariza, Mcevoy, Mark A., Woodward, Mark, Adam, Martin, Cocca, Massimiliano, Nauck, Matthia, Imboden, Medea, Waldenberger, Melanie, Pruijm, Menno, Metzger, Marie, Stumvoll, Michael, Evans, Michele K., Sale, Michele M., Kähönen, Mika, Boban, Mladen, Bochud, Murielle, Rheinberger, Myriam, Verweij, Niek, Bouatia Naji, Nabila, Martin, Nicholas G., Hastie, Nick, Probst Hensch, Nicole, Soranzo, Nicole, Devuyst, Olivier, Raitakari, Olli, Gottesman, Omri, Franco, Oscar H., Polasek, Ozren, Gasparini, Paolo, Munroe, Patricia B., Ridker, Paul M., Mitchell, Paul, Muntner, Paul, Meisinger, Christa, Smit, Johannes H., Abecasis, Goncalo R., Adair, Linda S., Alexander, Myriam, Altshuler, David, Amin, Najaf, Arking, Dan E., Arora, Pankaj, Aulchenko, Yurii, Bakker, Stephan J. L., Bandinelli, Stefania, Barroso, Ine, Beckmann, Jacques S., Beilby, John P., Bergman, Richard N., Bergmann, Sven, Bis, Joshua C., Boehnke, Michael, Bonnycastle, Lori L., Bornstein, Stefan R., Bots, Michiel L., Bragg Gresham, Jennifer L., Brand, Stefan Martin, Brand, Eva, Braund, Peter S., Brown, Morris J., Burton, Paul R., Casas, Juan P., Caulfield, Mark J., Chakravarti, Aravinda, Chambers, John C., Chandak, Giriraj R., Chang, Yen Pei C., Charchar, Fadi J., Chaturvedi, Nish, Cho, Yoon Shin, Clarke, Robert, Collins, Francis S., Collins, Rory, Connell, John M., Cooper, Jackie A., Cooper, Matthew N., Cooper, Richard S., Corsi, Anna Maria, Dörr, Marcu, Dahgam, Santosh, Danesh, John, Smith, George Davey, Day, Ian N. M., Deloukas, Pano, Denniff, Matthew, Dominiczak, Anna F., Dong, Yanbin, Doumatey, Ayo, Elliott, Paul, Elosua, Roberto, Erdmann, Jeanette, Eyheramendy, Susana, Farrall, Martin, Fava, Cristiano, Forrester, Terrence, Fowkes, F. 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S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., 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Subjects: 0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
Published: 2016

34. A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Author: Shanbeh Zienolddiny, Unnur Thorsteinsdottir, Thorunn Rafnar, Ian P. Hall, Gyda Bjornsdottir, Eva Rönmark, Thorgeir E. Thorgeirsson, Tomas Gudbjartsson, Lambertus A. Kiemeney, Aage Haugen, A. Sigvaldason, Steinn Jonsson, Hafdis T. Helgadottir, Angeles Panadero, Hronn Hardardottir, Solveig Gretarsdottir, Kari Stefansson, Anna Helgadottir, Daniel F. Gudbjartsson, Gunnar W Reginsson, Wilbur A. Franklin, Thorarinn Tyrfingsson, Helgi J Isaksson, Ingileif Jonsdottir, Gisli Masson, Asger Dirksen, Stefan E Matthiasson, Bo Lundbäck, Jose I. Mayordomo, Thorarinn Gislason, Patrick Sulem, Haseem Ashraf, Stacy Steinberg, Holly J. Wolf, and Jesper Holst Pedersen
Subjects: Male, 0301 basic medicine, Lung Neoplasms, Iceland, Receptors, Nicotinic, Nicotine, Pulmonary Disease, Chronic Obstructive, Missense mutation, Aged, 80 and over, COPD, biology, CHRNA5, Smoking, Tobacco Use Disorder, Middle Aged, 3. Good health, Psychiatry and Mental health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Medical Genetics, medicine.drug, Adult, Fagerstrom Test for Nicotine Dependence, medicine.medical_specialty, Adolescent, Mutation, Missense, White People, Peripheral Arterial Disease, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Lung cancer, Molecular Biology, Allele frequency, Genetic Association Studies, Aged, Medicinsk genetik, business.industry, Odds ratio, medicine.disease, 030104 developmental biology, Endocrinology, biology.protein, Immediate Communication, business, Neuroscience, Aortic Aneurysm, Abdominal
Abstract: Contains fulltext : 172466.pdf (Publisher’s version ) (Open Access) Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 x 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 x 10(-4)), COPD (OR=3.22, P=2.9 x 10(-4)), PAD (OR=3.47, P=9.2 x 10(-3)) and AAA (OR=6.44, P=6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 x 10(-5)), particularly for early-onset cases (P=2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha4beta2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
Published: 2016

35. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

Author: Patrick Sulem, Isleifur Olafsson, Davood Khalili, Aslaug Jonasdottir, Valgerdur Steinthorsdottir, Unnur Thorsteinsdottir, Gisli Masson, Riyaz S. Patel, Allan I. Levey, Ingibjorg J. Gudmundsdottir, Helgi Kristjansson, Fereidoun Azizi, Asgeir Sigurdsson, Thorunn Rafnar, Gudmundur I. Eyjolfsson, A Quyyumi, Asmundur Oddsson, Salim S. Hayek, Kari Stefansson, Gudmar Thorleifsson, Dorine W. Swinkels, Gudmundur Thorgeirsson, Olof Sigurdardottir, Gardar Sveinbjornsson, Anna Helgadottir, Lambertus A. Kiemeney, Hilma Holm, Maryam S. Daneshpour, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Audur Magnusdottir, Solveig Gretarsdottir, and Eirikur Hjartarson
Subjects: 0301 basic medicine, medicine.medical_specialty, Apolipoprotein B, Blood lipids, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Article, Coronary artery disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, cardiovascular diseases, Triglycerides, biology, Cholesterol, PCSK9, nutritional and metabolic diseases, medicine.disease, Lipids, 030104 developmental biology, Endocrinology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], chemistry, ABCA1, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins)
Abstract: Contains fulltext : 171919.pdf (Publisher’s version ) (Closed access) Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 x 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 x 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
Published: 2016

36. A rare variant in MYH6 is associated with high risk of sick sinus syndrome

Author: Gisli Masson, Daniel F. Gudbjartsson, Hilma Holm, Raafia Muhammad, Thomas Werge, Kari Stefansson, Gu∂mundur Thorgeirsson, Dawood Darbar, Carlo Zanon, Lambertus A. Kiemeney, Arnaldur Gylfason, Babar Parvez, Gudmar Thorleifsson, Hafdis T. Helgadottir, Dan M. Roden, Solveig Gretarsdottir, Hrafnhildur Stefansdottir, Jona Saemundsdottir, Thorunn Rafnar, Agnar Helgason, Aslaug Jonasdottir, Unnur Thorsteinsdottir, Augustine Kong, David O. Arnar, Stefan E Matthiasson, Asgeir Sigurdsson, G. Bragi Walters, Patrick Sulem, Hreinn Stefansson, and Olafur T. Magnusson
Subjects: medicine.medical_specialty, Genetics and epigenetic pathways of disease [NCMLS 6], Case-control study, Genome-wide association study, Odds ratio, Biology, medicine.disease, Penetrance, Gastroenterology, Article, Sick sinus syndrome, Molecular epidemiology [NCEBP 1], Endocrinology, Internal medicine, Genetics, medicine, Missense mutation, MYH6, Allele frequency, Molecular epidemiology Aetiology, screening and detection [NCEBP 1]
Abstract: Contains fulltext : 95597.pdf (Publisher’s version ) (Closed access) Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 x 10(2). We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
Published: 2011

37. Genetic profile of ischemic cerebrovascular disease and carotid stenosis

Author: K. Moraitis, S. Cheng, Jan Hillert, Konstantinos Kostulas, V. H. Brophy, Solveig Gretarsdottir, Andrei Manolescu, and Vasilios Kostulas
Subjects: Male, Apolipoprotein E, Pathology, medicine.medical_specialty, Angiotensinogen, Polymerase Chain Reaction, Brain Ischemia, chemistry.chemical_compound, Multiplex polymerase chain reaction, Humans, Medicine, Carotid Stenosis, Genetic Predisposition to Disease, Genotyping, Stroke, Lipoprotein lipase, Polymorphism, Genetic, Factor VII, business.industry, Vascular disease, General Medicine, Middle Aged, medicine.disease, Heterotrimeric GTP-Binding Proteins, Lipoprotein Lipase, Neurology, chemistry, Female, Neurology (clinical), business, Biomarkers, GNB3
Abstract: Objectives – Carotid artery stenosis (CS) is a major risk factor for ischemic cerebrovascular disease (ICVD) and is therefore of interest in genetic investigating. Here we report the distribution of 100 polymorphisms in 47 suspected susceptibility genes for ICVD and its risk factors. Materials and methods – Previously published markers in suspected susceptibility genes were genotyped in ICVD patients and controls (928/602). Genotyping was performed using multiplex polymerase chain reaction (PCR) and linear immobilized probe array assays. ICVD cases were subtyped according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) or subdivided into CS and non-CS patients by ultrasonography in a separate analysis. Results – Three polymorphisms located in the lipoprotein lipase (LPL), angiotensinogen (AGT) and guanine nucleotide-binding protein beta-3 (GNB3) genes were significantly associated with ICVD after correction for age and gender. The strongest association was found for the protective LPL Ser447Term polymorphism. All the significant markers showed varying frequencies in different subphenotypes of ICVD. Factor VII, apolipoprotein E and two renin polymorphisms were differentially frequent in patients with evidence of CS compared with non-CS patients. Conclusions – We have found that some previously described susceptibility polymorphisms are weakly associated with ICVD and that subdivision of patients into CS and non-CS groups may help to identify new candidate polymorphisms.
Published: 2008

38. Genetics of gene expression and its effect on disease

Author: Sonia Carlson, Steinunn Gunnarsdottir, Jeffrey R. Gulcher, Gyda Bjornsdottir, Marc L. Reitman, Valgerdur Steinthorsdottir, Daniel F. Gudbjartsson, Amy Leonardson, Hjörtur Gislason, Unnur Styrkarsdottir, Augustine Kong, Ragnheidur Fossdal, John Lamb, Inga Reynisdottir, Gudrun H. Eiriksdottir, Kristleifur Kristjansson, Valur Emilsson, Jun Zhu, Kristinn P. Magnusson, Björn Geir Leifsson, Aslaug Jonasdottir, Agnar Helgason, Anna Helgadottir, Eric E. Schadt, Solveig Gretarsdottir, Magali Mouy, Kari Stefansson, Hreinn Stefansson, Gudmar Thorleifsson, Florian Zink, Bin Zhang, G. Bragi Walters, Tryggvi Stefansson, Adalbjorg Jonasdottir, and Unnur Thorsteinsdottir
Subjects: Adult, Male, Adolescent, Quantitative Trait Loci, Iceland, Adipose tissue, Single-nucleotide polymorphism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, Body Mass Index, Cohort Studies, Mice, Animals, Humans, Obesity, Association mapping, Gene, Aged, Aged, 80 and over, Genetics, Multidisciplinary, Genome, Human, Waist-Hip Ratio, Gene Expression Profiling, Middle Aged, Phenotype, Gene expression profiling, Blood, Adipose Tissue, Gene Expression Regulation, Sample Size, Female, Lod Score, Functional genomics
Abstract: Common human diseases result from the interplay of many genes and environmental factors. Therefore, a more integrative biology approach is needed to unravel the complexity and causes of such diseases. To elucidate the complexity of common human diseases such as obesity, we have analysed the expression of 23,720 transcripts in large population-based blood and adipose tissue cohorts comprehensively assessed for various phenotypes, including traits related to clinical obesity. In contrast to the blood expression profiles, we observed a marked correlation between gene expression in adipose tissue and obesity-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to gene expression traits, including a strong genetic effect of proximal (cis) signals, with 50% of the cis signals overlapping between the two tissues profiled. Here we demonstrate an extensive transcriptional network constructed from the human adipose data that exhibits significant overlap with similar network modules constructed from mouse adipose data. A core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.
Published: 2008

39. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Author: Andrea Flex, Jeffrey R. Gulcher, Einar M. Valdimarsson, David A. Collier, Svati H. Shah, Harland Austin, Annette F. Baas, Hreinn Stefansson, Kristinn P. Magnusson, Viola Vaccarino, Bengt Lindblad, Gudmundur Thorgeirsson, Gregory T. Jones, Roberto Pola, Janet T. Powell, Gabriel J.E. Rinkel, Jan D. Blankensteijn, Shantel Weinsheimer, Gerard Tromp, Juha Hernesniemi, Helena Kuivaniemi, Thorbjorg Jonsdottir, Konstantinos Kostulas, Natzi Sakalihasan, Arshed A. Quyyumi, Dana Magnusdottir, Hulda B Magnadottir, Cisca Wijmenga, Knut Borch-Johnsen, Daniel J. Rader, Torben Jørgensen, Robert E. Ferrell, Steinunn Snorradottir, Guy M. Lenk, Valgerdur Steinthorsdottir, Torben Hansen, Raymond Limet, Diederick E. Grobbee, Solveig Gretarsdottir, Sigurlaug Sveinbjörnsdóttir, Oluf Pedersen, Anna Helgadottir, Allan I. Levey, Ebba Palsdottir, Augustine Kong, Juha Jääskeläinen, Jan Hillert, Stefan E Matthiasson, Gunnar Sigurdsson, Rafn Benediktsson, Joep A.W. Teijink, G. Bragi Walters, Eric L.G. Verhoeven, Gudmar Thorleifsson, Andre M. van Rij, Gudmundur H. Gudmundsson, Ynte M. Ruigrok, Karl Andersen, Anders Gottsäter, Gitte Andersen, Christopher B. Granger, Antti Ronkainen, Yoshiki Kyo, Mika Niemelä, Kari Stefansson, Andrei Manolescu, Unnur Thorsteinsdottir, Muredach P. Reilly, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Male, Myocardial Infarction, 030204 cardiovascular system & hematology, DISEASE, Linkage Disequilibrium, Coronary artery disease, Aortic aneurysm, 0302 clinical medicine, Gene Frequency, Risk Factors, Odds Ratio, Prevalence, Myocardial infarction, Heart, lung and circulation [UMCN 2.1], RISK, Likelihood Functions, 0303 health sciences, Cardiovascular diseases [NCEBP 14], SHEAR-STRESS, Homozygote, Middle Aged, Abdominal aortic aneurysm, ISCHEMIC-STROKE, Cardiology, Female, Chromosomes, Human, Pair 9, BEHAVIOR, Adult, Genetic Markers, medicine.medical_specialty, GENES, Biology, Polymorphism, Single Nucleotide, VALIDATION, White People, 03 medical and health sciences, Aneurysm, Internal medicine, Genetics, medicine, Humans, cardiovascular diseases, GENOME-WIDE ASSOCIATION, POLYMORPHISMS, Alleles, Aged, Probability, 030304 developmental biology, Chi-Square Distribution, Vascular disease, CDKN2BAS, Genetic Variation, Intracranial Aneurysm, Sequence Analysis, DNA, Odds ratio, medicine.disease, ATHEROSCLEROSIS, Haplotypes, Case-Control Studies, Aortic Aneurysm, Abdominal
Abstract: Contains fulltext : 70663.pdf (Publisher’s version ) (Closed access) Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.
Published: 2008

40. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Author: Thorunn Rafnar, Johan Hansson, Daniel F. Gudbjartsson, Raquel Andrés, Pablo Juberías, Margret Jakobsdottir, Solveig Gretarsdottir, Jeffrey R. Gulcher, Konstantinos Kostulas, Bardur Sigurgeirsson, Berta Saez, Kristin Thorisdottir, Rajesh Kumar, Jón Ólafsson, Margaret A. Tucker, Patrick Sulem, Veronica Magnusson, Kari Stefansson, Dominique Scherer, Simon N. Stacey, Eugene Gurzau, Stacy Steinberg, Augustine Kong, Eduardo Nagore, Lambertus A. Kiemeney, Peter Rudnai, Kristrun R. Benediktsdottir, Rafael Botella-Estrada, Annika Lindblom, Kvetoslava Koppova, Unnur Thorsteinsdottir, Matilde Grasa, Virtudes Soriano, Agnar Helgason, Steinunn G Sveinsdottir, Jose I. Mayordomo, Rafn Ragnarsson, and Alisa M. Goldstein
Subjects: Adult, Skin Neoplasms, Adolescent, Aetiology, screening and detection [ONCOL 5], Biology, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], Gene Frequency, Translational research [ONCOL 3], Genetics, medicine, Eye color, Odds Ratio, Humans, Basal cell carcinoma, Genetic Predisposition to Disease, TYRP1, Registries, Neoplasm Metastasis, Melanoma, Genetic association, Aged, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], Aged, 80 and over, Membrane Glycoproteins, Eye Color, Hereditary cancer and cancer-related syndromes [ONCOL 1], integumentary system, Monophenol Monooxygenase, Pigmentation, Haplotype, Cancer, Odds ratio, Middle Aged, medicine.disease, Molecular biology, Europe, Carcinoma, Basal Cell, Case-Control Studies, Cutaneous melanoma, Agouti Signaling Protein, Oxidoreductases, Receptor, Melanocortin, Type 1
Abstract: Contains fulltext : 69041.pdf (Publisher’s version ) (Closed access) Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.
Published: 2008

41. PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden

Author: Kari Stefansson, Unnur Thorsteinsdottir, Andrei Manolescu, Anna Helgadottir, Jeffrey R. Gulcher, Solveig Gretarsdottir, Gudmar Thorleifsson, Jan Hillert, Larus J. Gudmundsson, Vasilios Kostulas, and Konstantinos Kostulas
Subjects: Male, Linkage disequilibrium, Pathology, medicine.medical_specialty, Genotype, 5-Lipoxygenase-Activating Proteins, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Gastroenterology, Linkage Disequilibrium, Gene Frequency, Risk Factors, Polymorphism (computer science), Internal medicine, Odds Ratio, medicine, Humans, Allele, Risk factor, Allele frequency, Aged, Aged, 80 and over, Sweden, business.industry, Haplotype, Genetic Variation, Membrane Proteins, Odds ratio, Middle Aged, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, Cerebrovascular Disorders, Neurology, Female, Neurology (clinical), Carrier Proteins, business, Microsatellite Repeats
Abstract: Background Genetic variants in Phosphodiesterase 4D ( PDE4D ) and 5-lipoxygenase activating protein ( ALOX5AP ) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden. Methods Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype. Results The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P =0.063, SNP41: RR=1.57, P =0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P =0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P =0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype. Conclusion Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.
Published: 2007

42. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Author: Valur Emilsson, Shyamali Ghosh, Yuanxiu Chen, Unnur Styrkarsdottir, Ayo Doumatey, Mark E. Gurney, Juliana C.N. Chan, Kerrie Lashley, Adebowale Adeyemo, Augustine Kong, Kari Stefansson, Inga Reynisdottir, Gunnar Sigurdsson, Marten H. Hofker, Jeffrey R. Gulcher, Oluf Pedersen, Cisca Wijmenga, Hjordis Bjarnason, Wing-Yee So, Torben Hansen, Daniel J. Rader, Thorbjorg Jonsdottir, Knut Borch-Johnsen, Valgerdur Steinthorsdottir, Claus Christiansen, Guanjie Chen, Charles N. Rotimi, Gudmar Thorleifsson, Rafn Benediktsson, Torben Jørgensen, Robert L. Wilensky, Vilmundur Gudnason, Hanxia Huang, Unnur Thorsteinsdottir, Muredach P. Reilly, Adam Baker, Yu Z. Bagger, Gitte Andersen, Steinunn Snorradottir, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Ronald Ching-Wa Ma, Jie Zhou, Maggie C.Y. Ng, Solveig Gretarsdottir, Moleculaire Genetica, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: NUTRIM - R4 - Gene-environment interaction, Science in Healthy Ageing & healthcaRE (SHARE), Scientific Visualization and Computer Graphics, Host-Microbe Interactions, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Vascular Ageing Programme (VAP)
Subjects: Blood Glucose, Male, IMPACT, Transcription Factor 7-Like 1 Protein, Genome-wide association study, Type 2 diabetes, Linkage Disequilibrium, GLUCOSE, 0302 clinical medicine, Gene Frequency, Insulin Secretion, Insulin, Genetics, 0303 health sciences, SLC30A8, Intracellular Signaling Peptides and Proteins, Middle Aged, SECRETION, Female, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, STROKE, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, medicine, Humans, GENOME-WIDE ASSOCIATION, Allele frequency, CDKAL1, 030304 developmental biology, CONFERS RISK, IDENTIFICATION, Genome, Human, Case-control study, Odds ratio, medicine.disease, GENE, Endocrinology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Case-Control Studies, biology.protein, Insulin Resistance, Carrier Proteins, TCF7L2
Abstract: We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants(1), we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13 - 1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11 - 1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31 - 1.72) and 1.55 (1.23 - 1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.
Published: 2007

43. A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation

Author: David O. Arnar, Jona Saemundsdottir, Solveig Gretarsdottir, Patrick Sulem, Hrefna Johannsdottir, G Thorgeirsson, Sigurjon A. Gudjonsson, Hilma Holm, Daniel F. Gudbjartsson, Gisli Masson, Hafdis T. Helgadottir, Augustine Kong, Olafur T. Magnusson, Larry Baum, Inger Njølstad, Gunnlaugur Sigfússon, Unnur Thorsteinsdottir, Asmundur Oddsson, Kari Stefansson, Maja-Lisa Løchen, Ronald C.W. Ma, Hannes Helgason, and Jon Th. Sverrisson
Subjects: 0301 basic medicine, Male, Sarcomeres, medicine.medical_specialty, Heterozygote, Myosin Light Chains, Population, Iceland, Genes, Recessive, 030204 cardiovascular system & hematology, Frameshift mutation, Sick sinus syndrome, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Atrial Fibrillation, Medicine, Humans, Allele, education, Frameshift Mutation, Aged, Sick Sinus Syndrome, education.field_of_study, business.industry, Homozygote, Cardiac arrhythmia, Atrial fibrillation, Middle Aged, medicine.disease, Pedigree, Stroke, 030104 developmental biology, Death, Sudden, Cardiac, Case-Control Studies, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Sequence Alignment, Familial atrial fibrillation, Gene Deletion, Genome-Wide Association Study
Abstract: Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.
Published: 2015

44. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

Author: Anna Helgadottir, Helga Jonsdottir, Eric J. Topol, Jesus Sainz, Halldor Johannsson, Stefan E Matthiasson, Gudmundur Thorgeirsson, Olof Gudmundsdottir, Unnur Thorsteinsdottir, Jeffrey R. Gulcher, Gudmar Thorleifsson, Michael L. Frigge, Gudmundur Gudmundsson, Vilmundur Gudnason, Augustine Kong, Solveig Gretarsdottir, Nilesh J. Samani, Hakon Hakonarson, Einar M. Valdimarsson, Mark E. Gurney, Struan F.A. Grant, Margret B. Andresdottir, Kari Stefansson, Andrei Manolescu, Margret Thorhallsdottir, and Sigurlaug Sveinbjörnsdóttir
Subjects: Leukotriene B4, 5-Lipoxygenase-Activating Proteins, Leukotriene Production, Myocardial Infarction, Locus (genetics), Inflammation, Biology, Polymorphism, Single Nucleotide, Pathogenesis, chemistry.chemical_compound, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, 5-lipoxygenase-activating protein, Chromosomes, Human, Pair 13, Haplotype, Chromosome Mapping, Membrane Proteins, medicine.disease, Stroke, chemistry, Immunology, biology.protein, medicine.symptom, Carrier Proteins, Microsatellite Repeats
Abstract: We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
Published: 2004

45. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke

Author: Gudmundur Thorgeirsson, Shyamali Goss, Kari Stefansson, Asta Solilja Gudmundsdottir, Andrei Manolescu, Solveig Gretarsdottir, Daniel F. Gudbjartsson, Vilmundur Gudnason, Sigridur Th. Reynisdottir, Hrefna Gudmundsdottir, Malcolm Hawkins, Herdis M. Gudjonsdottir, Sif Jonsdottir, Joseph Nahmias, Sigurlaug Sveinbjörnsdóttir, Gudmar Thorleifsson, Matthildur Sigurdardottir, Finnbogi Jakobsson, Hjalti Andrason, Gudmundur Gudmundsson, Olafur B. Einarsson, Augustine Kong, Uggi Agnarsson, Jürgen Fingerle, Thorunn Gudmundsdottir, Michael L. Frigge, Sigrun M. Bjarnadottir, Thomas T. Chou, Mark E. Gurney, Thorbjorg Jonsdottir, Jeffrey R. Gulcher, and Einar M. Valdimarsson
Subjects: Gene isoform, Linkage disequilibrium, Molecular Sequence Data, Ischemia, Locus (genetics), Biology, Bioinformatics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Brain Ischemia, Pathogenesis, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Stroke, Polymorphism, Genetic, Base Sequence, Haplotype, Chromosome Mapping, Phosphodiesterase, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, Isoenzymes, 3',5'-Cyclic-AMP Phosphodiesterases, Chromosomes, Human, Pair 5, 5' Untranslated Regions, Microsatellite Repeats
Abstract: We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.
Published: 2003

46. Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12

Author: Jeffrey R. Gulcher, Klaus Lindpaintner, Einar M. Valdimarsson, Gisli Einarsson, Radinka Hadzic, Ramanjit Gill, Finnbogi Jakobsson, Sigrun M. Bjarnadottir, Solveig Gretarsdottir, Herdis M. Gudjonsdottir, Michael L. Frigge, Olafur B. Einarsson, Sif Jonsdottir, Vilmundur Gudnason, Gunnar Th. Sigurdsson, Elisabet Einarsdottir, Helgi H. Hannesson, Gudmundur Thorgeirsson, Jesus Sainz, H. Jonsson, Augustine Kong, Thorunn Gudmundsdottir, Dana Shkolny, Sigridur Th. Reynisdottir, Kari Stefansson, Uggi Agnarsson, Gudrun J. Gudlaugsdottir, and Sigurlaug Sveinbjörnsdóttir
Subjects: Genetic Markers, Male, Hypercholesterolemia, Population, Iceland, Locus (genetics), Pedigree chart, Biology, Genetic determinism, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Diabetes Mellitus, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetics(clinical), Allele, Family history, education, Stroke, Alleles, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Genome, Human, Chromosome Mapping, Articles, medicine.disease, Pedigree, Genetic marker, Hypertension, Chromosomes, Human, Pair 5, Female, Lod Score, 030217 neurology & neurosurgery
Abstract: Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P =3.9×10 −6 ). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as " STRK1, " does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.
Published: 2002
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47. Erratum: Corrigendum: Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Author: Unnur Styrkarsdottir, Hannes Helgason, Asgeir Sigurdsson, Gudmundur L Norddahl, Arna B Agustsdottir, Louise N Reynard, Amanda Villalvilla, Gisli H Halldorsson, Aslaug Jonasdottir, Audur Magnusdottir, Asmundur Oddson, Gerald Sulem, Florian Zink, Gardar Sveinbjornsson, Agnar Helgason, Hrefna S Johannsdottir, Anna Helgadottir, Hreinn Stefansson, Solveig Gretarsdottir, Thorunn Rafnar, Ina S Almdahl, Anne Brækhus, Tormod Fladby, Geir Selbæk, Farhad Hosseinpanah, Fereidoun Azizi, Jung Min Koh, Nelson L S Tang, Maryams Danesphour, Jose I Mayordomo, Corrine Welt, Peter S Braund, Nilesh J Samani, Lambertus A Kiemeney, L Stefan Lohmander, Claus Christiansen, Ole A Andreassen, arcOGEN consortium, Olafur Magnusson, Gisli Masson, Augustine Kong, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Helgi Jonsson, John Loughlin, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir, and Kari Stefansson
Subjects: Whole genome sequencing, Genotype, Genetics, Hip osteoarthritis, Computational biology, Biology
Abstract: Nat. Genet.; doi:10.1038/ng.3816; corrected online 17 April 2017 In the version of this article initially published online, the name of author Maryam S. Daneshpour was spelled incorrectly. The error has been corrected in the print, PDF and HTML versions of this article.
Published: 2017

48. Large-scale whole-genome sequencing of the Icelandic population

Author: Gisli Masson, Einar Björnsson, Hrefna Johannsdottir, Hilma Holm, Bjarni Thjodleifsson, Arnaldur Gylfason, Olafur Th Magnusson, Agnar Helgason, Asmundur Oddson, Gudmundur I. Eyjolfsson, Thora Steingrimsdottir, Thora S. Gudmundsdottir, Thorunn Rafnar, Augustine Kong, Asgeir Sigurdsson, Unnur Thorsteinsdottir, Hafdis T. Helgadottir, Sigurjon A. Gudjonsson, Olof Sigurdardottir, Søren Besenbacher, Eirikur Hjartarson, Simon N. Stacey, Daniel F. Gudbjartsson, Jon G. Jonasson, Florian Zink, David O. Arnar, Jon Th. Sverrisson, Gunnlaugur Sigfússon, Kari Stefansson, Gunnar Th. Sigurdsson, Petur Ludvigsson, G. Bragi Walters, Hildur Thorarinsdottir, Isleifur Olafsson, Ásgeir Theodórs, Hakon Gudbjartsson, Sigurdur Olafsson, Gyda Bjornsdottir, Patrick Sulem, Michael L. Frigge, Solveig Gretarsdottir, Hannes Helgason, Gisli Magnusson, Jon J. Jonsson, Bjarni V. Halldorsson, Ólafur Thorarensen, Jona Saemundsdottir, and Gudmundur Thorgeirsson
Subjects: Male, Risk, ATP Binding Cassette Transporter, Subfamily B, Myosin Light Chains, Hearing Loss, Sensorineural, Population, Bulbar Palsy, Progressive, Iceland, Thyrotropin, Genome-wide association study, Single-nucleotide polymorphism, Biology, Genome, Polymorphism, Single Nucleotide, Frameshift mutation, Receptors, G-Protein-Coupled, Gene Frequency, INDEL Mutation, Atrial Fibrillation, Genetics, Chromogranins, GTP-Binding Protein alpha Subunits, Gs, Humans, Genetic Predisposition to Disease, education, Frameshift Mutation, P-Glycoproteins, Allele frequency, Aged, Whole genome sequencing, Aged, 80 and over, education.field_of_study, Genome, Human, Liver Diseases, Molecular Sequence Annotation, Sequence Analysis, DNA, Middle Aged, Minor allele frequency, Phylogeography, Female, Genome-Wide Association Study
Abstract: Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.
Published: 2014

49. The Mitochondrial Genome of the Sperm Whale and a New Molecular Reference for Estimating Eutherian Divergence Dates

Author: Björn M. Ursing, Solveig Gretarsdottir, Axel Janke, Anette Gullberg, and Ulfur Arnason
Subjects: Mammals, Paraphyly, Genome, biology, Whale, Whales, Suina, Zoology, biology.organism_classification, Tylopoda, DNA, Mitochondrial, Evolution, Molecular, Hippopotamidae, Baleen, biology.animal, Sperm whale, Hippopotamus, Genetics, Animals, Molecular Biology, Phylogeny, Ecology, Evolution, Behavior and Systematics
Abstract: Extant cetaceans are systematically divided into two suborders: Mysticeti (baleen whales) and Odontoceti (toothed whales). In this study, we have sequenced the complete mitochondrial (mt) genome of an odontocete, the sperm whale (Physeter macrocephalus), and included it in phylogenetic analyses together with the previously sequenced complete mtDNAs of two mysticetes (the fin and blue whales) and a number of other mammals, including five artiodactyls (the hippopotamus, cow, sheep, alpaca, and pig). The most strongly supported cetartiodactyl relationship was: outgroup,((pig, alpaca), ((cow, sheep),(hippopotamus,(sperm whale,(baleen whales))))). As in previous analyses of complete mtDNAs, the sister-group relationship between the hippopotamus and the whales received strong support, making both Artiodactyla and Suiformes (pigs, peccaries, and hippopotamuses) paraphyletic. In addition, the analyses identified a sister-group relationship between Suina (the pig) and Tylopoda (the alpaca), although this relationship was not strongly supported. The paleontological records of both mysticetes and odontocetes extend into the Oligocene, suggesting that the mysticete and odontocete lineages diverged 32-34 million years before present (MYBP). Use of this divergence date and the complete mtDNAs of the sperm whale and the two baleen whales allowed the establishment of a new molecular reference, O/M-33, for dating other eutherian divergences. There was a general consistency between O/M-33 and the two previously established eutherian references, A/C-60 and E/R-50. Cetacean (whale) origin, i.e., the divergence between the hippopotamus and the cetaceans, was dated to approximately 55 MYBP, while basal artiodactyl divergences were dated to >/=65 MYBP. Molecular estimates of Tertiary eutherian divergences were consistent with the fossil record.
Published: 2000

50. New sequence variants associated with bone mineral density

Author: Tuan V. Nguyen, Daniel F. Gudbjartsson, Claus Christiansen, Jona Saemundsdottir, Solveig Gretarsdottir, Thorbjorg Jonsdottir, Jeffrey R. Gulcher, John A. Eisman, Gunnar Sigurdsson, Steinunn Snorradottir, Kari Stefansson, G. Bragi Walters, Unnur Thorsteinsdottir, Unnur Styrkarsdottir, Thorvaldur Ingvarsson, Augustine Kong, Peter Alexandersen, and Bjarni V. Halldorsson
Subjects: Male, Bone mineral, Genetics, Base Sequence, Bone density, Mineralogy, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, European descent, ADAM19, Fractures, Bone, Bone Density, Polymorphism (computer science), Humans, Wounds and Injuries, Female, Gene, Chromosomes, Human, Pair 17, Genome-Wide Association Study, Sequence (medicine)
Abstract: In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a follow-up in 8,510 subjects of European descent, we identified four new genome-wide significant loci. These are near the SOST gene at 17q21, the MARK3 gene at 14q32, the SP7 gene at 12q13 and the TNFRSF11A (RANK) gene at 18q21. Furthermore, nonsynonymous SNPs in the C17orf53, LRP4, ADAM19 and IBSP genes were suggestively associated with bone density.
Published: 2008

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