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1. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author: Momoko Horikoshi, Reedik Mӓgi, Martijn van de Bunt, Ida Surakka, Antti-Pekka Sarin, Anubha Mahajan, Letizia Marullo, Gudmar Thorleifsson, Sara Hӓgg, Jouke-Jan Hottenga, Claes Ladenvall, Janina S Ried, Thomas W Winkler, Sara M Willems, Natalia Pervjakova, Tõnu Esko, Marian Beekman, Christopher P Nelson, Christina Willenborg, Steven Wiltshire, Teresa Ferreira, Juan Fernandez, Kyle J Gaulton, Valgerdur Steinthorsdottir, Anders Hamsten, Patrik K E Magnusson, Gonneke Willemsen, Yuri Milaneschi, Neil R Robertson, Christopher J Groves, Amanda J Bennett, Terho Lehtimӓki, Jorma S Viikari, Johan Rung, Valeriya Lyssenko, Markus Perola, Iris M Heid, Christian Herder, Harald Grallert, Martina Müller-Nurasyid, Michael Roden, Elina Hypponen, Aaron Isaacs, Elisabeth M van Leeuwen, Lennart C Karssen, Evelin Mihailov, Jeanine J Houwing-Duistermaat, Anton J M de Craen, Joris Deelen, Aki S Havulinna, Matthew Blades, Christian Hengstenberg, Jeanette Erdmann, Heribert Schunkert, Jaakko Kaprio, Martin D Tobin, Nilesh J Samani, Lars Lind, Veikko Salomaa, Cecilia M Lindgren, P Eline Slagboom, Andres Metspalu, Cornelia M van Duijn, Johan G Eriksson, Annette Peters, Christian Gieger, Antti Jula, Leif Groop, Olli T Raitakari, Chris Power, Brenda W J H Penninx, Eco de Geus, Johannes H Smit, Dorret I Boomsma, Nancy L Pedersen, Erik Ingelsson, Unnur Thorsteinsdottir, Kari Stefansson, Samuli Ripatti, Inga Prokopenko, Mark I McCarthy, Andrew P Morris, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Published: 2015
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2. 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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3. Development and application of genomic control methods for genome-wide association studies using non-additive models.

Author: Yakov A Tsepilov, Janina S Ried, Konstantin Strauch, Harald Grallert, Cornelia M van Duijn, Tatiana I Axenovich, and Yurii S Aulchenko
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) comprise a powerful tool for mapping genes of complex traits. However, an inflation of the test statistic can occur because of population substructure or cryptic relatedness, which could cause spurious associations. If information on a large number of genetic markers is available, adjusting the analysis results by using the method of genomic control (GC) is possible. GC was originally proposed to correct the Cochran-Armitage additive trend test. For non-additive models, correction has been shown to depend on allele frequencies. Therefore, usage of GC is limited to situations where allele frequencies of null markers and candidate markers are matched. In this work, we extended the capabilities of the GC method for non-additive models, which allows us to use null markers with arbitrary allele frequencies for GC. Analytical expressions for the inflation of a test statistic describing its dependency on allele frequency and several population parameters were obtained for recessive, dominant, and over-dominant models of inheritance. We proposed a method to estimate these required population parameters. Furthermore, we suggested a GC method based on approximation of the correction coefficient by a polynomial of allele frequency and described procedures to correct the genotypic (two degrees of freedom) test for cases when the model of inheritance is unknown. Statistical properties of the described methods were investigated using simulated and real data. We demonstrated that all considered methods were effective in controlling type 1 error in the presence of genetic substructure. The proposed GC methods can be applied to statistical tests for GWAS with various models of inheritance. All methods developed and tested in this work were implemented using R language as a part of the GenABEL package.
Published: 2013
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4. Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.

Author: Gian Andri Thun, Medea Imboden, Ilaria Ferrarotti, Ashish Kumar, Ma'en Obeidat, Michele Zorzetto, Margot Haun, Ivan Curjuric, Alexessander Couto Alves, Victoria E Jackson, Eva Albrecht, Janina S Ried, Alexander Teumer, Lorna M Lopez, Jennifer E Huffman, Stefan Enroth, Yohan Bossé, Ke Hao, Wim Timens, Ulf Gyllensten, Ozren Polasek, James F Wilson, Igor Rudan, Caroline Hayward, Andrew J Sandford, Ian J Deary, Beate Koch, Eva Reischl, Holger Schulz, Jennie Hui, Alan L James, Thierry Rochat, Erich W Russi, Marjo-Riitta Jarvelin, David P Strachan, Ian P Hall, Martin D Tobin, Morten Dahl, Sune Fallgaard Nielsen, Børge G Nordestgaard, Florian Kronenberg, Maurizio Luisetti, and Nicole M Probst-Hensch
Subjects: Genetics, QH426-470
Abstract: Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF
Published: 2013
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5. A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.

Author: Ida Surakka, Aaron Isaacs, Lennart C Karssen, Pirkka-Pekka P Laurila, Rita P S Middelberg, Emmi Tikkanen, Janina S Ried, Claudia Lamina, Massimo Mangino, Wilmar Igl, Jouke-Jan Hottenga, Vasiliki Lagou, Pim van der Harst, Irene Mateo Leach, Tõnu Esko, Zoltán Kutalik, Nicholas W Wainwright, Maksim V Struchalin, Antti-Pekka Sarin, Antti J Kangas, Jorma S Viikari, Markus Perola, Taina Rantanen, Ann-Kristin Petersen, Pasi Soininen, Asa Johansson, Nicole Soranzo, Andrew C Heath, Theodore Papamarkou, Inga Prokopenko, Anke Tönjes, Florian Kronenberg, Angela Döring, Fernando Rivadeneira, Grant W Montgomery, John B Whitfield, Mika Kähönen, Terho Lehtimäki, Nelson B Freimer, Gonneke Willemsen, Eco J C de Geus, Aarno Palotie, Manj S Sandhu, Dawn M Waterworth, Andres Metspalu, Michael Stumvoll, André G Uitterlinden, Antti Jula, Gerjan Navis, Cisca Wijmenga, Bruce H R Wolffenbuttel, Marja-Riitta Taskinen, Mika Ala-Korpela, Jaakko Kaprio, Kirsten O Kyvik, Dorret I Boomsma, Nancy L Pedersen, Ulf Gyllensten, James F Wilson, Igor Rudan, Harry Campbell, Peter P Pramstaller, Tim D Spector, Jacqueline C M Witteman, Johan G Eriksson, Veikko Salomaa, Ben A Oostra, Olli T Raitakari, H-Erich Wichmann, Christian Gieger, Marjo-Riitta Järvelin, Nicholas G Martin, Albert Hofman, Mark I McCarthy, Leena Peltonen, Cornelia M van Duijn, Yurii S Aulchenko, Samuli Ripatti, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Published: 2011
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6. Discovery of sexual dimorphisms in metabolic and genetic biomarkers.

Author: Kirstin Mittelstrass, Janina S Ried, Zhonghao Yu, Jan Krumsiek, Christian Gieger, Cornelia Prehn, Werner Roemisch-Margl, Alexey Polonikov, Annette Peters, Fabian J Theis, Thomas Meitinger, Florian Kronenberg, Stephan Weidinger, Heinz Erich Wichmann, Karsten Suhre, Rui Wang-Sattler, Jerzy Adamski, and Thomas Illig
Subjects: Genetics, QH426-470
Abstract: Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values
Published: 2011
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7. Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.

Author: Carola Marzi, Eva Albrecht, Pirro G Hysi, Vasiliki Lagou, Melanie Waldenberger, Anke Tönjes, Inga Prokopenko, Katharina Heim, Hannah Blackburn, Janina S Ried, Marcus E Kleber, Massimo Mangino, Barbara Thorand, Annette Peters, Christopher J Hammond, Harald Grallert, Bernhard O Boehm, Peter Kovacs, Ludwig Geistlinger, Holger Prokisch, Bernhard R Winkelmann, Tim D Spector, H-Erich Wichmann, Michael Stumvoll, Nicole Soranzo, Winfried März, Wolfgang Koenig, Thomas Illig, and Christian Gieger
Subjects: Genetics, QH426-470
Abstract: Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10(-111)) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10(-11)) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins.
Published: 2010
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8. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.

Author: Tamra E Meyer, Germaine C Verwoert, Shih-Jen Hwang, Nicole L Glazer, Albert V Smith, Frank J A van Rooij, Georg B Ehret, Eric Boerwinkle, Janine F Felix, Tennille S Leak, Tamara B Harris, Qiong Yang, Abbas Dehghan, Thor Aspelund, Ronit Katz, Georg Homuth, Thomas Kocher, Rainer Rettig, Janina S Ried, Christian Gieger, Hanna Prucha, Arne Pfeufer, Thomas Meitinger, Josef Coresh, Albert Hofman, Mark J Sarnak, Yii-Der Ida Chen, André G Uitterlinden, Aravinda Chakravarti, Bruce M Psaty, Cornelia M van Duijn, W H Linda Kao, Jacqueline C M Witteman, Vilmundur Gudnason, David S Siscovick, Caroline S Fox, Anna Köttgen, Genetic Factors for Osteoporosis Consortium, and Meta Analysis of Glucose and Insulin Related Traits Consortium
Subjects: Genetics, QH426-470
Abstract: Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p
Published: 2010
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9. Establishment of a high-content imaging assay for tau aggregation in hiPSC-derived neurons differentiated from two protocols to routinely evaluate compounds and genetic perturbations

Author: Lamiaa Bahnassawy, Nathalie Nicolaisen, Christopher Untucht, Benjamin Mielich-Süss, Lydia Reinhardt, Janina S. Ried, Martina P. Morawe, Daniela Geist, Anja Finck, Elke Käfer, Jürgen Korffmann, Matthew Townsend, Brinda Ravikumar, Viktor Lakics, Miroslav Cik, and Peter Reinhardt
Subjects: Neurodegenerative diseases, In vitro screening, Human pluripotent stem cells, High content screening, Small molecule screening, Gene knockdown screening, Medicine (General), R5-920, Biotechnology, TP248.13-248.65
Abstract: Aberrant protein aggregation is a pathological cellular hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), where the tau protein is aggregating, forming neurofibrillary tangles (NFTs), and propagating from neuron to neuron. These processes have been linked to disease progression and a decline in cognitive function. Various therapeutic approaches aim at the prevention or reduction of tau aggregates in neurons. Human induced pluripotent stem cells (hiPSCs) are a very valuable tool in neuroscience discovery, as they offer access to potentially unlimited amounts of cell types that are affected in disease, including cortical neurons, for in vitro studies. We have generated an in vitro model for tau aggregation that uses hiPSC – derived neurons expressing an aggregation prone, fluorescently tagged version of the human tau protein after lentiviral transduction. Upon addition of tau seeds in the form of recombinant sonicated paired helical filaments (sPHFs), the neurons show robust, disease-like aggregation of the tau protein. The model was developed as a plate-based high content screening assay coupled with an image analysis algorithm to evaluate the impact of small molecules or genetic perturbations on tau. We show that the assay can be used to evaluate small molecules or screen targeted compound libraries. Using siRNA-based gene knockdown, genes of interest can be evaluated, and we could show that a targeted gene library can be screened, by screening nearly 100 deubiquitinating enzymes (DUBs) in that assay. The assay uses an imaging-based readout, a relatively short timeline, quantifies the extent of tau aggregation, and also allows the assessment of cell viability. Furthermore, it can be easily adapted to different hiPSC lines or neuronal subtypes. Taken together, this complex and highly relevant approach can be routinely applied on a weekly basis in the screening funnels of several projects and generates data with a turnaround time of approximately five weeks.
Published: 2024
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10. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023

11. Tau pathology vulnerable neuronal subpopulation in Alzheimer’s disease

Author: Taekyung Kwon, Gen Lin, Sarah E. Chancellor, Astrid Wachter, Aicha Abdourahman, Rachel E Bennett, Fan Liao, Timothy Pastika, Joseph A. Tamm, Nandini Venkat, Kiran Yanamandra, Yelena Grinberg, Markus P. Kummer, Sudeshna Das, Tammy L. Dellovade, Eric H Karran, Robert V. Talanian, Knut Biber, Janina S Ried, Alberto Serrano‐Pozo, Xavier Langlois, and Bradley T. Hyman
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022

12. Multi‐tissue profiling of RNA and DNA‐methylation signatures of progressive tau neuropathology in tau transgenic mice

Author: Ameya S Kulkarni, Justin Ideozu, Aparna Vasanthakumar, Areej Ammar, Erin Murphy, Elizabeth Asque, Christian Plaas, Corinna Klein, Janina S Ried, Stefan Barghorn, and Laura Gasparini
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022

13. Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer’s disease etiopathogenesis

Author: Philippe Amouyel, Pablo Garcia-Gonzalez, Qiong Yang, Joshua C. Bis, Alfredo Ramírez, Luca Kleineidam, Carmen Antúnez-Almagro, Myriam Fornage, Claudia L. Satizabal, Adela Orellana, Rebecca Sims, Juan Marín-Muñoz, Julie Williams, Eric Boerwinkle, Céline Bellenguez, María Eugenia Sáez, Laura Madrid, Rui Xia, Luis Miguel Real, Janina S. Ried, Xueqiu Jian, Shahzad Ahmad, M. Arfan Ikram, Sonia Moreno-Grau, Alzheimer’s Disease Neuroimaging Initiative (Adni), Cornelia M Van Duijn, Sudha Seshadri, Pamela V. Martino Adami, Vincent Damotte, Anita L. DeStefano, Itziar de Rojas, Benjamin Grenier-Boley, Antonio González-Pérez, Agustín Ruiz, Alfredo Cabrera-Socorro, Fuensanta Noguera-Perea, Jean-Charles Lambert, and Epidemiology
Subjects: Apolipoprotein E, Aging, Genome-wide association study, Computational biology, Disease, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, ddc:610, Risk factor, Allele, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, Haplotype, biomarkers, Cell Biology, medicine.disease, 3. Good health, lipids (amino acids, peptides, and proteins), business, Alzheimer’s disease, APOE, 030217 neurology & neurosurgery, Research Paper, integrative analysis
Abstract: Alzheimer’s disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analyzed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterized a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
Published: 2021

14. SETD7-mediated monomethylation is enriched on soluble Tau in Alzheimer’s disease

Author: Nuria Prat Oriol, Yu Tian, Borja Gomez Ramos, Laura Gasparini, Xue Wang, Vera Schwärzler, Maria Bichmann, Ebru Ercan-Herbst, Liang Jin, Marie Neu, David C. Schöndorf, Dagmar E. Ehrnhoefer, Chenqi Hu, Janina S. Ried, Annabelle Schlüter, and Per Haberkant
Subjects: 0301 basic medicine, Methyltransferase, Neurite, Mice, Transgenic, tau Proteins, Proteomics, Methylation, Mice, Protein methyl transferase, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Lysine methylation, mental disorders, medicine, Animals, Humans, RC346-429, Molecular Biology, Chemistry, Lysine, RC952-954.6, Histone-Lysine N-Methyltransferase, Human brain, medicine.disease, Cell biology, Alzheimer, Malaltia d', 030104 developmental biology, medicine.anatomical_structure, Geriatrics, Nuclear tau, Phosphorylation, Posttranslational modification, Neurology. Diseases of the nervous system, Neurology (clinical), Tauopathy, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Nuclear localization sequence, Research Article
Abstract: Background: Human tauopathies including Alzheimer's disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, which parallel the formation of insoluble Tau aggregates, neuronal dysfunction and degeneration. While PTMs on aggregated Tau have been studied in detail, much less is known about the modification patterns of soluble Tau. Furthermore, PTMs other than phosphorylation have only come into focus recently and are still understudied. Soluble Tau species are likely responsible for the spreading of pathology during disease progression and are currently being investigated as targets for immunotherapies. A better understanding of their biochemical properties is thus of high importance. Methods: We used a mass spectrometry approach to characterize Tau PTMs on a detergent-soluble fraction of human AD and control brain tissue, which led to the discovery of novel lysine methylation events. We developed specific antibodies against Tau methylated at these sites and biochemically characterized methylated Tau species in extracts from human brain, the rTg4510 mouse model and in hiPSC-derived neurons. Results: Our study demonstrates that methylated Tau levels increase with Tau pathology stage in human AD samples as well as in a mouse model of Tauopathy. Methylated Tau is enriched in soluble brain extracts and is not associated with hyperphosphorylated, high molecular weight Tau species. We also show that in hiPSC-derived neurons and mouse brain, methylated Tau preferentially localizes to the cell soma and nuclear fractions and is absent from neurites. Knock down and inhibitor studies supported by proteomics data led to the identification of SETD7 as a novel lysine methyltransferase for Tau. SETD7 specifically methylates Tau at K132, an event that facilitates subsequent methylation at K130. Conclusions: Our findings indicate that methylated Tau has a specific somatic and nuclear localization, suggesting that the methylation of soluble Tau species may provide a signal for their translocation to different subcellular compartments. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may shed light onto this disease-associated phenomenon. Funding: Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research
Published: 2021

15. Sample size calculations for detecting disease-modifying osteoarthritis drug effects on the incidence of end-stage knee osteoarthritis in clinical trials: Data from the Osteoarthritis Initiative

Author: Jeffrey B. Driban, Janina S. Ried, Klaus Flechsenhar, Lori Lyn Price, and Timothy E. McAlindon
Subjects: Male, medicine.medical_specialty, Databases, Factual, Knee Joint, medicine.medical_treatment, Knee replacement, Osteoarthritis, Rheumatology, medicine, Humans, Cumulative incidence, Arthroplasty, Replacement, Knee, Reimbursement, Aged, business.industry, Incidence, Incidence (epidemiology), Middle Aged, Osteoarthritis, Knee, medicine.disease, Clinical trial, Treatment Outcome, Anesthesiology and Pain Medicine, Clinical research, Research Design, Sample size determination, Antirheumatic Agents, Sample Size, Disease Progression, Physical therapy, Female, business
Abstract: Objective We previously published data representing calculations for sample sizes assuming that the reduction of the incidence of knee joint replacement (KJR) would be an endpoint to prove efficacy of a disease-modifying drug in osteoarthritis (DMOAD). The sample sizes required for such hypothetical studies appeared to be high, rendering those studies unrealistic in the clinical research setting for practical reasons. The purpose of this work is to calculate sample sizes for hypothetical trials for DMOAD efficacy using a proxy for reaching end-stage knee osteoarthritis (esKOA) as an endpoint. Methods Based on a sub-population of the Osteoarthritis Initiative, the cumulative incidence for both esKOA and KJR were calculated for a period of four years. The sample sizes of hypothetical DMOAD trials were then calculated for particular sub-cohorts of the OAI subpopulation, subdividing the groups according to age, Kellgren–Lawrence (KL) grades and gender. Results Both the incidence for esKOA and for KJR over the four year period increase along with rising age, severity of OA and being female. The sample sizes to detect DMOAD efficacy are considerably smaller if reduction of the incidence of esKOA is chosen as an endpoint instead of reduction of the incidence of KJR. Conclusion In the future, generating health-economic data may become increasingly important to gain reimbursement. By choosing esKOA as an endpoint in DMOAD trials, we are able to show in our work that clinical trials in the field of OA are feasible, merely including a few hundred study participants per study arm.
Published: 2019

16. Can OMICS data help us to understand the mechanisms of APOE?

Author: María Eugenia Sáez, Alfredo Ramirez, Janina S. Ried, Sonia Moreno-Grau, Agustín Ruiz, Antonio González-Pérez, and Laura Madrid
Subjects: Apolipoprotein E, Apolipoprotein B, biology, Epidemiology, business.industry, Health Policy, Disease, Computational biology, Omics data, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, biology.protein, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2020

17. Multilayer OMICS characterization of APOE‐modulated isogenic hiPSCs elucidates cell‐type–specific mechanisms modified by APOE: A study of the IMI ADAPTED Consortium

Author: Peter Reinhardt, Alfredo Cabrera Socorro, Eric G. Mohler, Margot H.M. Bakker, Marco Rocha Curado, Francesco V. Rao, Janina S. Ried, Laura Madrid, Armel Nicolas, Lamiaa Bahnassawy, Clara Grezella, Gayathri Ramaswamy, María Eugenia Sáez, and Heyne Lee
Subjects: Genetics, Apolipoprotein E, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Systems biology, Cell type specific, Neurology (clinical), Geriatrics and Gerontology, Biology, Omics
Published: 2020

18. Characterization of transcriptional and proteomics changes in brain cells derived from isogenic hiPSCs reveals cell type–and genotype‐specific mechanisms modified by APOE

Author: Janina S. Ried, Heyne Lee, Marco Rocha Curado, Clara Grezella, Armel Nicolas, Gayathri Ramaswamy, María Eugenia Sáez, Lamiaa Bahnassawy, Laura Madrid, Eric G. Mohler, Francesco V. Rao, Peter Reinhardt, Alfredo Cabrera Socorro, and Margot H.M. Bakker
Subjects: Genetics, Apolipoprotein E, Cell type, Apolipoprotein B, biology, Epidemiology, Health Policy, Disease, Proteomics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Genotype, biology.protein, Neurology (clinical), Geriatrics and Gerontology
Published: 2020

19. Modelling AD‐relevant pathophysiology in neurons, astrocytes and microglia from two complete sets of isogenic iPSC lines generated by the ADAPTED project

Author: Peter Reinhardt, Alfredo Cabrera Socorro, Clara Grezella, Bjørn Holst, Oliver Brüstle, Christian Clausen, Teresa Silva Lourenco, Agustín Ruiz, Carlos Vicario, Lamiaa Bahnassawy, Benjamin Schmid, Janina S. Ried, Gayathri Ramaswamy, Michael Peitz, Keiryn Bennett, María Eugenia Sáez, and Margot H.M. Bakker
Subjects: Microglia, Apolipoprotein B, Epidemiology, Health Policy, Disease, Biology, Pathophysiology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, medicine, biology.protein, Neurology (clinical), Geriatrics and Gerontology, Neuroscience
Published: 2020

20. Proteomic, metabolomic, and transcriptomic examination of APOE transgenic mice

Author: Armel Nicolas, Francesco V. Rao, Thomas Hankemeier, Marco Rocha Curado, Lamiaa Bahnassawy, Janina S. Ried, Gayathri Ramaswamy, Isabelle Kohler, Eric G. Mohler, María Eugenia Sáez, Margot H.M. Bakker, and Peter Reinhardt
Subjects: Genetics, Apolipoprotein E, Genetically modified mouse, Epidemiology, Health Policy, Systems biology, Biology, Omics, Transcriptome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Metabolomics, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology
Published: 2020

21. Identification of APOE phenotypes in microglia and neurons derived from isogenic hips cells: A study of the IMI ADAPTED consortium

Author: Viktor Lakics, Margot H.M. Bakker, Gayathri Ramaswamy, Janina S. Ried, Francesco V. Rao, Lamiaa Bahnassawy, María Eugenia Sáez, Juergen Korffmann, Oliver Brüstle, Clara Grezella, Marco Rocha Curado, Heyne Lee, M Cik, Armel Nicolas, Michael Peitz, Eric G. Mohler, Peter Reinhardt, Alfredo Cabrera Socorro, Johanna Buchheit, Charlotte Kaplan, Christopher Untucht, and Santos Mañes
Subjects: Apolipoprotein E, Microglia, Epidemiology, Health Policy, Biology, Phenotype, Cell biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, medicine, Identification (biology), Neurology (clinical), Geriatrics and Gerontology, Stem cell, Induced pluripotent stem cell
Published: 2020

22. APOE and sex‐stratified genome‐wide meta‐analyses of Alzheimer’s disease

Author: Agustín Ruiz, Janina S. Ried, Sonia Moreno-Grau, María Eugenia Sáez, Laura Madrid, Alfredo Ramirez, and Antonio González-Pérez
Subjects: Genetics, Apolipoprotein E, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Genome
Published: 2020

23. An hiPSC‐based genetic screening system to model aggregation of tau protein allows the identification and validation of possible targets for Alzheimer’s disease therapies

Author: Peter Reinhardt, Christopher Untucht, Juergen Korffmann, Justine Manos, Viktor Lakics, Daniela Geist, Nathalie Guillen, Janina S. Ried, and M Cik
Subjects: biology, Epidemiology, Health Policy, Tau protein, Computational biology, Disease, Model aggregation, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, biology.protein, Identification (biology), Neurology (clinical), Geriatrics and Gerontology
Published: 2020

24. Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-Derived Neurons: A Multi-Site Omics Study

Author: George Nicholson, Lyle Armstrong, Caroline Muschet, Adam E. Handel, Wendy E. Heywood, Eshita Sharma, Pieter J. Peeters, Philip W. Brownjohn, Frank Wessely, Georg C. Terstappen, Carlo Cusulin, Majlinda Lako, Katharina Janssen, Viktor Lakics, Satyan Chintawar, Kevin Mills, Jerzy Adamski, Thomas Barta, Anna Baud, Caleb Webber, Viola Volpato, Moustafa Attar, Roberta De Filippis, Janina S. Ried, Frederick J. Livesey, Peter Reinhardt, Martin Graf, Cynthia Sandor, Jérôme Nicod, Rory Bowden, M. Zameel Cader, Sarah E. Newey, Ines Royaux, Emma S. Whiteley, Aanna Artati, Victoria Stubbs, Paul Gissen, James Smith, An Verheyen, Christoph Patsch, Klaus Christensen, Colin J. Akerman, Smith, James [0000-0001-9131-5849], Brownjohn, Phil [0000-0002-4707-3077], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Proteomics, induced pluripotent stem cell, Genotype, Cellular differentiation, molecular profiling, Induced Pluripotent Stem Cells, Computational biology, Biology, single-cell sequencing, Biochemistry, Article, Cell Line, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Genetics, cross-site experimental variation, Humans, Induced pluripotent stem cell, lcsh:QH301-705.5, reproducibility, Regulation of gene expression, Neurons, lcsh:R5-920, Reproducibility, Cortical Neurons, Cross-site Experimental Variation, Gene Expression Profile, Induced Pluripotent Stem Cell, Molecular Profiling, Proteomic Profiles, Public-private Partnership, Single-cell Sequencing, Stembancc, cortical neurons, Reproducibility of Results, Cell Differentiation, Cell Biology, proteomic profiles, Phenotype, 3. Good health, public-private partnership, 030104 developmental biology, lcsh:Biology (General), Single cell sequencing, Gene Expression Regulation, gene expression profile, lcsh:Medicine (General), Factor Analysis, Statistical, 030217 neurology & neurosurgery, Developmental Biology, stembancc
Abstract: Summary Reproducibility in molecular and cellular studies is fundamental to scientific discovery. To establish the reproducibility of a well-defined long-term neuronal differentiation protocol, we repeated the cellular and molecular comparison of the same two iPSC lines across five distinct laboratories. Despite uncovering acceptable variability within individual laboratories, we detect poor cross-site reproducibility of the differential gene expression signature between these two lines. Factor analysis identifies the laboratory as the largest source of variation along with several variation-inflating confounders such as passaging effects and progenitor storage. Single-cell transcriptomics shows substantial cellular heterogeneity underlying inter-laboratory variability and being responsible for biases in differential gene expression inference. Factor analysis-based normalization of the combined dataset can remove the nuisance technical effects, enabling the execution of robust hypothesis-generating studies. Our study shows that multi-center collaborations can expose systematic biases and identify critical factors to be standardized when publishing novel protocols, contributing to increased cross-site reproducibility., Highlights • Cross-site reproducibility in iPSC-based molecular experiments is poor • Factor analysis-based normalization can be used to analyze nuisance variation • External validation of iPSC experimental molecular data is critical for reproducibility • Collaborative studies are needed to reveal systematic biases to improve reproducibility, In this article, Lakics and colleagues show that, while individual laboratories are able to identify consistent molecular and seemingly statistically robust differences between iPSC neuronal models, cross-site reproducibility is poor. Their findings support multi-center collaborations to expose systematic biases and identify critical factors to be standardized to improve reproducibility in iPSC-based molecular experiments.
Published: 2018

25. A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms[S]

Author: Salome Mack, Stefan Coassin, Rico Rueedi, Noha A. Yousri, Ilkka Seppälä, Christian Gieger, Sebastian Schönherr, Lukas Forer, Gertraud Erhart, Pedro Marques-Vidal, Janina S. Ried, Gerard Waeber, Sven Bergmann, Doreen Dähnhardt, Andrea Stöckl, Olli T. Raitakari, Mika Kähönen, Annette Peters, Thomas Meitinger, Konstantin Strauch, Ludmilla Kedenko, Bernhard Paulweber, Terho Lehtimäki, Steven C. Hunt, Peter Vollenweider, Claudia Lamina, and Florian Kronenberg
Subjects: genetics, epidemiology, QD415-436, Biochemistry, coronary artery disease
Abstract: High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10−30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10−10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the populationŉs mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.
Published: 2017

26. The genetic architecture of type 2 diabetes

Author: Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
Published: 2016

27. Harmonising and linking biomedical and clinical data across disparate data archives to enable integrative cross-biobank research

Author: Tõnu Esko, Ola Spjuth, Huei-Yi Shen, Eco J. C. de Geus, Mats-Ake Persson, Andres Metspalu, Jon Heggland, Leif Groop, Sandra Ose, Isabel Fortier, Johan Rung, Claes Ladenvall, Dorret I. Boomsma, Cornelia M. van Duijn, Samuli Ripatti, Linda Zaharenko, Arnulf Langhammer, Jouke-Jan Hottenga, Annette Peters, Janis Klovins, Christian Gieger, Jennifer R. Harris, Joern Dietrich, Kristian Hveem, Inga Prokopenko, Juni Palmgren, Melanie Waldenberger, Mark I. McCarthy, Jani Heikkinen, Nancy L. Pedersen, Janina S. Ried, Janna Hastings, Jan-Eric Litton, Juha Karvanen, Gonneke Willemsen, Maria Krestyaninova, Epidemiology, Biological Psychology, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Databases, Factual, Computer science, Information Storage and Retrieval, Sample (statistics), Ontology (information science), Endocrinology and Diabetes, Bioinformatics, computer.software_genre, data archives, Article, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, SDG 3 - Good Health and Well-being, Genetics, Use case, biomedical data, Genetics (clinical), Biological Specimen Banks, Genetics & Heredity, 0604 Genetics, Bioinformatics (Computational Biology), ta112, ta1184, Data science, Biobank, 3. Good health, cross-biotank research, 030104 developmental biology, Project planning, Exchange of information, Disparate system, Privacy, Bioinformatik (beräkningsbiologi), clinical data, computer, Data integration
Abstract: A wealth of biospecimen samples are stored in modern globally distributed biobanks. Biomedical researchers worldwide need to be able to combine the available resources to improve the power of large-scale studies. A prerequisite for this effort is to be able to search and access phenotypic, clinical and other information about samples that are currently stored at biobanks in an integrated manner. However, privacy issues together with heterogeneous information systems and the lack of agreed-upon vocabularies have made specimen searching across multiple biobanks extremely challenging. We describe three case studies where we have linked samples and sample descriptions in order to facilitate global searching of available samples for research. The use cases include the ENGAGE (European Network for Genetic and Genomic Epidemiology) consortium comprising at least 39 cohorts, the SUMMIT (surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools) consortium and a pilot for data integration between a Swedish clinical health registry and a biobank. We used the Sample avAILability (SAIL) method for data linking: first, created harmonised variables and then annotated and made searchable information on the number of specimens available in individual biobanks for various phenotypic categories. By operating on this categorised availability data we sidestep many obstacles related to privacy that arise when handling real values and show that harmonised and annotated records about data availability across disparate biomedical archives provide a key methodological advance in pre-analysis exchange of information between biobanks, that is, during the project planning phase. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published: 2016

28. Sample Size Calculations for Detecting Disease-Modifying Osteoarthritis Drug Effects on Knee Replacement Incidence in Clinical Trials: Data From the Osteoarthritis Initiative

Author: Daniel Crowther, Axel Dietrich, Janina S. Ried, Klaus Flechsenhar, Felix Eckstein, and Eckart Bartnik
Subjects: musculoskeletal diseases, medicine.medical_specialty, business.industry, medicine.medical_treatment, Incidence (epidemiology), Radiography, Immunology, Therapeutic effect, Knee replacement, Osteoarthritis, Knee Joint, medicine.disease, Clinical trial, Rheumatology, Sample size determination, medicine, Physical therapy, Immunology and Allergy, business
Abstract: Objective To evaluate the extent to which the current designs of clinical trials in knee osteoarthritis (OA) permit detection of a therapeutic effect of disease-modifying OA drugs (DMOADs) on the incidence of knee replacement, and to provide estimates of the required sample sizes. Methods We selected distinct subcohorts of the Osteoarthritis Initiative (OAI), based on available information on eligibility criteria for clinical knee OA trials (ClinicalTrials.gov) and additional subcohorts stratified for age, sex, and the severity of radiographic OA. The observed incidence of knee replacement in these OAI subcohorts was used to estimate the expected incidence of knee replacement in the control group of a clinical trial. Based on this estimate, the sample sizes required to detect hypothetical treatment effects on the incidence of knee replacement were calculated, assuming observation periods of 2, 5, or 7 years. Results The cumulative knee replacement incidence rates in the OAI subcohorts ranged from 0.9% to 12.9%. The corresponding sample sizes required to detect 50% improvement by the DMOAD, with a power of 80% and 95% confidence, were 5,459 and 362, respectively. Including only women with advanced age and radiographic OA increased the incidence of knee replacement and decreased the required sample size. Conclusion The sample sizes that are commonly used in clinical trials do not enable the effects of a DMOAD on incident knee replacement to be detected with sufficient power and confidence. The estimated incidence rates of knee replacement and the corresponding sample sizes are important for informing the design of trials for disease course–modifying effects as well as for socioeconomic evaluation of a DMOAD in terms of preventing knee replacement.
Published: 2015

29. P3‐139: SYSTEMATIC APOE GENOTYPE‐STRATIFIED ANALYSIS OF HUMAN OMICS DATA: A STUDY FROM THE IMI ADAPTED PROJECT

Author: María Eugenia Sáez, Begoña Hernández-Olasagarre, Janina S. Ried, Antonio González-Pérez, Margot H.M. Bakker, Agustín Ruiz, and Laura Madrid
Subjects: Stratified analysis, Omics data, Apolipoprotein E, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genotype, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published: 2018

30. P4‐057: MODELING ALZHEIMER'S DISEASE PATHOPHYSIOLOGY USING ISOGENIC HUMAN APOE IPSC‐DERIVED NEURAL CELLS

Author: Janina S. Ried, Margot H.M. Bakker, Claudia Kiefer, Lamiaa Bahnassawy, Juergen Korffmann, Viktor Lakics, Peter Reinhardt, Miroslav Cik, and Eric G. Mohler
Subjects: Apolipoprotein E, Epidemiology, business.industry, Health Policy, Disease, Pathophysiology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience
Published: 2018

31. High throughput screening of mitochondrial bioenergetics in human differentiated myotubes identifies novel enhancers of muscle performance in aged mice

Author: Wolfgang Hennerici, Thomas Leeuw, Axel Dietrich, Christian Asbrand, Janina S. Ried, Nadine Biesemann, Danping Ding-Pfennigdorff, Steffen Hahn, Christine Rudolph, and Carsten Strübing
Subjects: 0301 basic medicine, Muscle tissue, Bioenergetics, Muscle Fibers, Skeletal, lcsh:Medicine, Pharmacology, medicine.disease_cause, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, medicine, Animals, Humans, lcsh:Science, Muscle, Skeletal, Membrane Potential, Mitochondrial, Multidisciplinary, Chemistry, Myogenesis, Hesperidin, lcsh:R, Hesperetin, Skeletal muscle, Cell Differentiation, medicine.disease, Mitochondria, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, Sarcopenia, lcsh:Q, Energy Metabolism, Intracellular, Oxidative stress
Abstract: Mitochondrial dysfunction is increasingly recognized as a contributor to age-related muscle loss and functional impairment. Therefore, we developed a high throughput screening strategy that enabled the identification of compounds boosting mitochondrial energy production in a human skeletal muscle cell model. Screening of 7949 pure natural products revealed 22 molecules that significantly increased oxygen consumption and ATP levels in myotubes. One of the most potent compounds was the flavanone hesperetin. Hesperetin (10 µM) increased intracellular ATP by 33% and mitochondrial spare capacity by 25%. Furthermore, the compound reduced oxidative stress in primary myotubes as well as muscle tissue in vivo. In aged mice administration of hesperetin (50 mg/kg/d) completely reverted the age-related decrease of muscle fiber size and improved running performance of treated animals. These results provide a novel screening platform for the discovery of drugs that can improve skeletal muscle function in patients suffering from sarcopenia or other disorders associated with mitochondrial dysfunction.
Published: 2018

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

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018

33. Gender-specific pathway differences in the human serum metabolome

Author: Christian Gieger, Fabian J. Theis, Matthias Nauck, Thomas Illig, Jan Krumsiek, Florian Kronenberg, Jerzy Adamski, Kieu Trinh Do, Nele Friedrich, Annette Peters, Dennis O. Mook-Kanamori, Ferdinand Stückler, Karsten Suhre, Kirstin Mittelstrass, Maik Pietzner, Harald Grallert, Janina S. Ried, and Gabi Kastenmüller
Subjects: Genetics, Epidemiology, Endocrinology, Diabetes and Metabolism, Metabolite, Systems biology, Clinical Biochemistry, Metabolic network, Metabolic networks, Oxidative phosphorylation, Biology, Biochemistry, Molecular medicine, 3. Good health, chemistry.chemical_compound, Metabolomics, chemistry, Gender Differences, Metabolic Networks, Systems Biology, Metabolome, Gender differences, Original Article, Purine metabolism
Abstract: The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender-stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses. Electronic supplementary material The online version of this article (doi:10.1007/s11306-015-0829-0) contains supplementary material, which is available to authorized users.
Published: 2015

34. Nonadditive Effects of Genes in Human Metabolomics

Author: Christian Gieger, Tim D. Spector, Yakov A. Tsepilov, Cornelia Prehn, Nicole Soranzo, Yurii S. Aulchenko, Rui Wang-Sattler, Janina S. Ried, Jerzy Adamski, Gabi Kastenmüller, So-Youn Shin, and Konstantin Strauch
Subjects: Genetics, education.field_of_study, Kora, Genome-wide Association Studies, Genotypic Model, Metabolomics, Non-additive Models, Metabolite, Population, Inheritance Patterns, Genome-wide association study, Investigations, Biology, Polymorphism, Single Nucleotide, chemistry.chemical_compound, chemistry, Genetic Loci, Genetic model, Metabolome, Humans, SNP, education, Genome-Wide Association Study, Genetic association
Abstract: Genome-wide association studies (GWAS) are widely applied to analyze the genetic effects on phenotypes. With the availability of high-throughput technologies for metabolite measurements, GWAS successfully identified loci that affect metabolite concentrations and underlying pathways. In most GWAS, the effect of each SNP on the phenotype is assumed to be additive. Other genetic models such as recessive, dominant, or overdominant were considered only by very few studies. In contrast to this, there are theories that emphasize the relevance of nonadditive effects as a consequence of physiologic mechanisms. This might be especially important for metabolites because these intermediate phenotypes are closer to the underlying pathways than other traits or diseases. In this study we analyzed systematically nonadditive effects on a large panel of serum metabolites and all possible ratios (22,801 total) in a population-based study [Cooperative Health Research in the Region of Augsburg (KORA) F4, N = 1,785]. We applied four different 1-degree-of-freedom (1-df) tests corresponding to an additive, dominant, recessive, and overdominant trait model as well as a genotypic model with two degree-of-freedom (2-df) that allows a more general consideration of genetic effects. Twenty-three loci were found to be genome-wide significantly associated (Bonferroni corrected P ≤ 2.19 × 10−12) with at least one metabolite or ratio. For five of them, we show the evidence of nonadditive effects. We replicated 17 loci, including 3 loci with nonadditive effects, in an independent study (TwinsUK, N = 846). In conclusion, we found that most genetic effects on metabolite concentrations and ratios were indeed additive, which verifies the practice of using the additive model for analyzing SNP effects on metabolites.
Published: 2015

35. Psoriasis and Cardiometabolic Traits: Modest Association but Distinct Genetic Architectures

Author: Wolfgang Lieb, Stefan Schreiber, Elke Rodriguez, Catherine H. Smith, Henning Jansen, Barbara Thorand, Wolfgang Koenig, L Heinrich, Christina Willenborg, Natalie Volks, Michael Weichenthal, Jochen Schmitt, Heribert Schunkert, Jeanette Erdmann, Sören Mucha, Janina S. Ried, Jochen Seissler, James T. Elder, Florian Kronenberg, Annette Peters, Manja Koch, Ina Maria Rückert, Christian Gieger, Stephan Weidinger, Hansjörg Baurecht, Wolfgang Rathmann, Andre Franke, Lam C. Tsoi, Claudia Lamina, Ulrich Mrowietz, Joachim Thiery, Rajan P. Nair, Sabrina Schlesinger, and Jonathan Barker
Subjects: Male, medicine.medical_specialty, Genotype, Myocardial Infarction, Dermatology, Polymorphism, Single Nucleotide, Severity of Illness Index, Biochemistry, Article, Cohort Studies, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Germany, Internal medicine, Psoriasis, Epidemiology, medicine, Humans, Genetic Predisposition to Disease, Longitudinal Studies, Prospective Studies, Prospective cohort study, Molecular Biology, Aged, 030304 developmental biology, 0303 health sciences, Insurance, Health, business.industry, Incidence, Insurance Benefits, Confounding, Case-control study, Cell Biology, Odds ratio, Middle Aged, medicine.disease, Cross-Sectional Studies, Endocrinology, Diabetes Mellitus, Type 2, Case-Control Studies, Relative risk, Female, business, Cohort study
Abstract: Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study ( n =4,185) and a prospective cohort of German Health Insurance beneficiaries ( n =1,811,098). A potential genetic overlap was explored using genome-wide data from >22,000 coronary artery disease and >4,000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3,717 controls. After controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odds ratio (OR)=2.36; 95% confidence interval CI=1.26–4.41) and myocardial infarction (MI, OR=2.26; 95% CI=1.03–4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk (RR)=1.11; 95% CI=1.08–1.14) and MI (RR=1.14; 95% CI=1.06–1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the major histocompatibility complex, there was no evidence of genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases the risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct.
Published: 2015

36. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney

Author: Peter Vollenweider, Christophe Tzourio, Stefan Enroth, Cinzia Sala, Mark J. Caulfield, Murielle Bochud, Peter P. Pramstaller, Ozren Polasek, Paul Elliott, Dennis O. Mook-Kanamori, Daniel I. Chasman, Christian Gieger, Harriëtte Riese, Rodney J. Scott, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Priyanka Nandakumar, Tatijana Zemunik, Dragana Vuckovic, Tõnu Esko, Franco Giulianini, Michael Boehnke, Antonietta Robino, Anne U. Jackson, Roby Joehanes, Alanna C. Morrison, Kay-Tee Khaw, Alison Pattie, Peter J. van der Most, Mika Kähönen, Rick Jansen, Andrew D. Johnson, John M. Starr, Marcus Dörr, Anders Hamsten, Kenneth Rice, Alice Stanton, James F. Wilson, Nabi Shah, Weihua Zhang, Andrew A. Hicks, Jeffrey Damman, Jing Hua Zhao, Aarno Palotie, Veronique Vitart, Alan J. Gow, Caroline Hayward, Alan James, Ben A. Oostra, Janina S. Ried, John Beilby, David P. Strachan, Martin D. Tobin, Eco J. C. de Geus, Vilmundur Gudnason, Bruce M. Psaty, Zoltán Kutalik, Neil Poulter, Paul M. Ridker, Johan Sundström, Cornelia M. van Duijn, Eleftheria Zeggini, Christopher Oldmeadow, Borbala Mifsud, Giorgia Girotto, Aravinda Chakravarti, Jonathan Marten, Alexander Teumer, Joanne Knight, Robert A. Scott, Vilmantas Giedraitis, Paul F. O'Reilly, Marco Brumat, Brenda W.J.H. Penninx, Peter J. Munson, Olli T. Raitakari, Leo-Pekka Lyytikäinen, He Gao, Massimo Mangino, Benjamin Lehne, J. Wouter Jukema, Paul Knekt, Catharina A. Hartman, Rona J. Strawbridge, Jouke-Jan Hottenga, Jaspal S. Kooner, Nilesh J. Samani, Kristin L. Ayers, A. Mesut Erzurumluoglu, Joshua C. Bis, Archie Campbell, Dan E. Arking, Germaine C. Verwoert, John Attia, Samuli Ripatti, Yuri Milaneschi, Caterina Barbieri, Fabiola M. Del Greco, C M Lindgren, Peter K. Joshi, Helen R. Warren, Nicholas J. Wareham, Simon Thom, Seppo Koskinen, Tamara B. Harris, Ilaria Gandin, Kent D. Taylor, Andrew D. Morris, Anna Morgan, Chiara Batini, Terho Lehtimäki, Walter Palmas, David Conen, Harold Snieder, Martin H. de Borst, Sarah E. Harris, Igor Rudan, Ruth J. F. Loos, Claudia Langenberg, Anuj Goel, Christopher P. Nelson, Peter S. Braund, Rossella Sorice, Yasaman Saba, Oscar H. Franco, Yongmei Liu, Mattias Frånberg, David S. Siscovick, Patricia B. Munroe, Rainer Rettig, Michela Traglia, Daniel Levy, Li Lin, Michael R. Barnes, Elin Org, Anne-Claire Vergnaud, Andres Metspalu, Stéphanie Debette, Yusuf Demirkale, John M. C. Connell, Jian'an Luan, Paolo Gasparini, Tim D. Spector, Marina Ciullo, Antti-Pekka Sarin, Ian J. Deary, Teemu J. Niiranen, Marty Larson, Heather J. Cordell, Jerome I. Rotter, Sekar Kathiresan, Teresa Nutile, Andrew P. Morris, Denis C. Shields, Alan F. Wright, Lorna M. Lopez, Aki S. Havulinna, Gonçalo R. Abecasis, Edith Hofer, Siim Sõber, Sébastien Thériault, Ahmad Vaez, Albert Hofman, Gonneke Willemsen, Lynda M. Rose, John C. Chambers, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, François Mach, Massimiliano Cocca, Sarah H Wild, Reinhold Schmidt, Jaume Marrugat, Marc A. Seelen, Maris Laan, Aude Saint Pierre, David C. Liewald, Pim van der Harst, Sandosh Padmanabhan, Martin Farrall, Georg Ehret, Albert V. Smith, Quang Tri Nguyen, Ulf Gyllensten, Helena Schmidt, Ganesh Chauhan, Jennifer E. Huffman, Morris A. Swertz, Jaakko Tuomilehto, Louise V. Wain, Meixia Ren, Erwin P. Bottinger, Roberto Elosua, Ivana Kolcic, Veikko Salomaa, Stella Trompet, Bernard Keavney, Claudia P. Cabrera, Bram P. Prins, Jennie Hui, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Shih-Jen Hwang, Jie Yao, Francis S. Collins, Chrysovalanto Mamasoula, Kati Kristiansson, Markus Perola, Renée de Mutsert, Xiuqing Guo, Antti Jula, Daniela Toniolo, Ruifang Li-Gao, Åsa Johansson, Nick Shrine, Teresa Ferreira, Lars Lind, David J. Stott, Tineka Blake, Daniela Ruggiero, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Christopher Newton-Cheh, Marjo-Riitta Järvelin, Guillaume Paré, Joris Deelen, Morris Brown, Gail Davies, Annette Peters, Ioanna Tzoulaki, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Yingchang Lu, Wain, Lv, Vaez, A, Jansen, R, Joehanes, R, van der Most, Pj, Erzurumluoglu, Am, O'Reilly, Pf, Cabrera, Cp, Warren, Hr, Rose, Lm, Verwoert, Gc, Hottenga, Jj, Strawbridge, Rj, Esko, T, Arking, De, Hwang, Sj, Guo, X, Kutalik, Z, Trompet, S, Shrine, N, Teumer, A, Ried, J, Bis, Jc, Smith, Av, Amin, N, Nolte, Im, Lyytikäinen, Lp, Mahajan, A, Wareham, Nj, Hofer, E, Joshi, Pk, Kristiansson, K, Traglia, M, Havulinna, A, Goel, A, Nalls, Ma, Sõber, S, Vuckovic, Dragana, Luan, J, Del Greco, M. F, Ayers, Kl, Marrugat, J, Ruggiero, D, Lopez, Lm, Niiranen, T, Enroth, S, Jackson, Au, Nelson, Cp, Huffman, Je, Zhang, W, Marten, J, Gandin, I, Harris, Se, Zemunik, T, Lu, Y, Evangelou, E, Shah, N, de Borst, Mh, Mangino, M, Prins, Bp, Campbell, A, Li Gao, R, Chauhan, G, Oldmeadow, C, Abecasis, G, Abedi, M, Barbieri, Cm, Barnes, Mr, Batini, C, Beilby, J, Blake, T, Boehnke, M, Bottinger, Ep, Braund, P, Brown, M, Brumat, M, Campbell, H, Chambers, Jc, Cocca, M, Collins, F, Connell, J, Cordell, Hj, Damman, Jj, Davies, G, de Geus, Ej, de Mutsert, R, Deelen, J, Demirkale, Y, Doney, Asf, Dörr, M, Farrall, M, Ferreira, T, Frånberg, M, Gao, H, Giedraitis, V, Gieger, C, Giulianini, F, Gow, Aj, Hamsten, A, Harris, Tb, Hofman, A, Holliday, Eg, Hui, J, Jarvelin, Mr, Johansson, Å, Johnson, Ad, Jousilahti, P, Jula, A, Kähönen, M, Kathiresan, S, Khaw, Kt, Kolcic, I, Koskinen, S, Langenberg, C, Larson, M, Launer, Lj, Lehne, B, Liewald, Dcm, Lin, L, Lind, L, Mach, F, Mamasoula, C, Menni, C, Mifsud, B, Milaneschi, Y, Morgan, Anna, Morris, Ad, Morrison, Ac, Munson, Pj, Nandakumar, P, Nguyen, Qt, Nutile, T, Oldehinkel, Aj, Oostra, Ba, Org, E, Padmanabhan, S, Palotie, A, Paré, G, Pattie, A, Penninx, Bwjh, Poulter, N, Pramstaller, Pp, Raitakari, Ot, Ren, M, Rice, K, Ridker, Pm, Riese, H, Ripatti, S, Robino, A, Rotter, Ji, Rudan, I, Saba, Y, Saint Pierre, A, Sala, Cf, Sarin, Ap, Schmidt, R, Scott, R, Seelen, Ma, Shields, Dc, Siscovick, D, Sorice, R, Stanton, A, Stott, Dj, Sundström, J, Swertz, M, Taylor, Kd, Thom, S, Tzoulaki, I, Tzourio, C, Uitterlinden, Ag, Völker, U, Vollenweider, P, Wild, S, Willemsen, G, Wright, Af, Yao, J, Thériault, S, Conen, D, Attia, J, Sever, P, Debette, S, Mook Kanamori, Do, Zeggini, E, Spector, Td, van der Harst, P, Palmer, Cna, Vergnaud, Ac, Loos, Rjf, Polasek, O, Starr, Jm, Girotto, Giorgia, Hayward, C, Kooner, J, Lindgren, Cm, Vitart, V, Samani, Nj, Tuomilehto, J, Gyllensten, U, Knekt, P, Deary, Ij, Ciullo, M, Elosua, R, Keavney, Bd, Hicks, Aa, Scott, Ra, Gasparini, Paolo, Laan, M, Liu, Y, Watkins, H, Hartman, Ca, Salomaa, V, Toniolo, D, Perola, M, Wilson, Jf, Schmidt, H, Zhao, Jh, Lehtimäki, T, van Duijn, Cm, Gudnason, V, Psaty, Bm, Peters, A, Rettig, R, James, A, Jukema, Jw, Strachan, Dp, Palmas, W, Metspalu, A, Ingelsson, E, Boomsma, Di, Franco, Oh, Bochud, M, Newton Cheh, C, Munroe, Pb, Elliott, P, Chasman, Di, Chakravarti, A, Knight, J, Morris, Ap, Levy, D, Tobin, Md, Snieder, H, Caulfield, Mj, Ehret, G. b., Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Organ Transplantation (GIOT), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Epidemiology, Gastroenterology & Hepatology, Clinical Genetics, Internal Medicine, Erasmus MC other, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, Division 6, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
Subjects: 0301 basic medicine, cardiovascular risk, Netherlands Twin Register (NTR), hypertension, NETHERLANDS, Sistema cardiovascular -- Malalties, GWAS, blood pressure, complex traits, eSNP, Locus (genetics), Genome-wide association study, Disease, Biology, PERIPHERAL-BLOOD, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Internal Medicine, Journal Article, Cardiac and Cardiovascular Systems, 1000 Genomes Project, Gene, CENTRIC ARRAY, METAANALYSIS, Genetics, ddc:616, Kardiologi, PULSE PRESSURE, COMMON VARIANTS, 1103 Clinical Sciences, ta3121, 3. Good health, INDIVIDUALS, 030104 developmental biology, Blood pressure, TARGET, Cardiovascular System & Hematology, complex trait, GWAS, blood pressure, cardiovascular risk, complex traits, eSNP, hypertension, Hipertensió, Imputation (genetics), TRAITS
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Published: 2017

37. Novel blood pressure locus and gene discovery using GWAS and expression datasets from blood and the kidney

Author: Ganesh Chauhan, Dragana Vuckovic, Yingchang Lu, Bernard Keavney, Patricia B. Munroe, Tim D. Spector, Tamara B. Harris, Chiara Batini, Harold Snieder, Yusuf Demirkale, Ulf Gyllensten, Heather J. Cordell, Christopher Newton-Cheh, Anne-Claire Vergnaud, Christophe Tzourio, Giorgia Girotto, Morris A. Swertz, John C. Chambers, Xiuqing Guo, Caterina Barbieri, Joris Deelen, Morris Brown, Igor Rudan, Christopher P. Nelson, Paul Knekt, Antti-Pekka Sarin, Peter Vollenweider, Lynda M. Rose, Ozren Polasek, Nilesh J. Samani, Murielle Bochud, James F. Wilson, Anna Morgan, Gail Davies, Ian J. Deary, Massimiliano Cocca, Antti Jula, Ioanna Tzoulaki, Jaspal S. Kooner, Sarah H Wild, Peter S. Braund, John M. Starr, Simon Thom, Christian Gieger, Rainer Rettig, John M. C. Connell, Marina Ciullo, Jian'an Luan, Rodney J. Scott, Franco Giulianini, Brenda W.J.H. Penninx, Mika Kähönen, Alison Pattie, Nabi Shah, Weihua Zhang, Ruth J. F. Loos, Maris Laan, Martin Farrall, Rick Jansen, Albert V. Smith, Sarah E. Harris, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Paul M. Ridker, John Attia, Alanna C. Morrison, Kay-Tee Khaw, Jaume Marrugat, Hugh Watkins, David C. Liewald, Pim van der Harst, Benjamin Lehne, Jennifer E. Huffman, Meixia Ren, Zoltán Kutalik, Lars Lind, Walter Palmas, Teresa Ferreira, David J. Stott, Janina S. Ried, Bruce M. Psaty, Paul F. O'Reilly, Massimo Mangino, Tõnu Esko, Jonathan Marten, Nick Shrine, Anders Hamsten, Tineka Blake, Yuri Milaneschi, Jing Hua Zhao, David Conen, Kristin L. Ayers, Germaine C. Verwoert, Veikko Salomaa, Olli T. Raitakari, Jaakko Tuomilehto, Louise V. Wain, Jennie Hui, Elin Org, Gonçalo R. Abecasis, Vilmundur Gudnason, Andrew A. Hicks, Rossella Sorice, Borbala Mifsud, Helen R. Warren, Jerome I. Rotter, Erwin P. Bottinger, Roberto Elosua, Antonietta Robino, Ilaria Gandin, Andres Metspalu, Marjo-Riitta Järvelin, Guillaume Paré, Anne U. Jackson, Jie Yao, Kent D. Taylor, Denis C. Shields, Andrew D. Morris, Daniela Ruggiero, Samuli Ripatti, C M Lindgren, Mike A. Nalls, Erik Ingelsson, Michela Traglia, Jeffrey Damman, J. Wouter Jukema, Catharina A. Hartman, Eco J. C. de Geus, Colin N. A. Palmer, Peter J. van der Most, Neil Poulter, Robert A. Scott, Anuj Goel, Aude Saint Pierre, Annette Peters, Paul Elliott, Daniel I. Chasman, Marco Brumat, Dennis O. Mook-Kanamori, Priyanka Nandakumar, Roby Joehanes, Cornelia M. van Duijn, Joshua C. Bis, Eleftheria Zeggini, Archie Campbell, Ivana Kolcic, Terho Lehtimäki, Mattias Frånberg, David S. Siscovick, Dan E. Arking, Shih-Jen Hwang, Stella Trompet, Christopher Oldmeadow, A. Mesut Erzurumluoglu, Nicholas J. Wareham, Alice Stanton, Chrysovalanto Mamasoula, Seppo Koskinen, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Peter J. Munson, Aarno Palotie, Daniela Toniolo, He Gao, Ruifang Li-Gao, Claudia Langenberg, Kati Kristiansson, Åsa Johansson, Johan Sundström, Francis S. Collins, Alan J. Gow, Caroline Hayward, Markus Perola, Renée de Mutsert, Alan James, Ben A. Oostra, Alexander Teumer, Joanne Knight, Vilmantas Giedraitis, Marty Larson, Helena Schmidt, Sébastien Thériault, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, Marc A. Seelen, Georg Ehret, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Stéphanie Debette, Paolo Gasparini, Teemu J. Niiranen, Stefan Enroth, Mark J. Caulfield, Andrew P. Morris, Aki S. Havulinna, Cinzia Sala, Peter P. Pramstaller, Marcus Dörr, Quang Tri Nguyen, Claudia P. Cabrera, Bram P. Prins, Peter K. Joshi, Sekar Kathiresan, Lorna M. Lopez, Reinhold Schmidt, Sandosh Padmanabhan, Teresa Nutile, Gonneke Willemsen, François Mach, Michael Boehnke, John Beilby, Leo-Pekka Lyytikäinen, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Martin H. de Borst, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Aravinda Chakravarti, Jouke-Jan Hottenga, Fabiola M. Del Greco, Yasaman Saba, Daniel Levy, Li Lin, Michael R. Barnes, Rona J. Strawbridge, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, and Martin D. Tobin
Subjects: Genetics, 0303 health sciences, Genomics, Locus (genetics), Genome-wide association study, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Genetic variation, 1000 Genomes Project, Gene, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150,134 European ancestry individuals and sought significant evidence for independent replication in a further 228,245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12,607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in BP regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Published: 2017
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38. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Rob M. van Dam, Francis S. Collins, Konstantin Strauch, Raimund Erbel, Rafn Benediktsson, Philippe Froguel, Kyle J. Gaulton, Peter Donnelly, Torben Hansen, Longda Jiang, Lennart C. Karssen, Rona J. Strawbridge, David J. Hunter, Leena Kinnunen, Thomas Meitinger, Michael Stumvoll, Stéphane Cauchi, Ching-Ti Liu, Olga McLeod, Oluf Pedersen, Michael Boehnke, Denis Rybin, Karl Gertow, Tõnu Esko, Bernhard O. Boehm, Sonali Pechlivanis, Bo Isomaa, Anne U. Jackson, Clement Ma, Yingchang Lu, Nicola D. Kerrison, Ruth J. F. Loos, Caroline S. Fox, Chiara Scapoli, Jian'an Luan, Martina Müller-Nurasyid, Domenico Palli, Anke Tönjes, Natalie R. van Zuydam, Neil Robertson, Barbara Thorand, Natalia Pervjakova, Andrew R. Wood, Karin Leander, Unnur Thorsteinsdottir, Sara M. Willems, Karen L. Mohlke, Robert A. Scott, Markus M. Nöthen, Ulf de Faire, Qi Sun, Eric Boerwinkle, Roman Wennauer, Douglas M. Ruderfer, Marika Kaakinen, Nigel W. Rayner, Jaakko Tuomilehto, Nisa M. Maruthur, Richard N. Bergman, Janina S. Ried, Himanshu Chheda, Josée Dupuis, Juan Tajes-Fernandes, Steve E. Humphries, Reedik Mägi, Gonçalo R. Abecasis, B F Voight, David Couper, Cornelia M. van Duijn, Samuli Ripatti, Yeji Lee, Heikki A. Koistinen, Christian Dina, Andres Metspalu, Lu Qi, James S. Pankow, Han Chen, Damiano Baldassarre, Mattias Frånberg, Gerald Steinbach, Inga Prokopenko, Matthias Blüher, Jose C. Florez, Julia Meyer, Niels Grarup, Anders Hamsten, Valeriya Lyssenko, James B. Meigs, Pritam Chanda, Leif Groop, Sarah Edkins, Anubha Mahajan, Gunnar Sigurðsson, Marilyn C. Cornelis, Christian Gieger, Nancy L. Pedersen, Andrew T. Hattersley, Paul W. Franks, Nicholas J. Wareham, Stefan Gustafsson, Katharine R. Owen, Peter Kovacs, Andrew D. Johnson, Lori L. Bonnycastle, Tiinamaija Tuomi, Aurelio Barricarte Gurrea, Tune H. Pers, Eric J.G. Sijbrands, Phoenix Kwan, Emmi Tikkanen, Elisabeth M. van Leeuwen, Stéphane Lobbens, Claudia Langenberg, E. Eury, Thomas W. Mühleisen, Lewin Eisele, Veikko Salomaa, Satu Mӓnnistö, Christian Fuchsberger, Evelin Mihailov, David Altshuler, Timothy M. Frayling, Peter Almgren, Harald Grallert, Hans A. Kestler, Beverley Balkau, Erik Ingelsson, Colin N. A. Palmer, Yvonne T. van der Schouw, Michael Roden, Thomas Sparsø, Karl-Heinz Jöckel, Johan G. Eriksson, Inês Barroso, John D. Eicher, Bengt Sennblad, Bruna Gigante, Andrew D. Morris, Panagiotis Deloukas, Man Li, Allan Linneberg, Astradur B. Hreidarsson, Lars Lannfelt, Elena Tremoli, Liming Liang, Omri Gottesman, Letizia Marullo, Peter S. Chines, Kari Stefansson, Mark I. McCarthy, Andrew P. Morris, Erwin P. Bottinger, Augustine Kong, Torben Jørgensen, Tanya M. Teslovich, Frank B. Hu, Dorothée Thuillier, Peter Kraft, Heiner Boeing, Laura J. Scott, Gudmar Thorleifsson, Lars Lind, John R. B. Perry, Heather M. Stringham, Susanne Moebus, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Guillaume Charpentier, Eleftheria Zeggini, Leena Peltonen, Loic Yengo, Norman Klopp, Teresa Ferreira, Christian Theil Have, Marit E. Jørgensen, Epidemiology, Erasmus MC other, Internal Medicine, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Commission of the European Communities, and Wellcome Trust
Subjects: PROVIDES, 0301 basic medicine, SUSCEPTIBILITY LOCI, endocrine system diseases, Endocrinology, Diabetes and Metabolism, PATHOPHYSIOLOGY, European Continental Ancestry Group, Medizin, Genome-wide association study, Biology, Quantitative trait locus, Bioinformatics, White People, GENETIC ARCHITECTURE, NO, Endocrinology & Metabolism, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Diabetes Mellitus, Internal Medicine, Journal Article, Glucose homeostasis, Humans, 1000 Genomes Project, Allele frequency, METAANALYSIS, 11 Medical and Health Sciences, RISK, Genetics, Science & Technology, RECEPTOR, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Haplotype, Genetic Variation, nutritional and metabolic diseases, Genetic architecture, 030104 developmental biology, Diabetes Mellitus, Type 2, Gene Expression Regulation, RARE VARIANTS, LOW-FREQUENCY, Life Sciences & Biomedicine, Type 2, 030217 neurology & neurosurgery, Imputation (genetics), FASTING GLUCOSE, Genome-Wide Association Study
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Published: 2017

39. Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author: M. Carola Zillikens, Serkalem Demissie, Yi-Hsiang Hsu, Laura M. Yerges-Armstrong, Wen-Chi Chou, Lisette Stolk, Gregory Livshits, Linda Broer, Toby Johnson, Daniel L. Koller, Zoltán Kutalik, Jian’an Luan, Ida Malkin, Janina S. Ried, Albert V. Smith, Gudmar Thorleifsson, Liesbeth Vandenput, Jing Hua Zhao, Weihua Zhang, Ali Aghdassi, Kristina Åkesson, Najaf Amin, Leslie J. Baier, Inês Barroso, David A. Bennett, Lars Bertram, Rainer Biffar, Murielle Bochud, Michael Boehnke, Ingrid B. Borecki, Aron S. Buchman, Liisa Byberg, Harry Campbell, Natalia Campos Obanda, Jane A. Cauley, Peggy M. Cawthon, Henna Cederberg, Zhao Chen, Nam H. Cho, Hyung Jin Choi, Melina Claussnitzer, Francis Collins, Steven R. Cummings, Philip L. De Jager, Ilja Demuth, Rosalie A. M. Dhonukshe-Rutten, Luda Diatchenko, Gudny Eiriksdottir, Anke W. Enneman, Mike Erdos, Johan G. Eriksson, Joel Eriksson, Karol Estrada, Daniel S. Evans, Mary F. Feitosa, Mao Fu, Melissa Garcia, Christian Gieger, Thomas Girke, Nicole L. Glazer, Harald Grallert, Jagvir Grewal, Bok-Ghee Han, Robert L. Hanson, Caroline Hayward, Albert Hofman, Eric P. Hoffman, Georg Homuth, Wen-Chi Hsueh, Monica J. Hubal, Alan Hubbard, Kim M. Huffman, Lise B. Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John-Olov Jansson, Joanne M. Jordan, Antti Jula, Magnus Karlsson, Kay-Tee Khaw, Tuomas O. Kilpeläinen, Norman Klopp, Jacqueline S. L. Kloth, Heikki A. Koistinen, William E. Kraus, Stephen Kritchevsky, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L. Langdahl, Lenore J. Launer, Jong-Young Lee, Markus M. Lerch, Joshua R. Lewis, Lars Lind, Cecilia Lindgren, Yongmei Liu, Tian Liu, Youfang Liu, Östen Ljunggren, Mattias Lorentzon, Robert N. Luben, William Maixner, Fiona E. McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Simon Melov, Karl Michaëlsson, Braxton D. Mitchell, Andrew P. Morris, Leif Mosekilde, Anne Newman, Carrie M. Nielson, Jeffrey R. O’Connell, Ben A. Oostra, Eric S. Orwoll, Aarno Palotie, Stephen C. J. Parker, Munro Peacock, Markus Perola, Annette Peters, Ozren Polasek, Richard L. Prince, Katri Räikkönen, Stuart H. Ralston, Samuli Ripatti, John A. Robbins, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Eric E. Schadt, Sabine Schipf, Laura Scott, Joban Sehmi, Jian Shen, Chan Soo Shin, Gunnar Sigurdsson, Shad Smith, Nicole Soranzo, Alena Stančáková, Elisabeth Steinhagen-Thiessen, Elizabeth A. Streeten, Unnur Styrkarsdottir, Karin M. A. Swart, Sian-Tsung Tan, Mark A. Tarnopolsky, Patricia Thompson, Cynthia A. Thomson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J. Tranah, Jaakko Tuomilehto, Natasja M. van Schoor, Arjun Verma, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Michael N. Weedon, Ryan Welch, H.-Erich Wichmann, Elisabeth Widen, Frances M. K. Williams, James F. Wilson, Nicole C. Wright, Weijia Xie, Lei Yu, Yanhua Zhou, John C. Chambers, Angela Döring, Cornelia M. van Duijn, Michael J. Econs, Vilmundur Gudnason, Jaspal S. Kooner, Bruce M. Psaty, Timothy D. Spector, Kari Stefansson, Fernando Rivadeneira, André G. Uitterlinden, Nicholas J. Wareham, Vicky Ossowski, Dawn Waterworth, Ruth J. F. Loos, David Karasik, Tamara B. Harris, Claes Ohlsson, Douglas P. Kiel, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Luben, Robert [0000-0002-5088-6343], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: 17-Hydroxysteroid Dehydrogenases, NVAO Programmes, Science, Quantitative Trait Loci, General Physics and Astronomy, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 4202 Epidemiology, 010501 environmental sciences, 01 natural sciences, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 3105 Genetics, 03 medical and health sciences, ADAMTS Proteins, Versicans, Thinness, MD Multidisciplinary, Humans, Life Science, Regulatory Elements, Transcriptional, lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Extracellular Matrix Proteins, Multidisciplinary, Science & Technology, 42 Health Sciences, General Chemistry, Aldehyde Oxidoreductases, Onderwijsinstituut, Multidisciplinary Sciences, Phenotype, Body Composition, Insulin Receptor Substrate Proteins, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Erratum, Genome-Wide Association Study, 31 Biological Sciences
Abstract: Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
Published: 2017

40. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author: Jing Hua Zhao, Hyung Jin Choi, Leslie J. Baier, Vilmundur Gudnason, Melina Claussnitzer, Jian Shen, Mary F. Feitosa, Melissa E. Garcia, Douglas P. Kiel, Murielle Bochud, Christian Gieger, L. B. Husted, Kristina Åkesson, Alan Hubbard, John-Olov Jansson, Jacqueline S. L. Kloth, Yanhua Zhou, Richard L. Prince, Angela Döring, H.-Erich Wichmann, Thomas Girke, Monica J. Hubal, Mark A. Tarnopolsky, Laura M. Yerges-Armstrong, Yi-Hsiang Hsu, Patricia A. Thompson, Mattias Lorentzon, Gudmar Thorleifsson, Wen-Chi Chou, Karin M. A. Swart, Tim D. Spector, Braxton D. Mitchell, Kim M. Huffman, Inês Barroso, Igor Rudan, William E. Kraus, Nicholas J. Wareham, Chan Soo Shin, Jaakko Tuomilehto, Gunnar Sigurdsson, Bok Ghee Han, Munro Peacock, Mao Fu, Unnur Thorsteinsdottir, Gregory Livshits, Laura J. Scott, Jane A. Cauley, Heikki A. Koistinen, Arjun Verma, Peggy M. Cawthon, Carrie M. Nielson, Aron S. Buchman, Aarno Palotie, Daniel S. Evans, Elisabeth Widen, Caroline Hayward, Frances M K Williams, Nam H. Cho, Peter Vollenweider, Liisa Byberg, Robert Luben, Veikko Salomaa, Alena Stančáková, Markus M. Lerch, Jian'an Luan, Eric P. Hoffman, Thomas Lang, Jari Lahti, Mike Erdos, Stephen C. J. Parker, Ida Malkin, Jaspal S. Kooner, Francis S. Collins, Claes Ohlsson, James F. Wilson, Ben A. Oostra, Carolina Medina-Gomez, Toby Johnson, Cornelia M. van Duijn, Joel Eriksson, Natalia Campos Obanda, Samuli Ripatti, Kay-Tee Khaw, Ryan P. Welch, Jeffrey R. O'Connell, Karl Michaëlsson, Erik Ingelsson, Elizabeth A. Streeten, Eric E. Schadt, Markus Perola, Albert V. Smith, Henna Cederberg, Ruth J. F. Loos, Michael J. Econs, Thomas Illig, Ingrid B. Borecki, Unnur Styrkarsdottir, Kari Stefansson, Anne B. Newman, Ozren Polasek, Weihua Zhang, Shad B. Smith, Wen Chi Hsueh, Serkalem Demissie, Najaf Amin, Simon Melov, Lenore J. Launer, Harald Grallert, E. Steinhagen-Thiessen, Jean Wactawski-Wende, Stuart H. Ralston, Leif Mosekilde, Liesbeth Vandenput, Zoltán Kutalik, Nicole L. Glazer, Teemu Kuulasmaa, Lisette Stolk, Johanna Kuusisto, Lei Yu, Steven R. Cummings, Cynthia A. Thomson, Harry Campbell, Mark Walker, Lars Lind, André G. Uitterlinden, Albert Hofman, Linda Broer, Vicky Ossowski, John C. Chambers, Jerome I. Rotter, Gregory J. Tranah, Östen Ljunggren, Tamara B. Harris, Ali A. Aghdassi, Nicole Soranzo, Jong-Young Lee, Bruce M. Psaty, Magnus Karlsson, Luda Diatchenko, Nicole C. Wright, A.W. Enneman, Cecilia M. Lindgren, Yongmei Liu, Sabine Schipf, Tian Liu, Annette Peters, Daniel L. Koller, Georg Homuth, Ilja Demuth, Andrew P. Morris, Jagvir Grewal, Katri Räikkönen, Markku Laakso, Tuomas O. Kilpeläinen, Michael Boehnke, Fernando Rivadeneira, David A. Bennett, Joban Sehmi, Gudny Eiriksdottir, Rainer Biffar, Till Ittermann, Natasja M. van Schoor, Michael N. Weedon, Zhao Chen, Norman Klopp, Antti Jula, Bente L. Langdahl, William Maixner, Håkan Melhus, Rosalie A. M. Dhonukshe-Rutten, Dan Mellström, Robert L. Hanson, M. Carola Zillikens, Janina S. Ried, David Karasik, Suzanne Satterfield, Stephen B. Kritchevsky, Henry Völzke, Karol Estrada, Thomas Meitinger, Sian Tsung Tan, John A Robbins, Dawn M. Waterworth, Lars Bertram, Fiona E. McGuigan, Philip L. De Jager, Youfang Liu, Emmi Tikkanen, Eric S. Orwoll, Weijia Xie, Joanne M. Jordan, Johan G. Eriksson, Joshua R. Lewis, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, School of Medicine / Clinical Medicine, Internal Medicine, Epidemiology, Clinical Genetics, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Luben, Robert [0000-0002-5088-6343], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Societal Participation & Health, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, Epidemiology and Data Science, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Department of Medicine, Endokrinologian yksikkö, Medicum, Department of Psychology and Logopedics, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Department of Medical and Clinical Genetics, Quantitative Genetics, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, and Genomic Discoveries and Clinical Translation
Subjects: 0301 basic medicine, Medicin och hälsovetenskap, 17-Hydroxysteroid Dehydrogenases, General Physics and Astronomy, Physiology, Genome-wide association study, VARIANTS, Bioinformatics, Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, ADAMTS Proteins, Versicans, Regulatory Elements, Transcriptional, GENE-EXPRESSION, INSULIN-RESISTANCE, Extracellular Matrix Proteins, Multidisciplinary, Aldehyde Oxidoreductases, Multidisciplinary Sciences, Phenotype, OBESITY, Body Composition, Science & Technology - Other Topics, Medical genetics, BONE-MINERAL DENSITY, PHYSICAL-DISABILITY, Bioelectrical impedance analysis, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, medicine.medical_specialty, Science, Quantitative Trait Loci, UNITED-STATES, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Biology, Predictive markers, Polymorphism, Single Nucleotide, SARCOPENIA, General Biochemistry, Genetics and Molecular Biology, SKELETAL-MUSCLE MASS, 03 medical and health sciences, Insulin resistance, Thinness, MD Multidisciplinary, Journal Article, medicine, Humans, Life Science, Erfðafræði, Human height, Science & Technology, predictive markers, General Chemistry, Rannsóknir, Líkamsvöxtur, Arfgengi, medicine.disease, Obesity, Onderwijsinstituut, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Sarcopenia, genome-wide association studies, Lean body mass, Insulin Receptor Substrate Proteins, gene expression, Gene expression, HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer’s Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129.
Published: 2017

41. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author: Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed
Published: 2016

42. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Aravinda Chakravarti, Jennifer E. Huffman, Meixia Ren, Veikko Salomaa, Christopher Newton-Cheh, Johan Sundström, Alan L. James, Joris Deelen, Raha Pazoki, Michela Traglia, Tõnu Esko, Seppo Koskinen, Christopher J. O'Donnell, Csaba P. Kovesdy, Daniel I. Chasman, Paul F. O'Reilly, Roby Joehanes, Paul M. Ridker, G. Abecasis, Lars Lind, Dragana Vuckovic, Yingchang Lu, Antonietta Robino, Anders Hamsten, Muralidharan Sargurupremraj, Caterina Barbieri, Anne U. Jackson, Anna Morgan, Claudia Langenberg, Peter S. Braund, Rainer Rettig, Murielle Bochud, Vilmundur Gudnason, Eleftheria Zeggini, David J. Stott, Joop Jukema, Nick Shrine, Jun Ding, Olle Melander, Massimo Mangino, Borbala Mifsud, Frank H. Collins, Liewald Dcm., Tineka Blake, Peter K. Joshi, Yan V. Sun, Aarno Palotie, Maciej Tomaszewski, Jarvelin M-R., Kati Kristiansson, L. J. Launer, Sara M. Willems, Ian J. Deary, Christophe Tzourio, Alan J. Gow, Caroline Hayward, Guillaume Paré, Christopher Oldmeadow, John M. Starr, Paul Elliott, Morris A. Swertz, C M van Duijn, Sekar Kathiresan, Lorna M. Lopez, Neil R Poulter, Mike A. Nalls, Erik Ingelsson, Eric Boerwinkle, Catharina A. Hartman, Giorgia Girotto, Ben A. Oostra, Markus Perola, Paul Knekt, Lyytikäinen L-P., T.B. Harris, J. C. Bis, Harriëtte Riese, J. Marrugat, Samuli Ripatti, Howson Jmm., Archie Campbell, C M Lindgren, Adam S. Butterworth, Xiuqing Guo, Lin W-Y., Priyanka Nandakumar, David Mosen-Ansorena, Alison Pattie, Marco Brumat, Annette Peters, Georgios Ntritsos, Ivana Kolcic, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Stella Trompet, K. Witkowska, Hottenga J-J., Tim D. Spector, Maris Laan, Vilmantas Giedraitis, Bram P. Prins, Loos Rjf., M. H. de Borst, Antti Jula, Lynda M. Rose, Massimiliano Cocca, Daniela Toniolo, Igor Rudan, P. J. van der Most, Fu Liang Ng, Heather J. Cordell, Walter Palmas, John Danesh, John Attia, Dan E. Arking, Ganesh Chauhan, C Gieger, P. van der Harst, Penninx Bwjh., Kristin L. Ayers, Germaine C. Verwoert, Bruce M. Psaty, Jaspal S. Kooner, Ruifang Li-Gao, Benjamin Lehne, Khaw K-T., Sandosh Padmanabhan, Franco Giulianini, Erwin P. Bottinger, Roberto Elosua, Christopher P. Nelson, Ozren Polasek, D.R. Velez Edwards, Martin Farrall, Ioanna Tzoulaki, Peter Vollenweider, Uwe Völker, Albertine J. Oldehinkel, Åsa Johansson, Helen R. Warren, Evan Tzanis, Albert V. Smith, Hwang S-J., Teresa Ferreira, E.J.C. de Geus, Evangelos Evangelou, Niek Verweij, R. J. Scott, Pekka Jousilahti, Elin Org, Stefan Enroth, Dorret I. Boomsma, Harry Campbell, Andrew D. Johnson, David Conen, James F. Wilson, Edward G. Lakatta, Anuj Goel, Raymond Noordam, Najaf Amin, David P. Strachan, Martin D. Tobin, Francesco Cucca, Doney Asf., Todd L. Edwards, Jerome I. Rotter, Mika Kähönen, Hugh Watkins, Rossella Sorice, John M. C. Connell, David S. Siscovick, Sébastien Thériault, Jian'an Luan, Marty Larson, Philippe Amouyel, A C Morrison, Louise V. Wain, Reedik Mägi, Jonathan Marten, Thibaud Boutin, Nabi Shah, Weihua Zhang, Palmer Cna., Daniela Ruggiero, Zhao J-H., Olli T. Raitakari, Bernard Keavney, Peter S. Sever, Philip S. Tsao, Jie Yao, André G. Uitterlinden, Marina Evangelou, Zoltán Kutalik, Robert A. Scott, Helena Schmidt, J. Tuomilehto, Nilesh J. Samani, Quang Tri Nguyen, John Michael Gaziano, Georg Ehret, Praveen Surendran, Terho Lehtimäki, Mark J. Caulfield, Denis C. Shields, Rick Jansen, Sarin A-P., Alice Stanton, Mattias Frånberg, Cumhur Y Demirkale, Stéphanie Debette, Paolo Gasparini, Ilaria Gandin, Simon Thom, Kent D. Taylor, Andrew D. Morris, Claudia P. Cabrera, Teemu J. Niiranen, Nicholas J. Wareham, Andrew P. Morris, Yasaman Saba, Daniel Levy, Aki S. Havulinna, Kelly Cho, Sarah E. Harris, Li Lin, Janina S. Ried, Michael R. Barnes, Sarah H. Wild, Patricia B. Munroe, Vergnaud A-C., Lorenz Risch, Rona J. Strawbridge, Y. Milaneschi, John C. Chambers, Yong Qian, Cristina Menni, Anubha Mahajan, Peter Almgren, Gary Davies, Jacklyn N. Hellwege, Elizabeth G. Holliday, A. Metspalu, Ilja M. Nolte, Peter J. Munson, He Gao, Marcus Dörr, Cinzia Sala, Peter P. Pramstaller, Teresa Nutile, Wilson Pwf., Gonneke Willemsen, Markku Laakso, Chiara Batini, Harold Snieder, Ibrahim Karaman, Adriana M. Hung, Reinhold Schmidt, R. de Mutsert, Michael Boehnke, Lili Milani, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Marina Ciullo, Niki Dimou, Morris J. Brown, Crysovalanto Mamasoula, A.M. Erzurumluoglu, Andrew A. Hicks, Ayush Giri, Dennis O. Mook-Kanamori, Home Office, UNIVERSITY OF OULU, Commission of the European Communities, Medical Research Council (MRC), Action on Hearing Loss, British Heart Foundation, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd
Subjects: Genetics & Heredity, 0301 basic medicine, Netherlands Twin Register (NTR), Science & Technology, computer.internet_protocol, Million Veteran Program, Genome-wide association study, Computational biology, 06 Biological Sciences, Biology, Genetic analysis, 03 medical and health sciences, 030104 developmental biology, Genetics, Genome informatics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, computer, 11 Medical and Health Sciences, XML, Developmental Biology
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018

43. Dilution of candidates: the case of iron-related genes in restless legs syndrome

Author: Bertram Müller-Myhsok, H-Erich Wichmann, Darina Czamara, Janina S. Ried, Thomas Meitinger, G. Martin Fiedler, Angela Döring, Birgit Högl, Michael Specht, Birgit Frauscher, Holger Prokisch, Claudia Trenkwalder, Barbara Schormair, Peter Lichtner, Juliane Winkelmann, Katharina Heim, Annette Peters, Konrad Oexle, Joachim Thiery, and Christian Gieger
Subjects: Iron, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Restless Legs Syndrome, Iron Parameters, Meis1 Haplotype, Power Calculation, Linear Regression, Logistic Regression, 03 medical and health sciences, 0302 clinical medicine, Receptors, Transferrin, mental disorders, Genetics, medicine, Humans, Hemochromatosis Protein, Myeloid Ecotropic Viral Integration Site 1 Protein, education, Gene, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Soluble transferrin receptor, Adenosine Triphosphatases, Homeodomain Proteins, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, biology, medicine.diagnostic_test, Histocompatibility Antigens Class I, Transferrin, Case-control study, Membrane Proteins, Neoplasm Proteins, Ferritin, chemistry, Case-Control Studies, Ferritins, biology.protein, Serum iron, Katanin, 030217 neurology & neurosurgery
Abstract: Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.193.
Published: 2012

44. PSEA: Phenotype Set Enrichment Analysis-A New Method for Analysis of Multiple Phenotypes

Author: Karsten Suhre, Annette Peters, H-Erich Wichmann, Norman Klopp, Konrad Oexle, Thomas Meitinger, Angela Döring, Janina S. Ried, Christian Gieger, Christa Meisinger, and Juliane Winkelmann
Subjects: Genetics, 0303 health sciences, education.field_of_study, Epidemiology, 030305 genetics & heredity, Population, Univariate, Genome-wide association study, Biology, Phenotype, 03 medical and health sciences, Pleiotropy, Genotype, Identification (biology), education, Genetics (clinical), 030304 developmental biology, Genetic association
Abstract: Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called "phenotype set enrichment analysis" (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request.
Published: 2012

45. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

Author: Christian Herder, Thomas Illig, Gonneke Willemsen, Yixue Li, Tao Xu, Anne S. Quante, Toomas Haller, Janina S. Ried, Konstantin Strauch, Ana C. Messias, Werner Roemisch-Margl, Jerzy Adamski, Barbara Thorand, Martin Hrabé de Angelis, Ying He, Ayse Demirkan, Gabi Kastenmüller, Katarina Kasa, Annette Peters, Wolfgang Rathmann, Jonathan Adam, Tommaso Panni, Zhonghao Yu, Markus Rotter, Gisela Fobo, Bernd Stratmann, Dorret I. Boomsma, Karsten Suhre, Shen Chi, Michael Roden, Thomas Meitinger, Cornelia M. van Duijn, Ko Willems van Dijk, René Pool, Cornelia Prehn, Monica Campillos, Christa Meisinger, Stefan Brandmaier, Christian Gieger, Andres Metspalu, Christina Holzapfel, Harmen H.M. Draisma, Thomas Hankemeier, Margit Heier, H.-Erich Wichmann, Rui Wang-Sattler, Renee Stark, Andreas Ruepp, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Dermatology, and Epidemiology
Subjects: Fatty Acid Desaturases, Male, Netherlands Twin Register (NTR), medicine.medical_specialty, Genotype, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Metabolite, Population, Blood lipids, Type 2 diabetes, chemistry.chemical_compound, Delta-5 Fatty Acid Desaturase, SDG 3 - Good Health and Well-being, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Metabolomics, education, Aged, Advanced and Specialized Nursing, education.field_of_study, Cholesterol, business.industry, AMPK, nutritional and metabolic diseases, Cholesterol, LDL, Fasting, Genomics, Middle Aged, Lipid Metabolism, medicine.disease, Metformin, 3. Good health, Cross-Sectional Studies, Endocrinology, Diabetes Mellitus, Type 2, chemistry, Female, business, Diabetic Angiopathies, medicine.drug
Abstract: OBJECTIVE Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. RESEARCH DESIGN AND METHODS We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. RESULTS We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years’ follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. CONCLUSIONS Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.
Published: 2015

46. Human metabolic individuality in biomedical and pharmaceutical research

Author: Elin Grundberg, Nicole Soranzo, Florian Kronenberg, H.-Erich Wichmann, Kerrin S. Small, Christian Gieger, Hans-Werner Mewes, Thomas Meitinger, Christopher J Hammond, Jeanette Erdmann, Massimo Mangino, David Meredith, Ann-Kristin Petersen, Panos Deloukas, So-Youn Shin, Brigitte Wägele, Gabi Kastenmüller, Jerzy Adamski, Robert P. Mohney, Werner Römisch-Margl, Karsten Suhre, Cornelia Prehn, Thomas Illig, Janina S. Ried, Anna Köttgen, Tim D. Spector, Guangju Zhai, Elisabeth Altmaier, Nilesh J. Samani, Johannes Raffler, Martin Hrabé de Angelis, Christa Meisinger, and Michael V. Milburn
Subjects: 0303 health sciences, Multidisciplinary, Genome-wide association study, Disease, Biology, Bioinformatics, 3. Good health, 03 medical and health sciences, Diabetes mellitus genetics, 0302 clinical medicine, Kidney disorder, Allele, Pharmaceutical sciences, 030217 neurology & neurosurgery, Pharmacogenetics, 030304 developmental biology, Genetic association
Abstract: Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
Published: 2011

47. Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels

Author: G. Martin Fiedler, H.-Erich Wichmann, Joachim Thiery, Martin Gögele, Thomas Meitinger, Luigi Ferrucci, Irene Pichler, Thomas Illig, Angela Döring, Peter Lichtner, Toshiko Tanaka, Harry Campbell, Stefania Bandinelli, Juliane Winkelmann, Caroline Hayward, Mathias Bruegel, Christian Gieger, Igor Rudan, Andrew A. Hicks, Janina S. Ried, Bertram Müller-Myhsok, Alan F. Wright, Peter P. Pramstaller, Cosetta Minelli, Konrad Oexle, and Christine Schwienbacher
Subjects: Adult, Male, Transferrin Saturation Measurement, medicine.medical_specialty, TMPRSS6, Adolescent, Iron, Genome-wide association, Iron homeostasis, Common variants, Hemojuvelin, Hemochromatosis, Metabolism, Consortium, Mutations, Overload, Transferrin receptor, Cohort Studies, Gene product, Young Adult, Internal medicine, Receptors, Transferrin, Genetics, medicine, Humans, Subtilisins, Molecular Biology, Genetics (clinical), Aged, Soluble transferrin receptor, Aged, 80 and over, biology, Transferrin saturation, Association Studies Articles, General Medicine, Middle Aged, Proprotein convertase, Ferritin, Endocrinology, Biochemistry, biology.protein, Female, Genome-Wide Association Study
Abstract: The level of body iron storage and the erythropoietic need for iron are indicated by the serum levels of ferritin and soluble transferrin receptor (sTfR), respectively. A meta-analysis of five genome-wide association studies on sTfR and ferritin revealed novel association to the PCSK7 and TMPRSS6 loci for sTfR and the HFE locus for both parameters. The PCSK7 association was the most significant (rs236918, P = 1.1 x 10E-27) suggesting that proprotein convertase 7, the gene product of PCSK7, may be involved in sTfR generation and/or iron homeostasis. Conditioning the sTfR analyses on transferrin saturation abolished the HFE signal and substantially diminished the TMPRSS6 signal while the PCSK7 association was unaffected, suggesting that the former may be mediated by transferrin saturation whereas the PCSK7-associated effect on sTfR generation appears to be more direct.
Published: 2010

48. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

Author: Arthur W. Musk, John P. Kemp, Ioanna Ntalla, Igor Rudan, Suzanne Miller, Anubha Mahajan, Samuli Ripatti, Nicholas J. Wareham, Alan F. Wright, Jennie Hui, Jing Hua Zhao, Jonathan Marten, Olli T. Raitakari, Henry Voelzke, John Beilby, John M. Starr, Robert A. Scott, Harry Campbell, Ma'en Obeidat, Deborah Jarvis, David C. Nickle, Markku Heliövaara, Nick Shrine, Lars Lind, David M. Evans, Richard Hubbard, John Henderson, Ozren Polasek, Panos Deloukas, James F. Wilson, María Soler Artigas, Ian P. Hall, Jennifer E. Huffman, Juan R. González, Joachim Heinrich, Mika Kähönen, Tim D. Spector, Neil C. Thomson, Christopher J Hammond, Marjo-Riitta Järvelin, Erik Ingelsson, Stefan Enroth, Ida Surakka, Andrew P. Morris, Ivana Kolcic, Louise V. Wain, Sarah H. Wild, Lynne J. Hocking, Wendy L. McArdle, Rajesh Rawal, Nina Hutri-Kähönen, Tatijana Zemunik, Åsa Johansson, Terho Lehtimäki, Christian Gieger, Veronique Vitart, Erik Melén, Sarah E. Harris, Medea Imboden, Holly Trochet, Momoko Horikoshi, Don D. Sin, Ian J. Deary, Pau Navarro, Alexessander Couto Alves, Ashok Kumar, Abdul Kader Kheirallah, Caroline Hayward, Stefan Karrasch, Alan James, Alexander Teumer, Ulf Gyllensten, Victoria E. Jackson, Eleftheria Zeggini, Ian D. Pavord, Holger Schulz, Anna-Liisa Hartikainen, Ana Viñuela, Anna Hansell, Nicole Probst-Hensch, Leo-Pekka Lyytikäinen, Pirro G. Hysi, Ian Sayers, Jonathan Marchini, Claudia Flexeder, David P. Strachan, Martin D. Tobin, Raquel Granell, Beate Stubbe, Corry-Anke Brandsma, Sven Glaeser, Janina S. Ried, Eva Albrecht, Yohan Bossé, Peter K. Joshi, Lorna M. Lopez, Sandosh Padmanabhan, Harald Grallert, Medical Research Council (MRC), Groningen Research Institute for Asthma and COPD (GRIAC), Institute for Molecular Medicine Finland, Clinicum, Department of Public Health, Biostatistics Helsinki, and Complex Disease Genetics
Subjects: Lung Diseases, Male, Vital capacity, UK BiLEVE, General Physics and Astronomy, Genome-wide association study, 0302 clinical medicine, Missing heritability problem, MISSING HERITABILITY, Forced Expiratory Volume, Genotype, SEQUENCE VARIANTS, WIDE ASSOCIATION, SUSCEPTIBILITY LOCUS, Lung, GENE-EXPRESSION, Genetics, Aged, 80 and over, 0303 health sciences, ARCHITECTURE, Multidisciplinary, Middle Aged, Aparell respiratori, 3. Good health, ddc, Multidisciplinary Sciences, Science & Technology - Other Topics, Female, Adult, European Continental Ancestry Group, Biology, OBSTRUCTIVE PULMONARY-DISEASE, Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, FEV1/FVC ratio, Young Adult, MD Multidisciplinary, Humans, SMOKING-BEHAVIOR, 1000 Genomes Project, Genetik, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, spirometry, lung function, genetics, ta1184, General Chemistry, ta3121, Heritability, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, Pulmons, FORCED VITAL CAPACITY, Imputation (genetics), Genètica, Genome-Wide Association Study
Abstract: Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P, Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
Published: 2015

49. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author: Philippe Froguel, Pekka Jousilahti, Harry Campbell, Ellen M. Schmidt, Vasiliki Lagou, John Andrew Pospisilik, Ivana Kolcic, Igor Rudan, Mark A. Sarzynski, Brigitte Kühnel, Robin Haring, Paul Knekt, Christian Gieger, Eero Kajantie, Jian Yang, Tuomas O. Kilpeläinen, Hans L. Hillege, Niek Verweij, Sarah H Wild, Torben Hansen, Leena Taittonen, Michael Boehnke, Mark I. McCarthy, Joel N. Hirschhorn, Åsa K. Hedman, D. Timothy Bishop, James F. Wilson, Jian'an Luan, Leo-Pekka Lyytikäinen, Nita G. Forouhi, Mark Walker, Elodie Eury, Konstantin Strauch, Aroon D. Hingorani, Nam H. Cho, Peter Vollenweider, Erkki Vartiainen, Jong-Young Lee, Fredrik Karpe, Jiali Han, Joanne M. Jordan, Chen Lu, Henri Wallaschofski, Anna A. E. Vinkhuyzen, Alan R. Shuldiner, David J. Hunter, Mario Falchi, Aron S. Buchman, Caroline S. Fox, Robert A. Scott, Chan Soo Shin, Fernando Rivadeneira, Zari Dastani, Veikko Salomaa, Weihua Zhang, Rui Li, John C. Chambers, Thorkild I. A. Sørensen, André G. Uitterlinden, David A. Bennett, Marianna Sanna, Claire Bellis, Lars Bertram, Karl Michaëlsson, Yingchang Lu, Marie Loh, Loic Yengo, Bok-Ghee Han, Priya Srikanth, Laura Pascoe, Peter Wagner, Philip L. De Jager, Oscar H. Franco, Yongmei Liu, Stavroula Kanoni, Simone Gärtner, Ruth J. F. Loos, Eric E. Schadt, Claes Ohlsson, Cornelia M. van Duijn, Jorma S. A. Viikari, Stephan J. L. Bakker, Tamara B. Harris, Pirro G. Hysi, Samuli Ripatti, John R. B. Perry, Stefan A. Czerwinski, Tune H. Pers, Angela Döring, Ghazaleh Fatemifar, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Carrie M. Nielson, Claudia Langenberg, Carolina Medina-Gomez, Mike A. Nalls, Erik Ingelsson, Barbara McKnight, Niels Grarup, L. Adrienne Cupples, Torben Jørgensen, Satu Männistö, Jianbo Na, Cristen J. Willer, Tuomo Rankinen, Irene Mateo Leach, Cecilia M. Lindgren, Marie-Claude Vohl, Ryan W. Walker, Yun Ju Sung, Joanne M. Murabito, Natasja M. van Schoor, Mika Kivimäki, Nicholas J. Wareham, Lei Yu, Markku Laakso, Julia A. Newton Bishop, Pim van der Harst, Qibin Qi, Veronique Bataille, Clive Osmond, Alan F. Wright, Audrey C. Choh, Charles C. White, Felix R. Day, Ron T. Gansevoort, Tiina Laatikainen, Ozren Polasek, Johan G. Eriksson, Mark M. Iles, Dena G. Hernandez, Meena Kumari, Dmitry Shungin, Jeffrey R. O'Connell, Joseph M. Zmuda, Antti Jula, Hyung Jin Choi, Albert Hofman, Steven R. Cummings, Youfang Liu, Vilmundur Gudnason, J. Brent Richards, Michael Stumvoll, Ayse Demirkan, Teresa Ferreira, Rosalie A. M. Dhonukshe-Rutten, Rahel Eckardt, Lude Franke, Karen L. Mohlke, Uzma Afzal, Kijoung Song, Till Ittermann, Janina S. Ried, Allan Linneberg, Nicholas D. Hastie, Laticia Oozageer, Johanna Kuusisto, John Blangero, Amélie Bonnefond, Panos Deloukas, Andrew P. Morris, Oluf Pedersen, Adam E. Locke, Emmi Tikkanen, Veronique Vitart, Aki S. Havulinna, Olli T. Raitakari, Inga Prokopenko, Peter Lichtner, Harm-Jan Westra, Katja Borodulin, Teemu Kuulasmaa, Lars Lind, Bradford Towne, Christine G. Lee, Mika Kähönen, Anke W. Enneman, Terrence S. Furey, Treva Rice, Abbas Dehghan, Jaspal S. Kooner, Dabeeru C. Rao, Terrence Forrester, Jing Hua Zhao, Xin Li, Mary F. Feitosa, Melissa E. Garcia, Tian Liu, Aarno Palotie, Eric S. Orwoll, Reedik Mägi, Daniel S. Evans, Elisabeth Widen, Tim D. Spector, Caroline Hayward, Annette Peters, Markku Heliövaara, Harald Grallert, Niina Eklund, Robert C. Kaplan, Ilja Demuth, Luigi Ferrucci, Kati Kristiansson, Amy Luke, Tõnu Esko, Ken K. Ong, Gregory J. Tranah, Angelo Tremblay, Ben A. Oostra, Stefan Gustafsson, Zhihong Zhu, Nina Smolej Narančić, Cameron D. Palmer, William R. Scott, Alexander Teumer, Anne U. Jackson, Markus Perola, Toshiko Tanaka, Lavinia Paternoster, Henry Völzke, Terho Lehtimäki, Dominik Spira, Karin M. A. Swart, Louis Pérusse, Matthias Blüher, Jari Lahti, M. Carola Zillikens, Kari E. North, Yvonne Boettcher, Douglas P. Kiel, Bamidele O. Tayo, Elisabeth Steinhagen-Thiessen, Diana L. Cousminer, Joanne E. Curran, Peter Kovacs, David M. Evans, Claude Bouchard, Alena Stančáková, Seppo Koskinen, Jack W. Kent, Alexander W. Drong, Massimo Mangino, Frédéric Fumeron, Richard S. Cooper, Juha Karjalainen, Nathalie van der Velde, Martin L. Buchkovich, Stéphane Lobbens, Cristina Menni, Anubha Mahajan, Nele Friedrich, Anke Tönjes, Colin A. McKenzie, Tom Forsén, Anne E. Justice, Lisette C. P. G. M. de Groot, Ingrid B. Borecki, Mingfeng Zhang, Tommy Cederholm, IOO, Internal medicine, Epidemiology and Data Science, EMGO - Musculoskeletal health, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Internal Medicine, Erasmus MC other, Epidemiology, Clinical Genetics, Institute for Molecular Medicine Finland, Clinicum, Department of General Practice and Primary Health Care, Behavioural Sciences, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Aarno Palotie / Principal Investigator, Johan Eriksson / Principal Investigator, Children's Hospital, Lastentautien yksikkö, University of Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Medicin och hälsovetenskap, Drosophila melanogaster/genetics, Nutrition and Disease, General Physics and Astronomy, Genome-wide association study, Medical and Health Sciences, Body fat percentage, Voeding en Ziekte, CUTANEOUS NEVI, Mass index, Human Nutrition & Health, Adiposity, INSULIN-RESISTANCE, Multidisciplinary, body fat, cardiometabolic traits, genome-wide association study, meta-analysis, biology, Disease genetics, Leptin, Humane Voeding & Gezondheid, COMMON VARIANTS, Public Health, Global Health, Social Medicine and Epidemiology, 3. Good health, Biological sciences, Cardiovascular diseases, Drosophila melanogaster, Gene Knockdown Techniques, ENERGY-BALANCE, Medical Genetics, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Heart Diseases, 515 Psychology, Science, Quantitative Trait Loci, PROVIDES INSIGHTS, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MASS INDEX, Insulin resistance, Internal medicine, MD Multidisciplinary, Genetics, medicine, Life Science, Animals, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Medicinsk genetik, VLAG, Global Nutrition, Wereldvoeding, Gene Expression Regulation/physiology, C-reactive protein, Metabolic diseases, General Chemistry, ta3121, medicine.disease, Onderwijsinstituut, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Adiposity/genetics, Drosophila melanogaster/metabolism, Genome-Wide Association Study, Heart Diseases/genetics, Quantitative Trait Loci/genetics, 030104 developmental biology, Endocrinology, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, Lean body mass, IDENTIFIES COMMON
Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P, A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.
Published: 2015

50. The impact of low-frequency and rare variants on lipid levels

Author: Martina Müller-Nurasyid, Matthew Blades, Natalia Tšernikova, Tune H. Pers, Sara M. Willems, Christine Power, Momoko Horikoshi, Harald Grallert, Vilja Pietiäinen, Christian Gieger, Lude Franke, Brenda W.J.H. Penninx, Cornelia M. van Duijn, Samuli Ripatti, Joris Deelen, P. Eline Slagboom, Johannes Kettunen, Jorma Viikari, Jeanette Erdmann, Andres Metspalu, Dorret I. Boomsma, Vasiliki Lagou, Matti Pirinen, Antti-Pekka Sarin, Veikko Salomaa, Markus Perola, Elina Ikonen, Inga Prokopenko, Olli Kallioniemi, Sara Hägg, Anders Hamsten, Stefan Gustafsson, Lars Lind, Marjo-Riitta Järvelin, Valeriya Lyssenko, Elina Hyppönen, Christian Hengstenberg, Martin D. Tobin, Patrik K. E. Magnusson, Gudmar Thorleifsson, Aarno Palotie, John Patrick Mpindi, Unnur Thorsteinsdottir, Benjamin Miraglio, Claes Ladenvall, Annette Peters, Christopher P. Nelson, Heribert Schunkert, Ida Surakka, Johannes H. Smit, Reedik Mägi, Christina Willenborg, Erik Ingelsson, Gonneke Willemsen, Johan G. Eriksson, A Isaacs, Janina S. Ried, Jaakko Kaprio, Letizia Marullo, Lennart C. Karssen, Tõnu Esko, Eco J. C. de Geus, Jouke-Jan Hottenga, Leif Groop, Kari Stefansson, Olli T. Raitakari, Sanna Timonen, Terho Lehtimäki, Mark I. McCarthy, Nilesh J. Samani, Anubha Mahajan, Jeanine J. Houwing-Duistermaat, Anton J. M. de Craen, Nancy L. Pedersen, Juha Karjalainen, Elisabeth M. van Leeuwen, Harm-Jan Westra, Antti Jula, Evelin Mihailov, Johan Rung, Marian Beekman, Teresa Ferreira, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Andrew P. Morris, Aki S. Havulinna, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Psychiatry, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, Surakka, Ida, Horikoshi, Momoko, Mägi, Reedik, Sarin, Antti-Pekka, Hyppönen, Elina, Ripatti, Samuli, ENGAGE Consortium, Epidemiology, and General Practice
Subjects: Netherlands Twin Register (NTR), Linkage disequilibrium, LIVER, LOCI, Genome-wide association study, Linkage Disequilibrium, DISEASE, GLUCOSE, Gene Frequency, Lipid Metabolism/genetics, HETEROGENEITY, Dyslipidemias/genetics, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, Single Nucleotide, ENGAGE Consortium, CD300, lipid genetics, Life Sciences & Biomedicine, Sequence Analysis, EXPRESSION, GENES, Mutation, Missense, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, SEQUENCE, Article, SIALOMUCIN, Humans, 1000 Genomes Project, Polymorphism, GENOME-WIDE ASSOCIATION, Allele frequency, Dyslipidemias, Science & Technology, cholesterol, Sequence Analysis, DNA, DNA, IN-VITRO, ta3121, 06 Biological Sciences, Lipid Metabolism, Genetic Loci, Expression quantitative trait loci, Mutation, Missense, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract: Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples,we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci,SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing. Refereed/Peer-reviewed
Published: 2015

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