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49 results on '"Laura, Portas"'

1. Left-sided heart failure burden and mortality in idiopathic pulmonary fibrosis: a population-based study

Author

Ardita Koteci, Ann D. Morgan, Laura Portas, Hannah R. Whittaker, Constantinos Kallis, Peter M. George, and Jennifer K. Quint

Subjects
Idiopathic pulmonary fibrosis, Left-sided heart failure, Epidemiology, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Cardiovascular disease is prevalent in idiopathic pulmonary fibrosis (IPF), yet the extent of left-sided heart failure (HF) burden, whether this has changed with time and whether HF impacts mortality risk in these patients are unknown. The aims of this study were therefore to determine the temporal trends in incidence and prevalence of left-sided HF in patients with IPF in England and compare these to published estimates in the general population and those with comparable chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD), as well as determine the risk of all-cause and cause-specific mortality in patients with comorbid left-sided HF and IPF at population-level using electronic healthcare data. Methods Clinical Practice Research Datalink (CPRD) Aurum primary-care data linked to mortality and secondary-care data was used to identify IPF patients in England. Left-sided HF prevalence and incidence rates were calculated for each calendar year between 2010 and 2019, stratified by age and sex. Risk of all-cause, cardiovascular and IPF-specific mortality was calculated using multivariate Cox regression. Results From 40,577patients with an IPF code in CPRD Aurum, 25, 341 IPF patients met inclusion criteria. Left-sided HF prevalence decreased from 33.4% (95% CI 32.2–34.6) in 2010 to 20.9% (20.0–21.7) in 2019. Left-sided HF incidence rate per 100 person-years (95% CI) remained stable between 2010 and 2017 but decreased from 4.3 (3.9–4.8) in 2017 to 3.4 (3.0–3.9) in 2019. Throughout follow-up, prevalence and incidence were higher in men and with increasing age. Comorbid HF was associated with poorer survival (adjusted HR (95%CI) 1.08 (1.03–1.14) for all-cause mortality; 1.32 (1.09–1.59) for cardiovascular mortality). Conclusion Left-sided HF burden in IPF patients in England remains high, with incidence almost 4 times higher than in COPD, a comparable lung disease with similar cardiovascular risk factors. Comorbid left-sided HF is also a poor prognostic marker. More substantial reduction in left-sided HF prevalence than incidence suggests persistently high IPF mortality. Given rising IPF incidence in the UK, this calls for better management of comorbidities such as left-sided HF to help optimise IPF survival.

Published
2022
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2. Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]

Author

Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain

Subjects
Medicine, Science
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Published
2021
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3. Variants associated with HHIP expression have sex-differential effects on lung function [version 1; peer review: 2 approved]

Author

Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain

Subjects
Medicine, Science
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Published
2020
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4. Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families

Author

Claire L. Simpson, Anthony M. Musolf, Qing Li, Laura Portas, Federico Murgia, Roberto Y. Cordero, Jennifer B. Cordero, Bilal A. Moiz, Emily R. Holzinger, Candace D. Middlebrooks, Deyana D. Lewis, Joan E. Bailey-Wilson, and Dwight Stambolian

Subjects
Myopia, Genetic linkage, Family studies, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. Methods Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. Results Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. Conclusions We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.

Published
2019
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5. Seroepidemiology of Measles, Mumps, Rubella and Varicella in Italian Female School Workers: A Cross-Sectional Study

Author

Nicola Frau, Federico Meloni, Jacopo Fostinelli, Laura Portas, Igor Portoghese, Emma Sala, Ilaria Pilia, Luigi Isaia Lecca, Giuseppe De Palma, and Marcello Campagna

Subjects
early childhood teacher, school teacher, protective immunity, vaccine-preventable disease, public health surveillance, seroprevalence, Medicine
Abstract

Background: Determining the proportion of susceptible workers can represent a first step to the biological risk assessment related to measles, mumps, rubella and varicella exposure. This study aimed to assess the immunity against measles, mumps, rubella and varicella viruses in a cohort of female school workers. Methods: A cross-sectional seroepidemiological study in a sample of 263 school workers undergoing routine annual workplace health surveillance program was conducted. As part of the health surveillance program, serum samples were collected and tested for measles, mumps, rubella and varicella IgG antibodies. Results: Overall seropositivity was 90.5%, 85.2%, 94.7% and 97.3% for measles, mumps, rubella and varicella, respectively. In relation to mumps occupation-specific seropositivity, a statistically significant difference was observed, showing the lowest prevalence of protected individuals in other occupation groups. Moreover, in relation to rubella, school workers born in Centre Italy had the lowest seropositivity of protective antibodies and the difference between groups was statistically significant. Measles and rubella seropositivity showed a significant decrease after 2015. Conclusions: This study showed a relevant proportion of school workers susceptible to the aforementioned diseases. These results highlighted the need for proper health surveillance and immunological controls in school workers, especially for females, and provided useful insights to policymakers to select effective strategies aimed at containing the risk of vaccine-preventable diseases at schools.

Published
2021
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6. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

Author

Qiao Fan, Virginie J. M. Verhoeven, Robert Wojciechowski, Veluchamy A. Barathi, Pirro G. Hysi, Jeremy A. Guggenheim, René Höhn, Veronique Vitart, Anthony P. Khawaja, Kenji Yamashiro, S Mohsen Hosseini, Terho Lehtimäki, Yi Lu, Toomas Haller, Jing Xie, Cécile Delcourt, Mario Pirastu, Juho Wedenoja, Puya Gharahkhani, Cristina Venturini, Masahiro Miyake, Alex W. Hewitt, Xiaobo Guo, Johanna Mazur, Jenifer E. Huffman, Katie M. Williams, Ozren Polasek, Harry Campbell, Igor Rudan, Zoran Vatavuk, James F. Wilson, Peter K. Joshi, George McMahon, Beate St Pourcain, David M. Evans, Claire L. Simpson, Tae-Hwi Schwantes-An, Robert P. Igo, Alireza Mirshahi, Audrey Cougnard-Gregoire, Céline Bellenguez, Maria Blettner, Olli Raitakari, Mika Kähönen, Ilkka Seppälä, Tanja Zeller, Thomas Meitinger, Janina S. Ried, Christian Gieger, Laura Portas, Elisabeth M. van Leeuwen, Najaf Amin, André G. Uitterlinden, Fernando Rivadeneira, Albert Hofman, Johannes R. Vingerling, Ya Xing Wang, Xu Wang, Eileen Tai-Hui Boh, M. Kamran Ikram, Charumathi Sabanayagam, Preeti Gupta, Vincent Tan, Lei Zhou, Candice E. H. Ho, Wan’e Lim, Roger W. Beuerman, Rosalynn Siantar, E-Shyong Tai, Eranga Vithana, Evelin Mihailov, Chiea-Chuen Khor, Caroline Hayward, Robert N. Luben, Paul J. Foster, Barbara E. K. Klein, Ronald Klein, Hoi-Suen Wong, Paul Mitchell, Andres Metspalu, Tin Aung, Terri L. Young, Mingguang He, Olavi Pärssinen, Cornelia M. van Duijn, Jie Jin Wang, Cathy Williams, Jost B. Jonas, Yik-Ying Teo, David A. Mackey, Konrad Oexle, Nagahisa Yoshimura, Andrew D. Paterson, Norbert Pfeiffer, Tien-Yin Wong, Paul N. Baird, Dwight Stambolian, Joan E. Bailey Wilson, Ching-Yu Cheng, Christopher J. Hammond, Caroline C. W. Klaver, Seang-Mei Saw, and Consortium for Refractive Error and Myopia (CREAM)

Subjects
Science
Abstract

This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

Published
2016
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7. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox

Subjects
Science
Abstract

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Published
2016
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8. Assessment of the burden of disease for patients with peripheral artery disease undergoing revascularization in England

Author

Laura Portas, Rupert Bauersachs, Kevin Bowrin, Jean-Baptiste Briere, Alexander Cohen, Maria Huelsebeck, Schuyler Jones, and Jennifer K Quint

Subjects
Adult, Peripheral Arterial Disease, Treatment Outcome, Cost of Illness, Lower Extremity, Risk Factors, Endovascular Procedures, Humans, Cardiology and Cardiovascular Medicine, Amputation, Surgical, Aged, Retrospective Studies
Abstract

Background: Symptoms, severity, and acuteness of peripheral artery disease (PAD) are major determinants of severe limb symptoms, subsequent risk of cardiovascular events, and mortality. Lower-extremity revascularization (LER) is a key option to relieve symptoms and to prevent limb loss in symptomatic patients with PAD. This study aimed to quantify the burden of disease among patients with PAD-LER in England. Methods: A retrospective population-based study of linked primary and secondary care electronic health records, included 13,869 adult patients (aged ⩾ 18 years) with PAD-LER from 2003 to 2018. The incidence of first ever PAD-LER was estimated both overall and by type of procedure (endovascular/surgical). Health resource utilization associated with PAD-related complications and treatment patterns were assessed. Results: A high annual incidence of lower-limb revascularization (41.2 per 1000 person years) and a nearly double incidence of endovascular first revascularization compared with open surgery were observed. More than 70% of patients with PAD-LER had a history of hyperlipidemia and hypertension and roughly one-third were diabetic and had a history of coronary artery disease. Cardiovascular mortality accounted for one-third (34.1 per 1000 person years) of all-cause mortality. Over 93% of patients were hospitalized for any reason and the commonest reasons for hospitalization were cardiovascular diseases and PAD with about one-third hospitalized for revascularization reoccurrence. Conclusion: There is a significant burden of PAD-LER to the individual and society with ongoing healthcare resource utilization, treatment, and increasing mortality.

Published
2022

9. Study of animal remains dug out during the excavations of a Nuragic village in Sardinia

Author

Laura Portas, Stefania Bagella, Vittorio Farina, Marcella Carcupino, Antonio Cacchioli, Ferdinando Gazza, and Marco Zedda

Subjects
Animal remains, Archaeological excavations, Nuragic settlement, Sardinia, Biology (General), QH301-705.5
Abstract

This paper presents the results of the zooarchaeological analysis of the faunal materials brought to light during the excavations set up in the Nuragic village surrounding the Santu Antine Nuraghe, near Torralba (Sassari), Sardinia. Precisely, the remains come from the structure of the village named by archaeologists hut 12. They are 779 specimens out of thousands animal remains from the whole archaeological site. The majority of the rests belong to sheep (Ovis aries) or goats (Capra hircus), cattle (Bos taurus), pigs (Sus scrofa) and deers (Cervus elaphus). Such material may provide suggestions about the productive use of animals in the village and point out the importance of the economical management of animals in the Nuragic society. Indeed, many remains show signs with human origin, which testify that the hut may have been a workplace where bone fragments were processed to obtain different kind of tools.

Published
2015
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10. Anatomical study of animal remains from Phoenician-Punic amphorae found in the Santa Giusta Pond, Sardinia (Italy)

Author

Laura Portas, Vittorio Farina, Carla Del Vais, Marcella Carcupino, Ferdinando Gazza, Ignazio Sanna, and Marco Zedda

Subjects
Phoenician-Punic amphorae, Sheep, Goat, Cattle, Zooarchaeology, Biology (General), QH301-705.5
Abstract

During the underwater excavations carried out in the Santa Giusta Pond, near Oristano, Sardinia, a significant amount of Phoenician- Punic materials was brought to light including amphorae (dating back to 7th-2nd century BC) and vegetal and animal remains. All of these archaeological finds may come from Othoca, an important Phoenician- Punic city on the eastern shore of the pond, geographically corresponding with the modern-day town of Santa Giusta. Animal materials consist of more than 3000 very well-preserved remains, belonging to sheep (Ovis aries), goat (Capra hircus) and cattle (Bos taurus). Bone analyses allowed reconstructing the slaughtering methods, as well as manipulation procedures carried out to preserve meat in order to be exported overseas. Although pig (Sus scrofa) played an important economical role in other Sardinian Phoenician-Punic settlements, in this archaeological context this species is absent, suggesting that the meat contained in the amphorae was probably destined to other areas of the Mediterranean basin, where people did not eat pork.

Published
2015
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12. Modulation of genetic associations with serum urate levels by body-mass-index in humans.

Author

Jennifer E Huffman, Eva Albrecht, Alexander Teumer, Massimo Mangino, Karen Kapur, Toby Johnson, Zoltán Kutalik, Nicola Pirastu, Giorgio Pistis, Lorna M Lopez, Toomas Haller, Perttu Salo, Anuj Goel, Man Li, Toshiko Tanaka, Abbas Dehghan, Daniela Ruggiero, Giovanni Malerba, Albert V Smith, Ilja M Nolte, Laura Portas, Amanda Phipps-Green, Lora Boteva, Pau Navarro, Asa Johansson, Andrew A Hicks, Ozren Polasek, Tõnu Esko, John F Peden, Sarah E Harris, Federico Murgia, Sarah H Wild, Albert Tenesa, Adrienne Tin, Evelin Mihailov, Anne Grotevendt, Gauti K Gislason, Josef Coresh, Pio D'Adamo, Sheila Ulivi, Peter Vollenweider, Gerard Waeber, Susan Campbell, Ivana Kolcic, Krista Fisher, Margus Viigimaa, Jeffrey E Metter, Corrado Masciullo, Elisabetta Trabetti, Cristina Bombieri, Rossella Sorice, Angela Döring, Eva Reischl, Konstantin Strauch, Albert Hofman, Andre G Uitterlinden, Melanie Waldenberger, H-Erich Wichmann, Gail Davies, Alan J Gow, Nicola Dalbeth, Lisa Stamp, Johannes H Smit, Mirna Kirin, Ramaiah Nagaraja, Matthias Nauck, Claudia Schurmann, Kathrin Budde, Susan M Farrington, Evropi Theodoratou, Antti Jula, Veikko Salomaa, Cinzia Sala, Christian Hengstenberg, Michel Burnier, Reedik Mägi, Norman Klopp, Stefan Kloiber, Sabine Schipf, Samuli Ripatti, Stefano Cabras, Nicole Soranzo, Georg Homuth, Teresa Nutile, Patricia B Munroe, Nicholas Hastie, Harry Campbell, Igor Rudan, Claudia Cabrera, Chris Haley, Oscar H Franco, Tony R Merriman, Vilmundur Gudnason, Mario Pirastu, Brenda W Penninx, Harold Snieder, Andres Metspalu, Marina Ciullo, Peter P Pramstaller, Cornelia M van Duijn, Luigi Ferrucci, Giovanni Gambaro, Ian J Deary, Malcolm G Dunlop, James F Wilson, Paolo Gasparini, Ulf Gyllensten, Tim D Spector, Alan F Wright, Caroline Hayward, Hugh Watkins, Markus Perola, Murielle Bochud, W H Linda Kao, Mark Caulfield, Daniela Toniolo, Henry Völzke, Christian Gieger, Anna Köttgen, and Veronique Vitart

Subjects
Medicine, Science
Abstract

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

Published
2015
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13. El baile de las mareas

Author

Laura Portas and Laura Portas

Abstract

Una vida truncada por la tragedia. Un destino caprichoso. Una voluntad capaz de bailar al son de las mareas. Vila de Pazos, principios del siglo XX. Aurora es una joven mariscadora a punto de casarse. Su lucha por labrarse un futuro da un giro cuando empieza a trabajar como sirvienta en un pazo señorial. Allí no solo se adentra en un mundo noble e hidalgo, sino que se convierte en la protagonista de una historia de amor, misterio e intereses cruzados entre las familias más poderosas de la villa. Rodeada de traiciones y envuelta en el aura enigmática de una Galicia tan mágica como misteriosa, Aurora deberá sobreponerse a su origen humilde para vencer las dificultades que se le presentan y reconstruir su vida. En su primera y fascinante novela, Laura Portas, natural de Cambados, recrea los escenarios que la vieron crecer para explorar una época sobre la que se ha documentado a la perfección. Todo lector que entre en esta novela emprenderá un apasionante viaje por las Rías Baixas de hace cien años, una tierra marinera de albariño, pazos, leyenda, pasiones y belleza sin igual.

Published
2024

14. Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.

Author

Claire L Simpson, Robert Wojciechowski, Konrad Oexle, Federico Murgia, Laura Portas, Xiaohui Li, Virginie J M Verhoeven, Veronique Vitart, Maria Schache, S Mohsen Hosseini, Pirro G Hysi, Leslie J Raffel, Mary Frances Cotch, Emily Chew, Barbara E K Klein, Ronald Klein, Tien Yin Wong, Cornelia M van Duijn, Paul Mitchell, Seang Mei Saw, Maurizio Fossarello, Jie Jin Wang, DCCT/EDIC Research Group, Ozren Polašek, Harry Campbell, Igor Rudan, Ben A Oostra, André G Uitterlinden, Albert Hofman, Fernando Rivadeneira, Najaf Amin, Lennart C Karssen, Johannes R Vingerling, Angela Döring, Thomas Bettecken, Goran Bencic, Christian Gieger, H-Erich Wichmann, James F Wilson, Cristina Venturini, Brian Fleck, Phillippa M Cumberland, Jugnoo S Rahi, Chris J Hammond, Caroline Hayward, Alan F Wright, Andrew D Paterson, Paul N Baird, Caroline C W Klaver, Jerome I Rotter, Mario Pirastu, Thomas Meitinger, Joan E Bailey-Wilson, and Dwight Stambolian

Subjects
Medicine, Science
Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Published
2014
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15. Communication of personalised disease risk by general practitioners to motivate smoking cessation in England: a cost-effectiveness and research prioritisation study

Author

Deborah Jarvis, Gianluca Baio, Laura Portas, Simone Accordini, Cosetta Minelli, Alessandro Marcon, and Alexander Adamson

Subjects
Adult, medicine.medical_specialty, Cost effectiveness, medicine.medical_treatment, Cost-Benefit Analysis, Medicine (miscellaneous), Disease, tobacco, State Medicine, Value of information, General Practitioners, cost-effectiveness analysis, general practitioner, personalised disease risk, smoking cessation, tobacco, value of information, Credible interval, medicine, Humans, Stroke, business.industry, Communication, cost-effectiveness analysis, personalised disease risk, Bayes Theorem, Odds ratio, Middle Aged, medicine.disease, value of information, Psychiatry and Mental health, England, general practitioner, Family medicine, Population study, Smoking cessation, Smoking Cessation, business
Abstract

BACKGROUND AND AIMS Communication of personalised disease risk can motivate smoking cessation. We assessed whether routine implementation of this intervention by general practitioners (GPs) in England is cost-effective or whether we need further research to better establish its effectiveness. DESIGN Cost-effectiveness analysis (CEA) with value of information (VoI) analysis from the UK National Health Service perspective, using GP communication of personalised disease risk on smoking cessation versus usual care. SETTING GP practices in England. STUDY POPULATION Healthy smokers aged 35-60 attending the GP practice. MEASUREMENTS Effectiveness of GP communication of personalised disease risk on smoking cessation was estimated through systematic review and meta-analysis. A Bayesian CEA was then performed using a lifetime Markov model on smokers aged 35-60 that measured lifetime costs and quality-adjusted life-years (QALYs) assigned to the four diseases contributing the most to smoking-related morbidity, mortality and costs: chronic obstructive pulmonary disease, lung cancer, myocardial infarction, and stroke. Costs and QALYs for each disease state were obtained from the literature. VoI analysis identified sources of uncertainty in the CEA and assessed how much would be worth investing in further research to reduce this uncertainty. FINDINGS The meta-analysis odds ratio for the effectiveness estimate of GP communication of personalised disease risk was 1.48 (95% credibility interval (CrI): 0.91-2.26), an absolute increase in smoking cessation rates of 3.84%. The probability of cost-effectiveness ranged from 89-94% depending on sex and age. VoI analysis indicated that: 1) uncertainty in the effectiveness of the intervention was the driver of the overall uncertainty in the CEA and 2) a research investment to reduce this uncertainty is justified if lower than £27.6million (£7 per smoker). CONCLUSIONS Evidence to date shows that, in England, incorporating disease risk communication into general practitioners' practices to motivate smoking cessation is likely to be cost-effective compared with usual care.

Published
2021

16. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Author

Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud

Subjects
Genetics, QH426-470
Abstract

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Published
2013
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17. Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33

Author

Claire L. Simpson, Federico Murgia, Dwight Stambolian, Elise Ciner, Anthony M. Musolf, Theresa Alexander, Joan E. Bailey-Wilson, and Laura Portas

Subjects
Male, Candidate gene, Genetic Linkage, Quantitative Trait Loci, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Locus heterogeneity, Genetic linkage, Myopia, Genetics, medicine, Humans, Family, Genetic Predisposition to Disease, Child, Genetics (clinical), 030304 developmental biology, Linkage (software), 0303 health sciences, Chromosomes, Human, Pair 12, 030305 genetics & heredity, Haplotype, Pennsylvania, medicine.disease, Child, Preschool, Chromosomes, Human, Pair 5, Microsatellite, Female, Amish, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

Myopia is one of the most common ocular disorders in the world, yet the genetic etiology of the disease remains poorly understood. Specialized founder populations, such as the Pennsylvania Amish, provide the opportunity to utilize exclusive genomic architecture, like unique haplotypes, to better understand the genetic causes of myopia. We perform genetic linkage analysis on Pennsylvania Amish families that have a strong familial history of myopia to map any potential causal variants and genes for the disease. 293 individuals from 25 extended families were genotyped on the Illumina ExomePlus array and merged with previous microsatellite data. We coded myopia affection as a binary phenotype; myopia was defined as having a mean spherical equivalent (MSE) of less than or equal to - 1 D (diopters). Two-point and multipoint parametric linkage analyses were performed under an autosomal dominant model. When allowing for locus heterogeneity, we identified two novel genome-wide significantly linked variants at 12q15 (heterogeneity LOD, HLOD = 3.77) in PTPRB and at 8q21.3 (HLOD = 3.35) in CNGB3. We identified further three genome-wide significant variants within a single family. These three variants were located in exons of SLC6A18 at 5p15.33 (LODs ranged from 3.51 to 3.37). Multipoint analysis confirmed the significant signal at 5p15.33 with six genome-wide significant variants (LODs ranged from 3.6 to 3.3). Further suggestive evidence of linkage was observed in several other regions of the genome. All three novel linked regions contain strong candidate genes, especially CNGB3 on 8q21.3, which has been shown to affect photoreceptors and cause complete color blindness. Whole genome sequencing on these regions is planned to conclusively elucidate the causal variants.

Published
2019
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18. Variants associated with

Author

Katherine A, Fawcett, Ma'en, Obeidat, Carl, Melbourne, Nick, Shrine, Anna L, Guyatt, Catherine, John, Jian'an, Luan, Anne, Richmond, Marta R, Moksnes, Raquel, Granell, Stefan, Weiss, Medea, Imboden, Sebastian, May-Wilson, Pirro, Hysi, Thibaud S, Boutin, Laura, Portas, Claudia, Flexeder, Sarah E, Harris, Carol A, Wang, Leo-Pekka, Lyytikäinen, Teemu, Palviainen, Rachel E, Foong, Dirk, Keidel, Cosetta, Minelli, Claudia, Langenberg, Yohan, Bossé, Maarten, Van den Berge, Don D, Sin, Ke, Hao, Archie, Campbell, David, Porteous, Sandosh, Padmanabhan, Blair H, Smith, David M, Evans, Sue, Ring, Arnulf, Langhammer, Kristian, Hveem, Cristen, Willer, Ralf, Ewert, Beate, Stubbe, Nicola, Pirastu, Lucija, Klaric, Peter K, Joshi, Karina, Patasova, Mangino, Massimo, Ozren, Polasek, John M, Starr, Stefan, Karrasch, Konstantin, Strauch, Thomas, Meitinger, Igor, Rudan, Taina, Rantanen, Kirsi, Pietiläinen, Mika, Kähönen, Olli T, Raitakari, Graham L, Hall, Peter D, Sly, Craig E, Pennell, Jaakko, Kaprio, Terho, Lehtimäki, Veronique, Vitart, Ian J, Deary, Debbie, Jarvis, James F, Wilson, Tim, Spector, Nicole, Probst-Hensch, Nicholas J, Wareham, Henry, Völzke, John, Henderson, David P, Strachan, Ben M, Brumpton, Caroline, Hayward, Ian P, Hall, Martin D, Tobin, and Louise V, Wain

Subjects
genome-wide interaction study, HHIP, expression, sex, lung function, Articles, Research Article
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Published
2020

19. Lung Development Genes and Adult Lung Function

Author

Peter Burney, Miguel Pereira, Seif O. Shaheen, Charlotte H. Dean, Stephanie J. London, Matthew Hind, Laura Portas, Annah B. Wyss, Cosetta Minelli, and Royal Brompton & Harefield NHS Foundation Trust

Subjects
Oncology, Male, Respiratory System, Respiratory Epidemiology, Critical Care and Intensive Care Medicine, 0302 clinical medicine, Risk Factors, Epidemiology, Medicine, 030212 general & internal medicine, Respiratory system, FEV1/FVC, Lung, 11 Medical and Health Sciences, Lung function, Aged, 80 and over, COPD, respiratory system, Middle Aged, Respiratory Function Tests, medicine.anatomical_structure, genetic association study, Respiratory Physiological Phenomena, Female, Growth and Development, Pulmonary and Respiratory Medicine, Adult, UK Biobank, endocrine system, medicine.medical_specialty, Polymorphism, Single Nucleotide, 03 medical and health sciences, FEV1/FVC ratio, Genetic association study, FVC, Internal medicine, Humans, Genetic Predisposition to Disease, Gene, Aged, business.industry, Original Articles, medicine.disease, United Kingdom, respiratory tract diseases, Adult life, 030228 respiratory system, business, Developmental Biology, Genome-Wide Association Study
Abstract

Rationale: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. Objectives: To systematically investigate the effects of lung development genes on adult lung function. Methods: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV1/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger subset to select the most promising signals and the smaller subset for replication. Measurements and Main Results: We identified 55 genes, of which 36 (16 for FVC, 19 for FEV1/FVC, and one for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 replicated at nominal significance level. Of the 55 genes, 53 fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-to-cell adhesion; extracellular matrix), suggesting that these specific processes are important for adult lung health. Conclusions: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.

Published
2020

20. Genome-wide association and functional follow-up reveals new loci for kidney function.

Author

Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, Man Li, Xiaoyi Gao, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Conall M O'Seaghdha, Nicole Glazer, Aaron Isaacs, Ching-Ti Liu, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Andrew D Johnson, Hinco J Gierman, Mary Feitosa, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Åsa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Chouraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tõnu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Margherita Cavalieri, Madhumathi Rao, Frank B Hu, Ayse Demirkan, Ben A Oostra, Mariza de Andrade, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Ivana Kolcic, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Karlhans Endlich, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polasek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Shamika Ketkar, Helen Colhoun, Alex Doney, Antonietta Robino, Franco Giulianini, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Marie Metzger, Paul Mitchell, Marina Ciullo, Stuart K Kim, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, David S Siscovick, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline C M Witteman, Caroline Hayward, Paul Ridker, Afshin Parsa, Murielle Bochud, Iris M Heid, Wolfram Goessling, Daniel I Chasman, W H Linda Kao, and Caroline S Fox

Subjects
Genetics, QH426-470
Abstract

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

Published
2012
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21. Analysis of 12,517 inhabitants of a Sardinian geographic isolate reveals that predispositions to thrombocytopenia and thrombocytosis are inherited traits

Author

Ginevra Biino, Carlo L. Balduini, Laura Casula, Piergiorgio Cavallo, Simona Vaccargiu, Debora Parracciani, Donatella Serra, Laura Portas, Federico Murgia, and Mario Pirastu

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background Thrombocytopenia is a common finding in several diseases but almost nothing is known about the prevalence of thrombocytopenia in the general population. We examined the prevalence of thrombocytopenia and determinants of platelet count in a healthy population with a wide age range.Design and Methods We performed a cross-sectional study on 12,517 inhabitants of ten villages (80% of residents) in a secluded area of Sardinia (Ogliastra). Participants underwent a complete blood count evaluation and a structured questionnaire, used to collect epidemiological data.Results We observed a platelet count lower than 150×109/L in 3.2% (2.8%–3.6%) of females and 4.8% (4.3%–5.4%) of males, with a value of 3.9% (3.6%–4.3%) in the entire population. Thrombocytopenia was mild (platelet count: 100×109/L–150×109/L), asymptomatic and not associated with other cytopenias or overt disorders in most cases. Its standardized prevalence was quite different in different villages, with values ranging from 1.5% to 6.8%, and was negatively correlated with the prevalence of a mild form of thrombocytosis, which ranged from 0.9% to 4.5%. Analysis of platelet counts across classes of age revealed that platelet number decreased progressively with aging. As a consequence, thrombocytopenia was nearly absent in young people and its prevalence increased regularly during lifetime. The opposite occurred for thrombocytosis.Conclusions Given the high genetic differentiation among Ogliastra villages with “high” and “low” platelet counts and the substantial heritability of this quantitative trait (54%), we concluded that the propensity to present mild and transient thrombocytosis in youth and to acquire mild thrombocytopenia during aging are new genetic traits.

Published
2011
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22. Genetic Variants Associated with Circulating Parathyroid Hormone

Author

Mattias Lorentzon, Federico Murgia, Daniel L. Koller, Mario Pirastu, Matthias Nauk, Claes Ohlsson, Hoi Suen Wong, Weihong Tang, Joshua C. Bis, Jerome I. Rotter, Elizabeth A. Streeten, Carrie M. Nielson, Marcus E. Kleber, Bruce M. Psaty, Elizabeth Selvin, Lu-Chen Weng, Jack Pattee, Kathleen A. Ryan, Anke Hannemann, Georg Homuth, Michael J. Econs, Josef Coresh, Brenda W.J.H. Penninx, Uwe Völker, Alexander Teumer, David S. Siscovick, Henri Wallaschofski, Joel Eriksson, Braxton D. Mitchell, Pamela L. Lutsey, James S. Pankow, Bryan Kestenbaum, Frances M K Williams, Myles Wolf, Laura Portas, Andrew D. Paterson, Joseph M. Zmuda, Caroline S. Fox, Munro Peacock, Dongbing Lai, Stefan Pilz, Eric S. Orwoll, Maria Nethander, Cassianne Robinson-Cohen, Karen M. Eny, Yuri Milaneschi, José A. Riancho, W. März, Ian H. de Boer, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, APH - Mental Health, and APH - Digital Health

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Clinical Sciences, Parathyroid hormone, human genetics, Genome-wide association study, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, CYP24A1, Clinical Research, Internal medicine, medicine, Genetics, parathyroid hormone, SNP, Humans, 2.1 Biological and endogenous factors, Clinical Epidemiology, Polymorphism, Aetiology, Aged, genome-wide association study, Prevention, Human Genome, Genetic Variation, General Medicine, Single Nucleotide, Middle Aged, Urology & Nephrology, medicine.disease, mineral metabolism, Minor allele frequency, Europe, 030104 developmental biology, Endocrinology, Good Health and Well Being, Nephrology, Parathyroid Hormone, Secondary hyperparathyroidism, Female, Hormone
Abstract

© 2017 by the American Society of Nephrology. Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Published
2017
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23. Myopia in African Americans Is Significantly Linked to Chromosome 7p15.2-14.2

Author

Roberto Y. Cordero, Deyana D. Lewis, Anthony M. Musolf, Federico Murgia, Elise Ciner, Candace D. Middlebrooks, Laura Portas, Claire L. Simpson, Dwight Stambolian, Joan E. Bailey-Wilson, and Jennifer B. Cordero

Subjects
Adult, Male, Candidate gene, Genotype, genetic association, Genetic Linkage, Population, Single-nucleotide polymorphism, Locus (genetics), family studies, Biology, Refraction, Ocular, Genetic linkage, Myopia, Genetics, Humans, Genetic Predisposition to Disease, linkage analysis, education, Exome, Genetic association, Philadelphia, education.field_of_study, Genome, Human, Incidence, Chromosome Mapping, Transmission disequilibrium test, Middle Aged, Pedigree, Black or African American, Female, Chromosomes, Human, Pair 7
Abstract

Purpose: The purpose of this study was to perform genetic linkage analysis and association analysis on exome genotyping from highly aggregated African American families with nonpathogenic myopia. African Americans are a particularly understudied population with respect to myopia. Methods: One hundred six African American families from the Philadelphia area with a family history of myopia were genotyped using an Illumina ExomePlus array and merged with previous microsatellite data. Myopia was initially measured in mean spherical equivalent (MSE) and converted to a binary phenotype where individuals were identified as affected, unaffected, or unknown. Parametric linkage analysis was performed on both individual variants (single-nucleotide polymorphisms [SNPs] and microsatellites) as well as gene-based markers. Family-based association analysis and transmission disequilibrium test (TDT) analysis modified for rare variants was also performed. Results: Genetic linkage analysis identified 2 genomewide significant variants at 7p15.2 and 7p14.2 (in the intergenic region between MIR148A and NFE2L3 and in the noncoding RNA LOC401324) and 2 genomewide significant genes (CRHR2 and AVL9) both at 7p14.3. No genomewide results were found in the association analyses. Conclusions: This study identified a significant linkage peak in African American families for myopia at 7p15.2 to 7p14.2, the first potential risk locus for myopia in African Americans. Interesting candidate genes are located in the region, including PDE1C, which is highly expressed in the eyes, and known to be involved in retinal development. Further identification of the causal variants at this linkage peak will help elucidate the genetics of myopia in this understudied population.

Published
2021
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24. SNPs associated withHHIPexpression have differential effects on lung function in males and females

Author

Peter D. Sly, Re Foong, Ozren Polasek, Nicole Probst-Hensch, Ian P. Hall, Graham L. Hall, Tobin, Pirro G. Hysi, Teemu Palviainen, Mika Kähönen, Veronique Vitart, Louise V. Wain, Carl A. Melbourne, Don D. Sin, Anna L. Guyatt, Henry Völzke, Ca Wang, Katherine A. Fawcett, David J. Porteous, John M. Starr, Claudia Langenberg, Igor Rudan, Ke Hao, Stefan Weiss, Terho Lehtimäki, Kirsi H. Pietiläinen, David M. Evans, Ian J. Deary, Jian'an Luan, James F. Wilson, David P. Strachan, Taina Rantanen, Catherine John, Nicola Pirastu, O T Raitakari, Berge M van den, Karina Patasova, Claudia Flexeder, Medea Imboden, Thibaud Boutin, Mangino Massimo, Archie Campbell, Lucija Klaric, Leo-Pekka Lyytikäinen, Nick Shrine, Sebastian May-Wilson, Beate Stubbe, Ralf Ewert, Dirk Keidel, Sarah E. Harris, Tim D. Spector, Ma'en Obeidat, John Henderson, Cosetta Minelli, Moksnes, Raquel Granell, Blair H. Smith, Arnulf Langhammer, Craig E. Pennell, Nicholas J. Wareham, Caroline Hayward, Ben Michael Brumpton, Yohan Bossé, Peter K. Joshi, Susan M. Ring, Sandosh Padmanabhan, Cristen J. Willer, Kristian Hveem, Deborah Jarvis, J Kaprio, Laura Portas, and Anne Richmond

Subjects
Spirometry, 0303 health sciences, COPD, medicine.medical_specialty, Lung, medicine.diagnostic_test, Single-nucleotide polymorphism, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Endocrinology, 030228 respiratory system, Internal medicine, medicine, SNP, Allele, Beta (finance), Lung function, 030304 developmental biology
Abstract

Adult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P−8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P−6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 × 10−15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1β = 0.028 [SE 0.0022] litres in males vs β = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function andHHIPexpression in lung tissue. In our analyses, whileHHIPexpression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 × 10−6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. Establishing the mechanism by whichHHIPSNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases, such as chronic obstructive pulmonary disease (COPD), in both sexes.

Published
2019
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25. M8 Cost variations of asthma over 10 years in adults

Author

Isabelle Pin, M Wacker, Davíð Gíslason, Joachim Heinrich, Angelo Corsico, Alessandro Marcon, Lucia Calciano, Laura Portas, Margaret W. Gerbase, Isa Cerveri, Christer Janson, Lucia Cazzoletti, Simone Accordini, Deborah Jarvis, Rune Grønseth, Rain Jõgi, and Ane Johannessen

Subjects
Disease status, European community, Disease severity, business.industry, Asthma severity, Medicine, National level, business, medicine.disease, Respiratory health, Demography, Cohort study, Asthma
Abstract

We investigated the 10 year variation of asthma cost by the change of disease severity/control in adults from 11 European countries taking part in a cohort study (the European Community Respiratory Health Survey – ECRHS). We identified 562 adults (aged 29–56) with physician-diagnosed current asthma at the ECRHS II (1999–2003, baseline) and ECRHS III (2010–2013). At each survey, they were classified as ‘intermittent’ or ‘persistent’ (GINA 2002) with persistent asthmatics further classified as ‘controlled/partly controlled’ (CP) or ‘uncontrolled’ (U) (GINA 2016). Change in disease status was considered ‘worsened’ (from intermittent to persistent, from CP to U or U at both the occasions; n=146), ‘improved’ (from persistent to intermittent, from U to CP or CP at both the occasions; n=136) or ‘unchanged’ (intermittent at the ECRHS II and ECRHS III; n=128). The annual cost per patient was computed from the societal perspective following the bottom-up approach, using rates/wages/prices obtained at national level in 2004 (ECRHS II; converted to a 2013 equivalent) and 2013 (ECRHS III). The variation of the annual cost per patient was estimated by the change in disease status using a 2-level random-intercept Laplace quantile regression model, adjusting for sex, age, ever smoking, low socio-economic status (centre: level 2 unit). At baseline, the mean annual cost was 193€, 790€ and 3,120€ per patient with intermittent, CP persistent or U persistent asthma, respectively. Compared to patients whose disease status was unchanged, those with an improved or worsened asthma showed reduced [−145 (95% CI: −275,–15) €; p=0.029] and increased [185 (95%CI: 59, 311) €; p=0.005] annual costs, respectively. Our study suggests substantial cost savings if asthma severity/control improved among adult patients in Europe.

Published
2018
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26. P116 Developing a risk prediction tool for spirometrically defined COPD in adults; experience from the ageing lungs in european cohorts project

Author

Deborah Jarvis, Jarvelin, A Adamson, Laura Portas, Fadlalla G. Elfadaly, Judith Garcia-Aymerich, Shyamali C. Dharmage, John Henderson, Cosetta Minelli, C Svanes, and Nicole Probst-Hensch

Subjects
Gerontology, Spirometry, COPD, education.field_of_study, medicine.diagnostic_test, business.industry, Population, Repeated measures design, Disease, medicine.disease, FEV1/FVC ratio, medicine, Lifetime risk, business, education, Personally identifiable information
Abstract

Background The EU H2020 funded Ageing Lungs in European Cohorts study (ALEC www.alecstudy.org) is a consortia of population-based birth and adult inception cohorts with repeated measures of spirometry several years apart. Using these data, ALEC aims to identify risk factors for spirometrically defined COPD, and to develop an online risk prediction tool for use by the public/physicians. Our systematic review of available risk prediction tools (Matheson et al IJCOPD 2018;13:1927–35) showed previous attempts had used numerous variables (most commonly smoking, sex and age), but current models could not accurately rule in nor rule out future risk of COPD. Method Using Bayesian statistical methods we developed a model to predict a subject’s lifetime risk of developing COPD (FEV1/FVC Results R shiny provides a technically suitable web-based interface for input of personal information and linkage to model outputs. Feedback from potential users was cautiously positive with concerns expressed regarding presentation of risk, provision of information to patients directing them for further health advice, limitation of underlying data to white Caucasian populations, interpretation/management of ‘low risk of COPD’ in those who smoked, and absence of risk prediction of exacerbations in those with established disease. Conclusion Using appropriate statistical methods, it is possible to develop a risk prediction model by combining data across cohorts even when they have not all collected exactly the same information. R Shiny provides a user-friendly means to create online disease risk prediction tools; however many challenges remain regarding full-scale implementation. These are common to many risk prediction tools.

Published
2018
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27. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Symen Ligthart, Ahmad Vaez, Urmo Võsa, Maria G. Stathopoulou, Paul S. de Vries, Bram P. Prins, Peter J. Van der Most, Toshiko Tanaka, Elnaz Naderi, Lynda M. Rose, Ying Wu, Robert Karlsson, Maja Barbalic, Honghuang Lin, René Pool, Gu Zhu, Aurélien Macé, Carlo Sidore, Stella Trompet, Massimo Mangino, Maria Sabater-Lleal, John P. Kemp, Ali Abbasi, Tim Kacprowski, Niek Verweij, Albert V. Smith, Tao Huang, Carola Marzi, Mary F. Feitosa, Kurt K. Lohman, Marcus E. Kleber, Yuri Milaneschi, Christian Mueller, Mahmudul Huq, Efthymia Vlachopoulou, Leo-Pekka Lyytikäinen, Christopher Oldmeadow, Joris Deelen, Markus Perola, Jing Hua Zhao, Bjarke Feenstra, Marzyeh Amini, Jari Lahti, Katharina E. Schraut, Myriam Fornage, Bhoom Suktitipat, Wei-Min Chen, Xiaohui Li, Teresa Nutile, Giovanni Malerba, Jian’an Luan, Tom Bak, Nicholas Schork, Fabiola Del Greco M., Elisabeth Thiering, Anubha Mahajan, Riccardo E. Marioni, Evelin Mihailov, Joel Eriksson, Ayse Bilge Ozel, Weihua Zhang, Maria Nethander, Yu-Ching Cheng, Stella Aslibekyan, Wei Ang, Ilaria Gandin, Loïc Yengo, Laura Portas, Charles Kooperberg, Edith Hofer, Kumar B. Rajan, Claudia Schurmann, Wouter den Hollander, Tarunveer S. Ahluwalia, Jing Zhao, Harmen H.M. Draisma, Ian Ford, Nicholas Timpson, Alexander Teumer, Hongyan Huang, Simone Wahl, YongMei Liu, Jie Huang, Hae-Won Uh, Frank Geller, Peter K. Joshi, Lisa R. Yanek, Elisabetta Trabetti, Benjamin Lehne, Diego Vozzi, Marie Verbanck, Ginevra Biino, Yasaman Saba, Ingrid Meulenbelt, Jeff R. O’Connell, Markku Laakso, Franco Giulianini, Patrik K.E. Magnusson, Christie M. Ballantyne, Jouke Jan Hottenga, Grant W. Montgomery, Fernando Rivadineira, Rico Rueedi, Maristella Steri, Karl-Heinz Herzig, David J. Stott, Cristina Menni, Mattias Frånberg, Beate St. Pourcain, Stephan B. Felix, Tune H. Pers, Stephan J.L. Bakker, Peter Kraft, Annette Peters, Dhananjay Vaidya, Graciela Delgado, Johannes H. Smit, Vera Großmann, Juha Sinisalo, Ilkka Seppälä, Stephen R. Williams, Elizabeth G. Holliday, Matthijs Moed, Claudia Langenberg, Katri Räikkönen, Jingzhong Ding, Harry Campbell, Michele M. Sale, Yii-Der I. Chen, Alan L. James, Daniela Ruggiero, Nicole Soranzo, Catharina A. Hartman, Erin N. Smith, Gerald S. Berenson, Christian Fuchsberger, Dena Hernandez, Carla M.T. Tiesler, Vilmantas Giedraitis, David Liewald, Krista Fischer, Dan Mellström, Anders Larsson, Yunmei Wang, William R. Scott, Matthias Lorentzon, John Beilby, Kathleen A. Ryan, Craig E. Pennell, Dragana Vuckovic, Beverly Balkau, Maria Pina Concas, Reinhold Schmidt, Carlos F. Mendes de Leon, Erwin P. Bottinger, Margreet Kloppenburg, Lavinia Paternoster, Michael Boehnke, A.W. Musk, Gonneke Willemsen, David M. Evans, Pamela A.F. Madden, Mika Kähönen, Zoltán Kutalik, Magdalena Zoledziewska, Ville Karhunen, Stephen B. Kritchevsky, Naveed Sattar, Genevieve Lachance, Robert Clarke, Tamara B. Harris, Olli T. Raitakari, John R. Attia, Diana van Heemst, Eero Kajantie, Rossella Sorice, Giovanni Gambaro, Robert A. Scott, Andrew A. Hicks, Luigi Ferrucci, Marie Standl, Cecilia M. Lindgren, John M. Starr, Magnus Karlsson, Lars Lind, Jun Z. Li, John C. Chambers, Trevor A. Mori, Eco J.C.N. de Geus, Andrew C. Heath, Nicholas G. Martin, Juha Auvinen, Brendan M. Buckley, Anton J.M. de Craen, Melanie Waldenberger, Konstantin Strauch, Thomas Meitinger, Rodney J. Scott, Mark McEvoy, Marian Beekman, Cristina Bombieri, Paul M. Ridker, Karen L. Mohlke, Nancy L. Pedersen, Alanna C. Morrison, Dorret I. Boomsma, John B. Whitfield, David P. Strachan, Albert Hofman, Peter Vollenweider, Francesco Cucca, Marjo-Riitta Jarvelin, J. Wouter Jukema, Tim D. Spector, Anders Hamsten, Tanja Zeller, André G. Uitterlinden, Matthias Nauck, Vilmundur Gudnason, Lu Qi, Harald Grallert, Ingrid B. Borecki, Jerome I. Rotter, Winfried März, Philipp S. Wild, Marja-Liisa Lokki, Michael Boyle, Veikko Salomaa, Mads Melbye, Johan G. Eriksson, James F. Wilson, Brenda W.J.H. Penninx, Diane M. Becker, Bradford B. Worrall, Greg Gibson, Ronald M. Krauss, Marina Ciullo, Gianluigi Zaza, Nicholas J. Wareham, Albertine J. Oldehinkel, Lyle J. Palmer, Sarah S. Murray, Peter P. Pramstaller, Stefania Bandinelli, Joachim Heinrich, Erik Ingelsson, Ian J. Deary, Reedik Mägi, Liesbeth Vandenput, Pim van der Harst, Karl C. Desch, Jaspal S. Kooner, Claes Ohlsson, Caroline Hayward, Terho Lehtimäki, Alan R. Shuldiner, Donna K. Arnett, Lawrence J. Beilin, Antonietta Robino, Philippe Froguel, Mario Pirastu, Tine Jess, Wolfgang Koenig, Ruth J.F. Loos, Denis A. Evans, Helena Schmidt, George Davey Smith, P. Eline Slagboom, Gudny Eiriksdottir, Andrew P. Morris, Bruce M. Psaty, Russell P. Tracy, Ilja M. Nolte, Eric Boerwinkle, Sophie Visvikis-Siest, Alex P. Reiner, Myron Gross, Joshua C. Bis, Lude Franke, Oscar H. Franco, Emelia J. Benjamin, Daniel I. Chasman, Josée Dupuis, Harold Snieder, Abbas Dehghan, Behrooz Z. Alizadeh, H. Marike Boezen, Gerjan Navis, Marianne Rots, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Emelia Benjamin, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Josh Bis, Nathan Pankratz, Alex Rainer, James G. Wilson, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Terho Lehtimaki, Yalda Jamshidi, Sophie Siest, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey-Smith, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, J. Rotter, Ken Rice, Leslie Lange, Eco de Geus, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, Eline P. Slagboom, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center Groningen [Groningen] (UMCG), University of Isfahan, University of Tartu, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The University of Texas Health Science Center at Houston (UTHealth), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Brigham and Women's Hospital [Boston], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Split, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Process & Energy Laboratory, Delft University of Technology (TU Delft), Grand Lyon : communauté urbaine de Lyon, Interuniversity Cardiology Institute Netherlands, Department of Twin Research and Genetic Epidemiology, King's College London, London, Huazhong University of Science and Technology [Wuhan] (HUST), Division of Statistical Genomics, Washington University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Institut fuer Theoretische Physik (Institut fuer Theoretische Physik), Universität Heidelberg [Heidelberg] = Heidelberg University, Molecular Epidemiology, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Mahidol University [Bangkok], Northwest A and F University, Laboratoire d'Optimisation des Systèmes Industriels (LOSI), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Institute of Genetics and Biophysics, CNR, Naples, Università degli studi di Verona = University of Verona (UNIVR), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], University of Maryland School of Medicine, University of Maryland System, Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Pop. Genetics, CNR, Sassari, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, IT University of Copenhagen (ITU), Robertson Centre for Biostatistics, University of Glasgow, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, King‘s College London, Jinan University [Guangzhou], Institute of Oceanology [China], School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Shardna life science Pula Cagliari, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Medstar Research Institute, Department of Cardiology, Ernst-Moritz-Arndt University, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Department of Epidemiology, Harvard School of Public Health, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Metacohorts Consortium, INEOS Technologies (SWITZERLAND), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, University of Edinburgh, School of Population Health [Crawley, Western Australia], The University of Western Australia (UWA), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), The Scripps Translational Science Institute and Scripps Health, Tulane Center for Cardiovascular Health, Tulane University Health Sciences Center, Centre for Population Health Sciences, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Luleå University of Technology (LUT), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Austrian Institute of Technology [Vienna] (AIT), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC), Department of Rheumatology and Clinical Epidemiology [Leiden University Medical Center] (LUMC), Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden-Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Virginia, Tampere University Hospital, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Department of Pathological Biochemistry, Royal Infirmary, Oxford University, University of Oxford, University of Newcastle [Callaghan, Australia] (UoN), Department of neurology, Institute of Metabolic Science, MRC, The Wellcome Trust Centre for Human Genetics [Oxford], Uppsala Universitet [Uppsala], QIMR Berghofer Medical Research Institute, Institute of Genetic Epidemiology [Neuherberg, Germany], Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Schizophrenia Research Institute [Sydney], Department of Genetics, University of North Carolina System (UNC)-University of North Carolina System (UNC), Vrije Universiteit Brussel (VUB), Population Health Sciences and Education, St George's University of London, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Health Sciences and Biocenter Oulu, University of Oulu, Medizinische Klinik und Poliklinik, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institute of Clinical Chemistry and Laboratory Medicine, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Departments of Epidemiology and Nutrition, Institute of Epidemiology [Neuherberg] (EPI), Medical University Graz, Transplantation Laboratory [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], CLinical Psychology, Genetics and Pathology, Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Center For Narcolepsy, Stanford University, Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh, University of Maryland School of Medicine [Baltimore, MD, USA], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Physics [Stockholm], Stockholm University, University of Bristol [Bristol], Universiteit Leiden, Department of Epidemiology, University of Washington, University of Washington [Seattle], Department of Epidemiology [Rotterdam], University of Groningen [Groningen], Dutch Initiative on Crohn and Colitis (ICC), Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Physiology and Biophysics [Jackson, MS, USA], University of Southern Mississippi (USM), Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Department of Social Medicine, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Mathematical Institute [Oxford] (MI), Institute of Psychiatry, Psychology & Neuroscience, King's College London, LifeLines Cohort Study, CHARGE Inflammation Working Group, Ligthart, S., Vaez, A., Vosa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Mace, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikainen, L. -P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H. R., Wijmenga, C., Amini, M., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y. -H., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., Slagboom, E. P., Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W. -M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco, M. F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y. -C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H. -W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K. -H., Stott, D. J., Menni, C., Franberg, M., S, t. Pourcain B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Grossmann, V., Sinisalo, J., Seppala, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Raikkonen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y. -D. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellstrom, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kahonen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., Mcevoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M. -R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., Marz, W., Wild, P. S., Lokki, M. -L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Magi, R., Vandenput, L., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Loos, R. J. F., Evans, D. A., Schmidt, H., Slagboom, P. E., Tracy, R. P., Visvikis-Siest, S., Reiner, A. P., Bis, J. C., Franco, O. H., Benjamin, E. J., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Epidemiology, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), VU University medical center, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, APH - Digital Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Universität Heidelberg [Heidelberg], University of Verona (UNIVR), Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), IT University of Copenhagen, Technical University of Denmark [Lyngby] (DTU), Consiglio Nazionale delle Ricerche (CNR), University of Virginia [Charlottesville], Université de Lausanne (UNIL), University of Oxford [Oxford], University of Newcastle [Australia] (UoN), Centre d'économie industrielle i3 (CERNA i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Helmholtz-Zentrum München (HZM), Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Universitätsmedizin der Johannes-Gutenberg Universität Mainz, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Cardiff University-Medical Research Council, University of California-University of California, and DE CARVALHO, Philippe

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Bipolar Disorder, LD SCORE REGRESSION, [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, inflammatory disorder, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, ta318, International HapMap Project, Child, Genetics (clinical), 2. Zero hunger, Genetics, Genetics & Heredity, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C-reactive proteingenome-wide association studyinflammationMendelian randomizationinflammatory disordersDEPICTcoronary artery diseaseschizophreniasystem biology, system biology, DEPICT, Mendelian Randomization Analysis, 11 Medical And Health Sciences, Middle Aged, C-reactive protein, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, Adolescent, Adult, Aged, Biomarkers, C-Reactive Protein, Female, Genetic Loci, Genome-Wide Association Study, Humans, Inflammation, Liver, Metabolic Networks and Pathways, Schizophrenia, Young Adult, 3. Good health, [SDV] Life Sciences [q-bio], Medical genetics, Biomarker (medicine), Life Sciences & Biomedicine, Human, medicine.medical_specialty, CHARGE Inflammation Working Group, Biology, IMMUNITY, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, CORONARY-HEART-DISEASE, Mendelian Randomization Analysi, 1000 Genomes Project, METAANALYSIS, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, ta1184, Metabolic Networks and Pathway, Biomarker, INSTRUMENTS, 06 Biological Sciences, 030104 developmental biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, LifeLines Cohort Study
Abstract

International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.

Published
2018
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28. Cost variations of asthma over 10 years in adults

Author

Angelo Corsico, Deborah Jarvis, Laura Portas, Margaret W. Gerbase, Isa Cerveri, Simone Accordini, Margarethe Wacker, Alessandro Marcon, Lucia Cazzoletti, Lucia Calciano, Rain Jögi, Joachim Heinrich, David Gislason, Rune Grønseth, Isabelle Pin, Ane Johannessen, and Christer Janson

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Medicine, business, medicine.disease, Asthma
Published
2018
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29. Asthma control and decline in FEV1/FVC ratio over 10 years in adults

Author

Deborah Jarvis, Lucia Cazzoletti, Simone Accordini, Bénédicte Leynaert, Angelo Corsico, Christer Janson, David Gislason, Joachim Heinrich, Josep M. Antó, Alessandro Marcon, Isabelle Pin, Joost Weyler, Rain Jõgi, Judith Garcia-Aymerich, Ane Johannessen, Andrei Malinovschi, Laura Portas, and Isa Cerveri

Subjects
medicine.medical_specialty, business.industry, Total ige, respiratory system, medicine.disease, Annual change, Lung function, asthma control, respiratory tract diseases, Uncontrolled asthma, FEV1/FVC ratio, Lung function, asthma control, Asthma control, Internal medicine, medicine, In patient, business, Asthma
Abstract

Persistent symptoms may predict greater lung function decline in patients with asthma. As part of the ALEC study (EU Horizon 2020 grant #633212), we evaluated FEV1/FVC decline over 10 years in adult asthmatics by disease control and daily ICS use. In the ECRHS II study (1999-2002, baseline), 440 subjects (aged 29-55) with a physician-diagnosed current asthma were classified as well-controlled (non-daily ICS use, n=126; daily ICS use, n=19), partially controlled (145; 33) or uncontrolled (72; 45) patients (GINA 2006). The annual change in pre-bronchodilator FEV1/FVC ratio (%/year) between the ECRHS II and ECRHS III (2010-2013) was computed adjusting for gender, age, smoking habits, BMI and total IgE (>100 kU/L) by a 2-level random-intercept linear model (centre: level 2 unit). On average, patients had a lower FEV1/FVC ratio at baseline according to decreased levels of asthma control (from 79.4 to 73.2%; p Adults with uncontrolled asthma have greater decline in FEV1/FVC ratio compared to well-controlled subjects even if they report daily ICS use. Those in contact with the hospital seem to be at particular risk of greater decline.

Published
2018
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30. A three-generation study on the association of tobacco smoking with asthma

Author

Angelo Corsico, John W. Holloway, Lucia Calciano, Joachim Heinrich, Bertil Forsberg, Bénédicte Leynaert, Sandra Dorado Arenas, Jesús Martínez-Moratalla Rovira, Deborah Jarvis, Roberto Bono, Anne-Elie Carsin, Julia Dratva, Dennis Nowak, Joost Weyler, Vivi Schlünssen, Shyamali C. Dharmage, Alessandro Marcon, Cecilie Svanes, Francisco Gómez Real, Randi Jacobsen Bertelsen, Andrei Malinovschi, Pascal Demoly, Christer Janson, Lennart Bråbäck, Bryndis Benediktsdottir, Simone Accordini, José Luis Sánchez-Ramos, Rain Jõgi, Ane Johannessen, Laura Portas, Mathias Holm, Chantal Raherison, Isabelle Pin, Medical Research Council (MRC), Commission of the European Communities, CIBER de Epidemiología y Salud Pública (CIBERESP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), University of Verona (UNIVR), Cancer environnement (EPICENE ), 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)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'allergologie et de pneumologie [Hôpital Arnaud de Villeneuve], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Department of Medicine and Public Health, Università degli Studi di Verona, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, Male, Parents, fathers' smoking during puberty, Epidemiology, Respiratory Medicine and Allergy, [SDV]Life Sciences [q-bio], Ageing Lungs in European Cohorts (ALEC) Study, RESPIRATORY-HEALTH-SURVEY, OBSTRUCTIVE LUNG-DISEASE, 616: Innere Medizin und Krankheiten, smoking during pregnancy, mothers' smoking during pregnancy, Risk Factors, Tabac, father, fathers’ smoking during puberty, Medicine, Meðganga, Young adult, Child, Lungmedicin och allergi, Public, Environmental & Occupational Health, Smoking, 0104 Statistics, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Foreldrar, Middle Aged, grandmothers’ smoking during pregnancy, Astmi, Obstructive lung disease, 3. Good health, Europe, smoking during puberty, PREGNANCY, 1117 Public Health And Health Services, Child, Preschool, Prenatal Exposure Delayed Effects, Cohort, Multilevel Analysis, Regression Analysis, Asthma, mothers’ smoking during pregnancy, grandmothers’ smoking during pregnancy, fathers’ smoking during puberty, multilevel mediation model, Ageing Lungs in European Cohorts (ALEC) Study, Female, TRANSGENERATIONAL RESPONSES, Biological plausibility, Reykingar, Life Sciences & Biomedicine, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Offspring, mothers’ smoking during pregnancy, INHERITANCE, 03 medical and health sciences, Arbetsmedicin och miljömedicin, Young Adult, Environmental health, Tobacco, Tobacco Smoking, MATERNAL NICOTINE EXPOSURE, Humans, COHORT, multilevel mediation model, tobacco smoking, Preschool, Asma, Asthma, Aged, Pregnancy, ageing lungs in European cohorts (ALEC) stud, Science & Technology, business.industry, Infant, Newborn, Australia, Infant, CHILDHOOD ASTHMA, Occupational Health and Environmental Health, medicine.disease, Newborn, Health Surveys, Grandparents, grandmothers' smoking during pregnancy, mothers, parent, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, Óbeinar reykingar, Human medicine, Smoking in pregnancy, business, FOLLOW-UP
Abstract

Publisher's version (útgefin grein), Background Mothers’ smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers’ smoking may have a similar effect, and biological plausibility that fathers’ smoking during adolescence may influence offspring’s health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma. Methods Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged ≤51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents’ (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Results Fathers’ smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01–2.01] and mothers’ smoking during pregnancy (RRR = 1.27, 95% CI: 1.01–1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers’ smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17–2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02–1.55). Conclusions Fathers’ smoking during early adolescence and grandmothers’ and mothers’ smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception., The present analyses are part of the Ageing Lungs in European Cohorts (ALEC) Study [www.alecstudy.org], which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 633212. The coordination of the European Community Respiratory Health Survey (ECRHS) was supported by the European Commission (phases 1 and 2) and the Medical Research Council (phase 3). Local funding agencies for the ECRHS are reported in the Supplementary Appendix, available as Supplementary data at IJE online. Conflict of interest: J.W.H. reports grants from the European Union’s Horizon 2020 programme (633212), the Medical Research Council UK (MC_PC_15078) and the National Institutes of Health USA (R01 AI091905, R01 AI121226) during the conduct of the study. R.J. reports grants from the Estonian Research Council (personal grant No. 562) during the conduct of the study, grants/grants pending from the Estonian Research Council (personal research grant No. 562), personal fees for consulting and lecturing from GlaxoSmithKline, Boehringer and Novartis and travel/accommodation/meeting expenses paid by GlaxoSmithKline and Boehringer, outside the submitted work. C.R. reports personal fees for consulting and lecturing from ALK, Astra Zeneca, GSK, Boheringer and Novartis, outside the submitted work. A.G.C. reports grants from Chiesi Farmaceutici and GlaxoSmithKline Italy, during the conduct of the study. P.D. reports personal fees for consulting and lecturing from ALK and Stallergenes Greer and personal fees for consulting from Circassia, Chiesi Farmaceutici, ThermofisherScientific and Menarini, outside the submitted work. D.J. reports grants from the Medical Research Council and the European Union’s Horizon 2020 programme, during the conduct of the study. All other authors declare no competing interests.

Published
2018
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31. Myopia in Chinese families shows linkage to 10q26.13

Author

Anthony M, Musolf, Claire L, Simpson, Kyle A, Long, Bilal A, Moiz, Deyana D, Lewis, Candace D, Middlebrooks, Laura, Portas, Federico, Murgia, Elise B, Ciner, Joan E, Bailey-Wilson, and Dwight, Stambolian

Subjects
Adult, Male, Chromosomes, Human, Pair 10, Genetic Linkage, Tumor Suppressor Proteins, High-Temperature Requirement A Serine Peptidase 1, eye diseases, Asian People, Haplotypes, Genetic Loci, Myopia, Humans, Family, Female, Genetic Predisposition to Disease, Carrier Proteins, Child, Aged, Retrospective Studies, Research Article
Abstract

Purpose To determine genetic linkage between myopia and Han Chinese patients with a family history of the disease. Methods One hundred seventy-six Han Chinese patients from 34 extended families were given eye examinations, and mean spherical equivalent (MSE) in diopters (D) was calculated by adding the spherical component of the refraction to one-half the cylindrical component and taking the average of both eyes. The MSE was converted to a binary phenotype, where all patients with an MSE of -1.00 D or less were coded as affected. Unaffected individuals had an MSE greater than 0.00 D (ages 21 years and up), +1.50 (ages 11–20), or +2.00 D (ages 6–10 years). Individuals between the given upper threshold and −1.00 were coded as unknown. Patients were genotyped on an exome chip. Three types of linkage analyses were performed: single-variant two-point, multipoint, and collapsed haplotype pattern (CHP) variant two-point. Results The CHP variant two-point results identified a significant peak (heterogeneity logarithm of the odds [HLOD] = 3.73) at 10q26.13 in TACC2. The single-variant two-point and multipoint analyses showed highly suggestive linkage to the same region. The single-variant two-point results identified 25 suggestive variants at HTRA1, also at 10q26.13. Conclusions We report a significant genetic linkage between myopia and Han Chinese patients at 10q26.13. 10q26.13 contains several good candidate genes, such as TACC2 and the known age-related macular degeneration gene HTRA1. Targeted sequencing of the region is planned to identify the causal variant(s).

Published
2017

32. Late Breaking Abstract - The socio-economic cost of asthma, COPD and chronic bronchitis in Europe

Author

Christer Janson, Rune Grønseth, Angelo Corsico, Laura Portas, Rain Jõgi, Isabelle Pin, Ane Johannessen, David Gislason, Joachim Heinrich, Margaret W. Gerbase, Alessandro Marcon, Isa Cerveri, Lucia Cazzoletti, Deborah Jarvis, Simone Accordini, and Margarethe Wacker

Subjects
Chronic bronchitis, COPD, medicine.medical_specialty, education.field_of_study, business.industry, Phlegm, Population, medicine.disease, respiratory tract diseases, FEV1/FVC ratio, Chronic cough, Internal medicine, Economic cost, medicine, medicine.symptom, education, business, Asthma
Abstract

Background: The present study is aimed at providing a real-world evaluation of the economic cost of asthma, COPD and chronic bronchitis among adults in Europe. Methods: A prevalence-based cost-of-illness study was carried out on subjects (aged 39-68 years) with asthma (n=965), COPD (post-bronchodilator FEV1/FVC Results: The mean annual cost per patient with asthma was EUR 1467 (95%CI: 1112-1862) and it was largely driven (56.6%) by premature retirement/productivity losses/leisure time forgone. The cost of COPD ranged from EUR 227 (95%CI: 48-517) among the patients without coexisting chronic cough or phlegm to EUR 1725 (95%CI: 176-3918) among the patients with these symptoms. The cost of chronic bronchitis was EUR 233 (95%CI: 99-415). When the costs due to comorbidities were included in our estimates, the mean annual cost per patient dramatically increased for all diseases (e.g. asthma: EUR 3689; COPD with coexisting chronic cough or phlegm: EUR 4439). Conclusions: Among the European adults, the cost of asthma, COPD and chronic bronchitis is substantial even in patients identified from the general population.

Published
2017
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33. Three-generation effects of tobacco smoking on lung function within the paternal line

Author

Bryndis Benediktsdottir, Lucia Calciano, Cecilie Svanes, Shyamali C. Dharmage, Alessandro Marcon, Jesús Martínez-Moratalla Rovira, Francisco Gómez Real, Lennart Bråbäck, Rain Jõgi, Laura Portas, Ane Johannessen, Mathias Holm, Vivi Schlünssen, José Luis Sánchez-Ramos, Andrei Malinovschi, Simone Accordini, Deborah Jarvis, and Randi Jacobsen Bertelsen

Subjects
Chronic bronchitis, Pregnancy, COPD, business.industry, Offspring, Grandparent, respiratory system, 010501 environmental sciences, medicine.disease, 01 natural sciences, respiratory tract diseases, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, medicine, 030212 general & internal medicine, Respiratory system, business, circulatory and respiratory physiology, 0105 earth and related environmental sciences, Asthma, Demography
Abstract

Mothers’ smoking in pregnancy may permanently affect the development of the lungs in offspring and may cause heritable modifications of the epigenome. Little is known regarding the preconception effects of smoking on offspring’s lung function within the paternal line. We assessed the effects of grandmothers’ smoking in pregnancy and fathers’ smoking in puberty ( 1 (or FVC) as the outcome; fathers9 pre-bronchodilator FEV 1 /FVC as the mediator; grandmothers’ smoking habits, grandparents’ reported asthma/COPD/emphysema/chronic bronchitis, fathers’ age and smoking habits, offspring’s age, gender, height and smoking habits as potential predictors. Grandparents’ respiratory diseases were associated with a reduced FEV 1 /FVC in fathers (-2.7%; p=0.047) and, in turn, a lower FEV 1 /FVC in fathers was associated with a reduced FEV 1 in their offspring (1-percent decrease: -1.4 cl; p 1 /FVC (-2.2%; p=0.045) and had a direct effect on offspring’s FEV 1 (-6.8 cl; p=0.058). Fathers’ smoking in puberty reduced both FEV 1 (-6.4 cl; p Our preliminary results show that grand-maternal and paternal smoking may affect lung function across three generations. This analysis is part of the ALEC Study (EU Horizon 2020 Grant N° 633212).

Published
2017
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34. Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p

Author

Elise Ciner, Laura Portas, Bilal A. Moiz, Anthony M. Musolf, Kyle A. Long, Joan E. Bailey-Wilson, Federico Murgia, Claire L. Simpson, and Dwight Stambolian

Subjects
0301 basic medicine, Adult, Male, Candidate gene, Genotype, Genotyping Techniques, Genetic Linkage, case-control study, Quantitative Trait Loci, Genome-wide association study, Single-nucleotide polymorphism, family studies, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Myopia, Genetics, Humans, Exome, linkage analysis, Genome, Human, Chromosomes, Human, Pair 11, Haplotype, Chromosome Mapping, Penetrance, 3. Good health, Pedigree, 030104 developmental biology, 030221 ophthalmology & optometry, Female, Lod Score, Genome-Wide Association Study
Abstract

Purpose Myopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia. Methods Individuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed. Results Single variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13. Conclusions We identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region.

Published
2017

35. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

Author

Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)

Subjects
Netherlands Twin Register (NTR), Erythrocytes, Genome-wide association study, UNCERTAINTY, Regulatory Sequences, Nucleic Acid, VARIANTS, ANNOTATION, COLORECTAL-CANCER, Histones, 0302 clinical medicine, BINDING, Cluster Analysis, Myeloid Cells, Genetics (clinical), Genetics, hematological trait, 0303 health sciences, Chromosome Mapping, MRP4 ABCC4, Chromatin, Nucleosomes, Phenotype, Organ Specificity, 030220 oncology & carcinogenesis, Blood Platelets, Quantitative Trait Loci, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, DYNAMIN 3, 03 medical and health sciences, Quantitative Trait, Heritable, MEGAKARYOCYTES, Humans, Cell Lineage, ddc:610, GENOME-WIDE ASSOCIATION, Enhancer, Transcription factor, Gene, ChIA-PET, 030304 developmental biology, Research, Genetic Variation, DNA, Chromatin Assembly and Disassembly, Genetic architecture, Gene Expression Regulation, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Published
2013
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36. Association between candidate gene polymorphisms and asthma severity in adults. A Bayesian analysis

Author

Lucia Calciano, Marcello Ferrari, Giovanni Malerba, Simone Accordini, Laura Portas, Cristina Bombieri, and John R. Thompson

Subjects
Genetics, Candidate gene, medicine.medical_specialty, COPD, education.field_of_study, business.industry, Population, Single-nucleotide polymorphism, medicine.disease, FCER1A, Internal medicine, Credible interval, Medicine, SNP, business, education, Asthma
Abstract

Aim: The present analysis is aimed at identifying genetic variants associated with disease severity in adult subjects with ever asthma. Methods: We evaluated 326 subjects (aged 20-64) with ever asthma, who were identified from the general population between 2008 and 2010 in Verona (Italy), in the Gene Environment Interactions in Respiratory Diseases study. A panel of 236 tag-SNPs, which are representative of 51 candidate gene regions with a previous indication of a possible association with asthma/COPD/rhinitis, was genotyped by a custom GoldenGate Genotyping Assay. Measures of asthma severity were: a Symptom frequency and anti-asthmatic Treatment intensity Score (STS), which ranges from 0 to 10 (high values represent severe conditions), and pre-bronchodilator FEV1%predicted. The association of SNPs with STS and FEV1%predicted was evaluated by using Bayesian least absolute shrinkage and selection operator zero-inflated Poisson and linear regression models, respectively. These models allows the simultaneous selection of genetic variants and the estimation of their effect, adjusting for the effect of gender, BMI and smoking habits. Results: SNP rs2427829 in FCER1A is significantly associated with FEV1%predicted (mean = -0.323, 95% credible interval=[-4.533, -0.2677]). SNP rs676750 in CHML (mean= -0.2482, 95% credible interval=[-0.434, -0.072]), rs4334089 in VDR (mean= -0.255, 95% credible interval=[-0.254, -0.059]) and rs11080344 in NOS2 (mean= -0.2239, 95% credible interval=[-0.390, -0.064]) are independently associated with STS. Conclusion: These preliminary results suggest that FCER1A, CHML, VDR and NOS2 could play a role in disease severity among adult subjects with ever asthma.

Published
2016
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37. A population-based study of an Italian genetic isolate reveals that mean platelet volume is not a risk factor for thrombosis

Author

Carlo L. Balduini, Federico Murgia, Mario Pirastu, Ginevra Biino, Laura Portas, Debora Parracciani, and Simona Vaccargiu

Subjects
Adult, Male, medicine.medical_specialty, Genetic Linkage, Population, Comorbidity, Risk Assessment, Varicose Veins, Age Distribution, Pregnancy, Risk Factors, Internal medicine, Varicose veins, Prevalence, Humans, Medicine, Genetic Predisposition to Disease, Platelet, Obesity, Sex Distribution, Risk factor, Mean platelet volume, education, education.field_of_study, Platelet Count, business.industry, Thrombosis, Hematology, Middle Aged, medicine.disease, Surgery, Venous thrombosis, Italy, Cardiology, Population study, Female, medicine.symptom, business
Abstract

Introduction Several studies revealed that mean platelet volume (MPV) was larger in the acute phase of arterial and venous thrombosis and predicted a poor clinical outcome. It has been suggested that MPV is a risk factor for thrombosis. However, it is unclear whether increased platelet size is a cause or a consequence of thrombosis. It was the objective of this study to verify whether MPV is a risk factor for arterial and venous thrombosis. Methods We search for associations between platelet parameters and thrombosis by a population-based study in 11,084 inhabitants of an Italian genetic isolate characterized by wide variability of platelet parameters. To validate this methodology of investigation, we also evaluated whether it was able to identify several well known thrombotic risk factors in the study population. Results Statistical analysis confirmed that male gender, ageing, hypertension, high total cholesterol, low HDL cholesterol, diabetes, obesity and smoking were risk factors for arterial thrombosis, while alcohol consumption had a protective effect. Female gender, ageing, pregnancy, estroprogestinic treatment, obesity, varicose veins were associated with venous thrombosis. At variance, MPV and platelet count were unrelated to previous thrombotic events. However, MPV was negatively correlated with the time since the last thrombotic event. Conclusions This study indicated that an epidemiologic study of a population isolate is appropriate for the identification of thrombotic risk factors, but it failed to identify such a role for MPV. Thus, we suggest that the increased MPV previously described in subjects with acute thrombosis was a consequence instead of a cause of thrombosis.

Published
2012
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38. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Author

W. H. Linda Kao, Nicole Probst-Hensch, Florian Ernst, Paul Mitchell, Christa Meisinger, Florian Kronenberg, Sharon L.R. Kardia, Paul M. Ridker, Vilmundur Gudnason, Jeanette S. Andrews, Ming-Huei Chen, Frank B. Hu, Jean-Charles Lambert, Mario Pirastu, Ozren Polasek, Xiaoyi Gao, Sven Bergmann, Catherine Helmer, Wilmar Igl, Jie Jin Wang, Barry I. Freedman, Anke Tönjes, Jacqueline C. M. Witteman, Sheila Ulivi, Conall M. O'Seaghdha, Mika Kähönen, Mariza de Andrade, Daniel I. Chasman, Meredith C. Foster, Rossella Sorice, Mathias Gorski, Eric Boerwinkle, Karlhans Endlich, Maksim Struchalin, Bernhard K. Krämer, Bénédicte Stengel, Caroline Hayward, Giorgio Pistis, Andres Metspalu, Peter Kovacs, Jorma Viikari, Guo Li, Cristian Pattaro, Adrienne Tin, Igor Rudan, Christian Gieger, Mary F. Feitosa, Stephen T. Turner, Gary C. Curhan, Shamika Ketkar, Ian Ford, Peter Vollenweider, Wolfgang Koenig, Madhumathi Rao, Iris M. Heid, Stuart K. Kim, Heather E. Wheeler, Matthias Olden, Hinco J. Gierman, Alex S. F. Doney, Lenore J. Launer, Mladen Boban, Georg Homuth, Paolo Gasparini, Harshal Deshmukh, Henry Völzke, Daniela Ruggiero, Medea Imboden, Elizabeth J. Atkinson, Ben A. Oostra, Stefan Coassin, Ute Nöthlings, Marilyn C. Cornelis, David S. Siscovick, Yongmei Liu, Gian Andri Thun, Gunnar Jacobs, Franco Giulianini, Uwe Völker, Tõnu Esko, Alexander Teumer, Jeffrey R. O'Connell, Brendan M. Buckley, Heyo K. Kroemer, Albert V. Smith, Ulf Gyllensten, Federico Murgia, Man Li, Harry Campbell, Antonietta Robino, Abbas Dehghan, Inga Prokopenko, Shih-Jen Hwang, Sylvia Stracke, Michael Stumvoll, Alan R. Shuldiner, Christian Fuchsberger, Claudia Hundertmark, Luigi Ferrucci, David Ellinghaus, Laura Portas, Caroline S. Fox, Afshin Parsa, Carsten A. Böger, Toshiko Tanaka, Terho Lehtimäki, Ayse Demirkan, James F. Wilson, Elizabeth G. Holliday, Yurii S. Aulchenko, Murielle Bochud, Helen M. Colhoun, Jingzhong Ding, Nicole L. Glazer, Rainer Rettig, Bernhard Paulweber, Margherita Cavalieri, Andre Franke, Ingrid B. Borecki, Olli T. Raitakari, Josef Coresh, Tamara B. Harris, Sarah H. Wild, Reinhold Schmidt, Ching-Ti Liu, Zoltán Kutalik, André G. Uitterlinden, J. Wouter Jukema, Helena Schmidt, Martin Adam, Audrey Y. Chu, Fernando Rivadeneira, Cornelia M. van Duijn, Braxton D. Mitchell, Gudny Eiriksdottir, Tatijana Zemunik, Andrew D. Johnson, Ghazal Zaboli, Reiner Biffar, Thor Aspelund, Cinzia Sala, Peter P. Pramstaller, Veronique Vitart, Michael A. Province, Anna Köttgen, Nicholas D. Hastie, Daniel Taliun, Marina Ciullo, Cosetta Minelli, Kurt Lohman, Matthias Nauck, Thomas Illig, Alan F. Wright, Albert Hofman, Colin N. A. Palmer, Daniela Toniolo, Qiong Yang, Lina Zgaga, Åsa Johansson, Margot Haun, Stella Trompet, Aaron Isaacs, Reedik Mägi, Tiit Nikopensius, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Internal Medicine, Chasman, Di, Fuchsberger, C, Pattaro, C, Teumer, A, Böger, Ca, Endlich, K, Olden, M, Chen, Mh, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, Mc, O'Seaghdha, Cm, Glazer, N, Isaacs, A, Liu, Ct, Smith, Av, O'Connell, Jr, Struchalin, M, Tanaka, T, Li, G, Johnson, Ad, Gierman, Hj, Feitosa, Mf, Hwang, Sj, Atkinson, Ej, Lohman, K, Cornelis, Mc, Johansson, A, Tönjes, A, Dehghan, A, Lambert, Jc, Holliday, Eg, Sorice, R, Kutalik, Z, Lehtimäki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, Ay, Murgia, F, Trompet, S, Imboden, M, Coassin, S, Pistis, G, Cardiogram, Consortium, Icbp, Consortium, the CARe, Consortium, Wtccc2, Harris, Tb, Launer, Lj, Aspelund, T, Eiriksdottir, G, Mitchell, Bd, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, F, Demirkan, A, Oostra, Ba, de Andrade, M, Turner, St, Ding, J, Andrews, J, Freedman, Bi, Giulianini, F, Koenig, W, Illig, T, Meisinger, C, Gieger, C, Zgaga, L, Zemunik, T, Boban, M, Minelli, C, Wheeler, He, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Ernst, F, Homuth, G, Kroemer, Hk, Nauck, M, Stracke, S, Völker, U, Völzke, H, Kovacs, P, Stumvoll, M, Mägi, R, Hofman, A, Uitterlinden, Ag, Rivadeneira, F, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, Jj, Stengel, B, Ruggiero, D, Bergmann, S, Kähönen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, Antonietta, Krämer, Bk, Portas, L, Ford, I, Buckley, Bm, Adam, M, Thun, Ga, Paulweber, B, Haun, M, Sala, C, Mitchell, P, Ciullo, M, Kim, Sk, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, Paolo, Pirastu, M, Jukema, Jw, Probst Hensch, Nm, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, D, van Duijn, Cm, Borecki, Ib, Kardia, Sl, Liu, Y, Curhan, Gc, Rudan, I, Gyllensten, U, Wilson, Jf, Franke, A, Pramstaller, Pp, Rettig, R, Prokopenko, I, Witteman, J, Hayward, C, Ridker, Pm, Parsa, A, Bochud, M, Heid, Im, Kao, Wl, Fox, C, and Köttgen, A.

Subjects
Candidate gene, Amino Acid Transport Systems, Basic/genetics, Genome-wide association study, Gene, Genome, Inhibin-beta Subunits/genetics, GWAS, kidney, eGFR, Genetics (clinical), Inhibin-beta Subunits, Glomerular Filtration Rate/genetics, Genetics, 0303 health sciences, Genetic Predisposition to Disease/genetics, Association Studies Articles, 030305 genetics & heredity, Intracellular Signaling Peptides and Proteins, General Medicine, Low Density Lipoprotein Receptor-Related Protein-2/genetics, Polymorphism, Single Nucleotide/genetics, LRP2, 3. Good health, Low Density Lipoprotein Receptor-Related Protein-2, Genome-Wide Association Study/methods, Single Nucleotide/genetics, Glomerular Filtration Rate, Fusion Regulatory Protein 1, Heavy Chain, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome-Wide Association Studies, Humans, SNP, Genetic Predisposition to Disease, ddc:610, Membrane Proteins/genetics, Polymorphism, Molecular Biology, 030304 developmental biology, Genetic association, Fusion Regulatory Protein 1, Heavy Chain/genetics, Fusion Regulatory Protein 1, Genes, Kidney Function, Membrane Proteins, ta3121, Amino Acid Transport Systems, Basic, Amino Acid Transport Systems, Basic/genetics, Heavy Chain/genetics, Intracellular Signaling Peptides and Proteins/genetics, Candidate Disease Gene, Genome-Wide Association Study
Abstract

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Published
2012

39. Anatomical study of animal remains from Phoenician-Punic amphorae found in the Santa Giusta Pond, Sardinia (Italy)

Author

Marco Zedda, Carla Del Vais, Vittorio Farina, I. Sanna, Marcella Carcupino, Laura Portas, and Ferdinando Gazza

Subjects
Sheep, biology, Biochemistry (medical), Context (language use), Excavation, Plant Science, Zooarchaeology, biology.organism_classification, Archaeology, Mediterranean Basin, General Biochemistry, Genetics and Molecular Biology, language.human_language, Phoenician-Punic amphorae, Geography, lcsh:Biology (General), language, Capra hircus, Goat, Cattle, Phoenician, Ovis, lcsh:QH301-705.5
Abstract

During the underwater excavations carried out in the Santa Giusta Pond, near Oristano, Sardinia, a significant amount of Phoenician- Punic materials was brought to light including amphorae (dating back to 7th-2nd century BC) and vegetal and animal remains. All of these archaeological finds may come from Othoca, an important Phoenician- Punic city on the eastern shore of the pond, geographically corresponding with the modern-day town of Santa Giusta. Animal materials consist of more than 3000 very well-preserved remains, belonging to sheep (Ovis aries), goat (Capra hircus) and cattle (Bos taurus). Bone analyses allowed reconstructing the slaughtering methods, as well as manipulation procedures carried out to preserve meat in order to be exported overseas. Although pig (Sus scrofa) played an important economical role in other Sardinian Phoenician-Punic settlements, in this archaeological context this species is absent, suggesting that the meat contained in the amphorae was probably destined to other areas of the Mediterranean basin, where people did not eat pork.

Published
2015

40. Study of animal remains dug out during the excavations of a Nuragic village in Sardinia

Author

Stefania Bagella, Laura Portas, Ferdinando Gazza, Marcella Carcupino, Vittorio Farina, Marco Zedda, and Antonio Cacchioli

Subjects
biology, Biochemistry (medical), Excavation, Plant Science, biology.organism_classification, Sardinia, Archaeology, General Biochemistry, Genetics and Molecular Biology, Geography, lcsh:Biology (General), Nuragic settlement, Capra hircus, Cervus elaphus, Archaeological excavations, Ovis, Animal remains, lcsh:QH301-705.5
Abstract

This paper presents the results of the zooarchaeological analysis of the faunal materials brought to light during the excavations set up in the Nuragic village surrounding the Santu Antine Nuraghe, near Torralba (Sassari), Sardinia. Precisely, the remains come from the structure of the village named by archaeologists hut 12. They are 779 specimens out of thousands animal remains from the whole archaeological site. The majority of the rests belong to sheep (Ovis aries) or goats (Capra hircus), cattle (Bos taurus), pigs (Sus scrofa) and deers (Cervus elaphus). Such material may provide suggestions about the productive use of animals in the village and point out the importance of the economical management of animals in the Nuragic society. Indeed, many remains show signs with human origin, which testify that the hut may have been a workplace where bone fragments were processed to obtain different kind of tools.

Published
2015

41. Biomarkers related to respiratory symptoms and lung function in adults with asthma

Author

Mario Olivieri, Marcello Ferrari, Maria Elisabetta Zanolin, Laura Portas, Lucia Calciano, Angelo Corsico, Roberto de Marco, Anna Fratta Pasini, Alessandro G. Fois, Simone Accordini, Paolo Degan, and Andrea Pasini

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Population, Disease, Dinoprost, Nitric Oxide, Severity of Illness Index, Gastroenterology, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, peripheral blood cells, Internal medicine, Severity of illness, medicine, oxidative stress, Humans, Peripheral blood cell, FeNO, 030212 general & internal medicine, asthma severity, FeNO, biomarkers, lung function, oxidative stress, peripheral blood cells, respiratory symptoms, Respiratory system, education, Asthma, education.field_of_study, asthma severity, business.industry, Respiration, respiratory symptoms, Exhalation, lung function, medicine.disease, Respiratory Function Tests, Breath Tests, 030228 respiratory system, Female, business, Biomarkers
Abstract

Background: There is a need for easily measurable biomarkers that are able to identify different levels of asthma severity. Aim: To assess the association between peripheral blood cell counts, fractional nitric oxide in exhaled air (FeNO), urinary biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine and 8-isoprostane), and asthma severity in adult patients from the general population. Methods: In the Gene Environment Interactions in Respiratory Diseases study, 287 subjects with asthma (aged 20–64) were identified from the general population in Verona (Italy) (2008–2010). Self-reported asthma attacks, asthma-like symptoms and the use of hospital services in the past year were synthesized in a score of respiratory symptoms (SRS). The association of biomarkers with SRS and lung function measures (pre-bronchodilator FEV1% predicted and FEV1/FVC) was assessed using quasi-Poisson and Gaussian regression models, respectively. Results: Eosinophils (ratio of expected scores: RES[95%CI] = 1.19[1.09,1.30]), basophils (RES[95%CI] = 1.24[1.10,1.40]), lymphocytes (RES[95%CI] = 1.27[1.12,1.45]) and FeNO (RES[95%CI] = 1.18[1.02,1.37]) were positively associated with SRS. However, only eosinophils (RES[95%CI] = 1.15[1.02,1.30]) and lymphocytes (RES[95%CI] = 1.25[1.06,1.47]) showed an independent association. Furthermore, eosinophils (change in the expected outcome for 1-SD increase: CEO[95%CI] = −1.18[−2.09, −0.27]%), basophils (CEO[95%CI] = −1.24[−2.16, −0.33]%) and lymphocytes (CEO[95%CI] = −1.07[−1.99, −0.14]%) were individually, but not independently, associated with FEV1/FVC. Finally, neutrophils were negatively associated with FEV1% predicted (CEO[95%CI] = −2.22[−4.00, −0.44]%). Conclusions: We identified a pattern of association between a set of biomarkers and asthma endotypes in adult patients from the general population, which could improve understanding of the heterogeneity and severity of the disease and could be useful in defining targeted therapeutic approaches.

Published
2018
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42. Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function

Author

Afshin Parsa, 1§ Christian Fuchsberger, 2§ Anna Köttgen, 3, 4§ Conall M. O'Seaghdha, 5, 6§ Cristian Pattaro, 7§ Mariza de Andrade, 8§ Daniel I. Chasman, 9, 11 Alexander Teumer, 12 Karlhans Endlich, Matthias Olden, 15 Ming-Huei Chen, 17 Adrienne Tin, 4 Young J. Kim, 125 Daniel Taliun, 7 Man Li, 4 Mary Feitosa, 18 Mathias Gorski, 20 Qiong Yang, 21 Claudia Hundertmark, 22 Meredith C. Foster, 5 Nicole Glazer, 23 Aaron Isaacs, 25 Madhumathi Rao, 26 Albert V. Smith, 28 Jeffrey R. O'Connell, 29 Maksim Struchalin, 30 Toshiko Tanaka, 31 Guo Li, 32 Shih-Jen Hwang, 5 Elizabeth J. Atkinson, 8 Kurt Lohman, 33 Marilyn C. Cornelis, 34 Åsa Johansson, 35 Anke Tönjes, 37 Abbas Dehghan, 38 Vincent Couraki39 Elizabeth G. Holliday, 41 Rossella Sorice, 42 Zoltan Kutalik, 44 Terho Lehtimäki, 45 Tõnu Esko, 47 Harshal Deshmukh, 48 Sheila Ulivi, 49 Audrey Y. Chu, 50 Federico Murgia, 51 Stella Trompet, 52 Medea Imboden, 118 Barbara Kollerits, 54 Giorgio Pistis, 55 Tamara B. Harris, 56 Lenore J. Launer, 56 Thor Aspelund, 28 Gudny Eiriksdottir, 27 Braxton D. Mitchell, 29 Eric Boerwinkle, 57 Helena Schmidt, 58 Edith Hofer, 59 Frank Hu, 34 Ayse Demirkan, 24 Ben A. Oostra, 126 Stephen T. Turner, 60 Jingzhong Ding, 61 Jeanette S. Andrews, 62 Barry I. Freedman, 63 Franco Giulianini, 64 Wolfgang Koenig, 65 Thomas Illig, 116, 117Angela Döring, 20 H.-Erich Wichmann, 68 Lina Zgaga, 69 Tatijana Zemunik, 70 Mladen Boban, 70 Cosetta Minelli, 7 Heather E. Wheeler, 72 Wilmar Igl, 35 Ghazal Zaboli, 35 Sarah H Wild, 69 Alan F Wright, 73 Harry Campbell, 69 David Ellinghaus, 74 Ute Nöthlings, 121, 122 Gunnar Jacobs, 121 Reiner Biffar, 76 Florian Ernst, 12 Georg Homuth, 12 Heyo K. Kroemer, 77 Matthias Nauck, 78 Sylvia Stracke, 79 Uwe Völker, 12 Henry Völzke, 80 Peter Kovacs, 81 Michael Stumvoll, 37 Reedik Mägi, 83 Albert Hofman, 38 Andre G. Uitterlinden, 84 Fernando Rivadeneira, 84 Yurii S Aulchenko, 38 Ozren Polasek, 85 Nick Hastie, 86 Veronique Vitart, 86 Catherine Helmer, 88 Jie Jin Wang, 90 Bénédicte Stengel, 124 Daniela Ruggiero, 42 Sven Bergmann, 44 Mika Kähönen, 92 Jorma Viikari, 93 Tiit Nikopensius, 94 Michael Province, 18 Helen Colhoun, 48 Alex Doney, 95 Antonietta Robino, 49 Bernhard K. Krämer, 96 Laura Portas, 51 Ian Ford, 97 Brendan M. Buckley, 98 Martin Adam, 118 Gian-Andri Thun, 118 Bernhard Paulweber, 99 Margot Haun, 100 Cinzia Sala, 55 Paul Mitchell, 89 Marina Ciullo, 42 Peter Vollenweider, 101 Olli Raitakari, 102 Andres Metspalu, 47 Colin Palmer, 103 Paolo Gasparini, 49 Mario Pirastu, 51 J. Wouter Jukema, 104, 119, 120 Nicole M. Probst-Hensch, 118 Florian Kronenberg, 54 Daniela Toniolo, 128 Vilmundur Gudnason, 28 Alan R. Shuldiner, 105 Josef Coresh, 4, 106 Reinhold Schmidt, 59 Luigi Ferrucci, 31 Cornelia M. van Duijn, 127 Ingrid Borecki, 18 Sharon L.R. Kardia, 107 Yongmei Liu, 33 Gary C. Curhan, 108 Igor Rudan, 69 Ulf Gyllensten, 35 James F. Wilson, 69 Andre Franke, 74 Peter P. Pramstaller, 7 Rainer Rettig, 109 Inga Prokopenko, 123 Jacqueline Witteman, 38 Caroline Hayward, 86 Paul M Ridker, 110 Murielle Bochud, 111 Iris M. Heid, 112, 113 David S. Siscovick, 32§ Caroline S. Fox, 114§ W. Linda Kao, 106§ Carsten A. Böger115§ §Writing/Working group, Parsa, A, Fuchsberger, C, Köttgen, A, O'Seaghdha, Cm, Pattaro, C, de Andrade, M, Chasman, Di, Teumer, A, Endlich, K, Olden, M, Chen, Mh, Tin, A, Kim, Yj, Taliun, D, Li, M, Feitosa, M, Gorski, M, Yang, Q, Hundertmark, C, Foster, Mc, Glazer, N, Isaacs, A, Rao, M, Smith, Av, O'Connell, Jr, Struchalin, M, Tanaka, T, Li, G, Hwang, Sj, Atkinson, Ej, Lohman, K, Cornelis, Mc, Johansson, A, Tönjes, A, Dehghan, A, Couraki, V, Holliday, Eg, Sorice, R, Kutalik, Z, Lehtimäki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, Ay, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, Tb, Launer, Lj, Aspelund, T, Eiriksdottir, G, Mitchell, Bd, Boerwinkle, E, Schmidt, H, Hofer, E, Hu, F, Demirkan, A, Oostra, Ba, Turner, St, Ding, J, Andrews, J, Freedman, Bi, Giulianini, F, Koenig, W, Illig, T, Döring, A, Wichmann, He, Zgaga, L, Zemunik, T, Boban, M, Minelli, C, Wheeler, He, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Ernst, F, Homuth, G, Kroemer, Hk, Nauck, M, Stracke, S, Völker, U, Völzke, H, Kovacs, P, Stumvoll, M, Mägi, R, Hofman, A, Uitterlinden, Ag, Rivadeneira, F, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, Jj, Stengel, B, Ruggiero, D, Bergmann, S, Kähönen, M, Viikari, J, Nikopensius, T, Province, M, Colhoun, H, Doney, A, Robino, Antonietta, Krämer, Bk, Portas, L, Ford, I, Buckley, Bm, Adam, M, Thun, Ga, Paulweber, B, Haun, M, Sala, C, Mitchell, P, Ciullo, M, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, Paolo, Pirastu, M, Jukema, Jw, Probst Hensch, Nm, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, van Duijn, Cm, Borecki, I, Kardia, Sl, Liu, Y, Curhan, Gc, Rudan, I, Gyllensten, U, Wilson, Jf, Franke, A, Pramstaller, Pp, Rettig, R, Prokopenko, I, Witteman, J, Hayward, C, Ridker, Pm, Bochud, M, Heid, Im, Siscovick, D, Fox, C, Kao, Wl, Böger, Ca, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, and Internal Medicine

Subjects
Kidney Disease, Kidney/physiology, Population, 030232 urology & nephrology, Genome-wide association study, Single-nucleotide polymorphism, Biology, Kidney, Renal Insufficiency, Chronic/genetics, Polymorphism, Single Nucleotide, White People, Chronic/genetics, 03 medical and health sciences, symbols.namesake, Databases, 0302 clinical medicine, Genetic, Gene Frequency, Clinical Research, Databases, Genetic, OMIM : Online Mendelian Inheritance in Man, Humans, Renal Insufficiency, Renal Insufficiency, Chronic, Polymorphism, European Continental Ancestry Group/genetics, education, Mendelian kidney disease, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Genetic Variation, Mendelian Randomization Analysis, General Medicine, Single Nucleotide, ta3121, Kidney disease, renal function, genetic variants, 3. Good health, Minor allele frequency, Phenotype, Nephrology, Mendelian inheritance, symbols, Common disease-common variant, Genome-Wide Association Study
Abstract

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Published
2013
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43. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Author

Jacqueline C.M. Witteman, Nicole Probst-Hensch, Gail Davies, Anna Köttgen, Qunyuan Zhang, Pio D'Adamo, Nicholas G. Martin, Silvia Tore, Stephan J. L. Bakker, Gian Andri Thun, Cinzia Sala, Peter P. Pramstaller, Tamara B. Harris, Aaron Isaacs, Sheila Ulivi, Rossella Sorice, Xuan Liu, Andrew A. Hicks, Henry Völzke, Daniela Ruggiero, Arnold von Eckardstein, Yukinori Okada, Andres Metspalu, Jeffrey Metter, Serena Sanna, Jennifer E. Huffman, Philipp S. Wild, Florian Ernst, Eva Albrecht, Mary F. Feitosa, Claudia Schurmann, Kathrin Budde, Veikko Salomaa, Darina Czamara, Elizabeth G. Holliday, Marcel Bruinenberg, Laura Portas, Maris Laan, Alan J. Gow, Caroline Hayward, Tim D. Spector, Ozren Polasek, Ilja M. Nolte, Rodney J. Scott, Massimo Mangino, David S. Siscovick, Nilesh J. Samani, Toomas Haller, Laura Frogheri, A. Jula, Mika Kähönen, Bruce H. R. Wolffenbuttel, Caroline S. Fox, David R. Jacobs, Julia Shi, Yusuke Nakamura, Daniel I. Chasman, Fabian J. Theis, Alan F. Wright, Ayse Demirkan, Francesco Cucca, Paolo Gasparini, Paul M. Ridker, Olli T. Raitakari, Daniela Toniolo, Maristella Steri, Mario Pirastu, Susan Campbell, Maksim Struchalin, So-Youn Shin, Mark J. Caulfield, H.-Erich Wichmann, Grant W. Montgomery, Åsa Johansson, Alexander Teumer, Ulf Gyllensten, Robert M. Plenge, Michel Burnier, Michael Schallert, Jan Krumsiek, Jing Hua Zhao, Andres Salumets, Poorva Mudgal, Anke Tönjes, James F. Meschia, Gauti Kjartan Gislason, Perttu Salo, Angela Döring, Afshin Parsa, Vilmundur Gudnason, Patrick F. McArdle, Rita P. S. Middelberg, W. H. Linda Kao, Aldi Kraja, Christopher Oldmeadow, Adrienne Tin, Loic Yengo, Murielle Bochud, Gerjan Navis, Christian Gieger, Toshiko Tanaka, Cornelia M. van Duijn, Samuli Ripatti, Terho Lehtimäki, Claudia Langenberg, Bernhard O. Boehm, Conall M. O'Seaghdha, Eric Boerwinkle, Nicole Soranzo, Tõnu Esko, Susan M. Farrington, Mike A. Nalls, John F. Peden, Hyon K. Choi, Anuj Goel, Andrew D. Johnson, Norman Klopp, Anne Grotevendt, Halit Ongen, Marcus E. Kleber, Myriam Fornage, Malcolm G. Dunlop, Igor Rudan, Federico Murgia, Beverley Balkau, Jorma Viikari, Christopher P. Nelson, Gérard Waeber, Lenore J. Launer, Ivana Persico, Inga Prokopenko, Guo Li, Tatijana Zemunik, Elisabetta Trabetti, Tanja Zeller, Hugh Watkins, Qiong Yang, James F. Wilson, Peter Vollenweider, Veronique Vitart, Markus Perola, Nicola Pirastu, Olivier Devuyst, Irene Mateo Leach, John Attia, Bruce M. Psaty, Nicholas J. Wareham, Susanne Lucae, Josef Coresh, Ingrid B. Borecki, Claudia Hundertmark, Weihua Zhang, Luigi Ferrucci, Jaspal S. Kooner, Stefan Kloiber, Lynda M. Rose, Naoyuki Kamatani, Zoltán Kutalik, Giovanni Malerba, Ian J. Deary, Albert V. Smith, Helena Schmidt, Eva Lattka, Philippe Froguel, Harry Campbell, Medea Imboden, Antonio Lupo, Angelo L. Gaffo, Vasiliki Lagou, Alan R. Shuldiner, John Whitfield, Abbas Dehghan, Winfried März, Elin Org, Albert Hofman, Margus Viigimaa, Konstantin Strauch, Toshihiro Tanaka, Andrew B. Singleton, Stefania Bandinelli, Christian Hengstenberg, Xinzhong Li, Wiek H. van Gilst, Pim van der Harst, Giorgio Pistis, Jerome I. Rotter, Maria Grazia Piras, Gary C. Curhan, Brenda W.J.H. Penninx, Ramaiah Nagaraja, Nabila Bouatia-Naji, Christian Müller, Ronald P. Stolk, Pau Navarro, Lorna M. Lopez, Ruth J. F. Loos, Albert Tenesa, Johannes H. Smit, Peter Kraft, Giovanni Gambaro, Sarah H. Wild, Patricia B. Munroe, André G. Uitterlinden, Ivana Kolcic, Bernhard R. Winkelmann, Pankaj Sharma, John C. Chambers, Nicholas D. Hastie, Matthias Nauck, Harold Snieder, Michael Stumvoll, Reinhold Schmidt, Hans L. Hillege, Kiang Liu, Fernando Rivadeneira, Owen M. Woodward, Morris J. Brown, Margus Putku, Sabine Schipf, Mirna Kirin, Kay-Tee Khaw, Melanie Waldenberger, Evropi Theodoratou, Marina Ciullo, Michiaki Kubo, Köttgen, A, Albrecht, E, Teumer, A, Vitart, V, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, Cm, Haller, T, Yang, Q, Tanaka, T, Johnson, Ad, Kutalik, Z, Smith, Av, Shi, J, Struchalin, M, Middelberg, Rp, Brown, Mj, Gaffo, Al, Pirastu, Nicola, Li, G, Hayward, C, Zemunik, T, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, G, Lopez, Lm, van der Harst, P, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Wild, Sh, Bakker, Sj, Peden, Jf, Dehghan, A, Steri, M, Tenesa, A, Lagou, V, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Okada, Y, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Harris, Tb, Launer, Lj, Mcardle, P, Shuldiner, Ar, Boerwinkle, E, Coresh, J, Schmidt, H, Schallert, M, Martin, Ng, Montgomery, Gw, Kubo, M, Nakamura, Y, Munroe, Pb, Samani, Nj, Jacobs DR, Jr, Liu, K, D'Adamo, ADAMO PIO, Ulivi, S, Rotter, Ji, Psaty, Bm, Vollenweider, P, Waeber, G, Campbell, S, Devuyst, O, Navarro, P, Kolcic, I, Hastie, N, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Wareham, Nj, Isaacs, A, Kraja, A, Zhang, Q, Wild, P, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, A, Trabetti, E, Sorice, R, Döring, A, Lattka, E, Strauch, K, Theis, F, Waldenberger, M, Wichmann, He, Davies, G, Gow, Aj, Bruinenberg, M, Stolk, Rp, Kooner, J, Zhang, W, Winkelmann, Br, Boehm, Bo, Lucae, S, Penninx, Bw, Smit, Jh, Curhan, G, Mudgal, P, Plenge, Rm, Portas, L, Persico, I, Kirin, M, Wilson, Jf, Leach, Im, van Gilst, Wh, Goel, A, Ongen, H, Hofman, A, Rivadeneira, F, Uitterlinden, Ag, Imboden, M, von Eckardstein, A, Cucca, F, Nagaraja, R, Piras, Mg, Nauck, M, Schurmann, C, Budde, K, Ernst, F, Farrington, Sm, Theodoratou, E, Prokopenko, I, Stumvoll, M, Jula, A, Perola, M, Salomaa, V, Shin, Sy, Spector, Td, Sala, C, Ridker, Pm, Kähönen, M, Viikari, J, Hengstenberg, C, Nelson, Cp, Meschia, Jf, Nalls, Ma, Sharma, P, Singleton, Ab, Kamatani, N, Zeller, T, Burnier, M, Attia, J, Laan, M, Klopp, N, Hillege, Hl, Kloiber, S, Choi, H, Pirastu, M, Tore, S, Probst Hensch, Nm, Völzke, H, Gudnason, V, Parsa, A, Schmidt, R, Whitfield, Jb, Fornage, M, Gasparini, Paolo, Siscovick, D, Polašek, O, Campbell, H, Rudan, I, Bouatia Naji, N, Metspalu, A, Loos, Rj, van Duijn, Cm, Borecki, Ib, Ferrucci, L, Gambaro, G, Deary, Ij, Wolffenbuttel, Bh, Chambers, Jc, März, W, Pramstaller, Pp, Snieder, H, Gyllensten, U, Wright, Af, Navis, G, Watkins, H, Witteman, Jc, Sanna, S, Schipf, S, Dunlop, Mg, Tönjes, A, Ripatti, S, Soranzo, N, Toniolo, D, Chasman, Di, Raitakari, O, Kao, Wh, Ciullo, M, Fox, C, Caulfield, M, Bochud, M, Gieger, C, LifeLines Cohort, Study, Cardiogram, Consortium, Diagram, Consortium, Icbp, Consortium, Magic, Consortium, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, EMGO - Mental health, EMGO+ - Mental Health, LifeLines Cohort Study, CARDIoGRAM Consortium, DIAGRAM Consortium, ICBP Consortium, MAGIC Consortium, Epidemiology, Public Health, and Internal Medicine

Subjects
Candidate gene, Inhibins/genetics, Genome-wide association study, GENETIC-LOCI, chemistry.chemical_compound, 0302 clinical medicine, serum urate, Gene Frequency, Gout/blood, association analysis, serum urate, Glucose/metabolism, Settore MED/14 - NEFROLOGIA, Hyperuricemia, serum, urate, gene, POPULATION, METABOLIC SYNDROME, Genetics, 0303 health sciences, education.field_of_study, biology, Polymorphism, Single Nucleotide/genetics, 3. Good health, HYPERURICEMIA, Genetic Loci/genetics, SLC22A12, Single Nucleotide/genetics, SNPs, Signal Transduction, MOLECULAR PHYSIOLOGY, serum urate concentrations, gout, genome-wide meta-analysis, European Continental Ancestry Group, Population, Polymorphism, Single Nucleotide, White People, Uric Acid/blood, serum urate concentrations, genome-wide meta-analysis, 03 medical and health sciences, SDG 3 - Good Health and Well-being, uric acid, medicine, Humans, Inhibins, Polymorphism, education, 030304 developmental biology, 030203 arthritis & rheumatology, Analysis of Variance, GOUT, IDENTIFICATION, TRANSPORTER, CARDIOVASCULAR-DISEASE RISK, ta3121, medicine.disease, association analysis, Gout, meta-analysis, Glucose, chemistry, Genetic Loci, genome-wide association studies, biology.protein, Signal Transduction/genetics, Uric acid, URIC-ACID LEVELS, Genome-Wide Association Study, SLC2A9
Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.

Published
2013
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44. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Author

Ching-Yu Cheng, Maria Schache, M. Kamran Ikram, Terri L. Young, Jeremy A. Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J.M. Verhoeven, Veluchamy A. Barathi, Jiemin Liao, Pirro G. Hysi, Joan E. Bailey-Wilson, Beate St. Pourcain, John P. Kemp, George McMahon, Nicholas J. Timpson, David M. Evans, Grant W. Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polasek, Alan F. Wright, Najaf Amin, Elisabeth M. van Leeuwen, James F. Wilson, Craig E. Pennell, Cornelia M. van Duijn, Paulus T.V.M. de Jong, Johannes R. Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, Kathryn P. Burdon, Jamie E. Craig, Sudha K. Iyengar, Robert P. Igo, Jonathan H. Lass, Emily Y. Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L. Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J. Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M. Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E. Klein, S. Mohsen Hosseini, Andrew D. Paterson, Kari-Matti Makela, Terho Lehtimaki, Mika Kahonen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K.H. Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J. Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G. Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W. Hewitt, Cathy Williams, Ben A. Oostra, Yik-Ying Teo, Christopher J. Hammond, Dwight Stambolian, David A. Mackey, Caroline C.W. Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N. Baird, William Reinhart, Michael W. Belin, Robert L. Schultze, Todd Morason, Alan Sugar, Shahzad Mian, Hunson Kaz Soong, Kathryn Colby, Ula Jurkunas, Richard Yee, Mark Vital, Eduardo Alfonso, Carol Karp, Yunhee Lee, Sonia Yoo, Kristin Hammersmith, Elisabeth Cohen, Peter Laibson, Christopher Rapuano, Brandon Ayres, Christopher Croasdale, James Caudill, Sanjay Patel, Keith Baratz, William Bourne, Leo Maguire, Joel Sugar, Elmer Tu, Ali Djalilian, Vinod Mootha, James McCulley, Wayne Bowman, H. Dwight Cavanaugh, Steven Verity, David Verdier, Ann Renucci, Matt Oliva, Walter Rotkis, David R. Hardten, Ahmad Fahmy, Marlene Brown, Sherman Reeves, Elizabeth A. Davis, Richard Lindstrom, Scott Hauswirth, Stephen Hamilton, W. Barry Lee, Francis Price, Marianne Price, Kathleen Kelly, Faye Peters, Michael Shaughnessy, Thomas Steinemann, B.J. Dupps, David M. Meisler, Mark Mifflin, Randal Olson, Anthony Aldave, Gary Holland, Bartly J. Mondino, George Rosenwasser, Mark Gorovoy, Steven P. Dunn, David G. Heidemann, Mark Terry, Neda Shamie, Steven I. Rosenfeld, Brandon Suedekum, David Hwang, Donald Stone, James Chodosh, Paul G. Galentine, David Bardenstein, Katrina Goddard, Hemin Chin, Mark Mannis, Rohit Varma, Ingrid Borecki, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Obstetrics & Gynecology, and Netherlands Institute for Neuroscience (NIN)

Subjects
Adult, Male, Refractive error, Adolescent, Gene Expression, Locus (genetics), Genome-wide association study, Biology, Ocular Axial Length, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, SDG 3 - Good Health and Well-being, medicine, Genetics, Humans, GWAS, Genetic Predisposition to Disease, Genetics(clinical), RSPO1, Eye Proteins, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, Aged, 0303 health sciences, ta1184, Heritability, Middle Aged, ta3121, medicine.disease, Refractive Errors, Axial Length, Eye, Genetic Loci, 030221 ophthalmology & optometry, Eye disorder, Female, Genome-Wide Association Study, Signal Transduction
Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Published
2013
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45. Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium

Author

Beate St Pourcain, Vilmundur Gudnason, Taina Rantanen, Joan E. Bailey-Wilson, Anke Tönjes, Sudha K. Iyengar, Caroline Hayward, Ben A. Oostra, Lennart C. Karssen, Yi Lu, Barbara E.K. Klein, Igor Rudan, Federico Murgia, Wan Ting Tay, Veronique Vitart, M. Kamran Ikram, Tien Yin Wong, James F. Wilson, Seang-Mei Saw, Kyoko Ohno-Matsui, Tin Aung, Christian Wolfram, Liang Kee Goh, Ozren Polasek, Olavi Pärssinen, Cathy Williams, Paul Mitchell, Thomas Meitinger, Thomas Bettecken, Mika Kähönen, Dominiek D. G. Despriet, Guðný Eiríksdóttir, Angela Döring, Alireza Mirshahi, Eranga N. Vithana, Yi-Ju Li, Jie Jin Wang, David A. Mackey, Brian W Fleck, Laura Portas, Isao Nakata, Tõnu Esko, George McMahon, Tanja Zeller, Terri L. Young, Albert V. Smith, Phillippa M. Cumberland, Shomi S. Bhattacharya, Norbert Pfeiffer, Karl J. Lackner, Johannes R. Vingerling, Fernando Rivadeneira, Andres Metspalu, Caroline C W Klaver, Xin Zhou, Alan F. Wright, Priya Duggal, Leslie J. Raffel, Albert Hofman, Jugnoo S Rahi, Kenji Yamashiro, Ryo Yamada, Reedik Mägi, Cornelia M. van Duijn, Jeremy A. Guggenheim, Virginie J. M. Verhoeven, René Höhn, Nagahisa Yoshimura, Xueling Sim, Terho Lehtimäki, Harry Campbell, Pirro G. Hysi, Konrad Oexle, Raphaële Castagné, Mary Frances Cotch, Robert Wojciechowski, E-Shyong Tai, Tim D. Spector, Claire L. Simpson, Dwight Stambolian, Yik Ying Teo, André G. Uitterlinden, Larry D. Atwood, Abhishek Nag, Paul N. Baird, Qiao Fan, Najaf Amin, Chiea Chuen Khor, Paulus T. V. M. de Jong, Xiaohui Li, Christopher J Hammond, Sarayut Janmahasatian, Fumihiko Matsuda, Alex W. Hewitt, Leonieke M E van Koolwijk, Ophthalmology, Erasmus MC other, Epidemiology, Clinical Genetics, and Internal Medicine

Subjects
Population, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Myopia, Genetics, Humans, SNP, Genetics(clinical), Allele, education, Alleles, Genetics (clinical), Original Investigation, 030304 developmental biology, Genetic association, Chromosomes, Human, Pair 15, 0303 health sciences, education.field_of_study, 3. Good health, Phenotype, 030221 ophthalmology & optometry, Population study, RE
Abstract

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10−12 for SNP rs634990 in Caucasians, and 9.65 × 10−4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10−23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P

Published
2012
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46. Seventy-five genetic loci influencing the human red blood cell

Author

Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Male, Netherlands Twin Register (NTR), Candidate gene, Erythrocytes, PROTEIN, Genome-wide association study, DISEASE, Hemoglobins, Mice, 0302 clinical medicine, Genetics, Genomics, blood, 0303 health sciences, Multidisciplinary, biology, Cell Cycle, COMMON VARIANTS, Genomics, Phenotype, anemia, 3. Good health, Haematopoiesis, DROSOPHILA, Drosophila melanogaster, medicine.anatomical_structure, HEMOGLOBIN LEVELS, Organ Specificity, 030220 oncology & carcinogenesis, Cytokines, Female, RNA Interference, TRAITS, Signal Transduction, EXPRESSION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic, blood, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, RECEPTOR, CONSORTIUM, ta3121, hemoglobin, biology.organism_classification, Hematopoiesis, meta-analysis, Red blood cell, Gene Expression Regulation, Genetic Loci, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract

Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Published
2012
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47. Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways

Author

Mario Pirastu, Ginevra Biino, Ozren Polasek, Laura Portas, Igor Rudan, Marina Ciullo, Sheila Ulivi, Nicola Pirastu, Paolo Gasparini, Giorgia Girotto, Nicholas D. Hastie, Rossella Sorice, Alan F. Wright, Teresa Nutile, Harry Campbell, Adamo Pio d'Adamo, Caroline Hayward, Tatijana Zemunik, Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, Institute of Genetics and Biophysics, CNR, Naples, Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, University of Edinburgh, MRC Human Gentics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Croatian Global Health Research Center, University of Split Medical School, MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh, Girotto, Giorgia, Pirastu, Nicola, R., Sorice, G., Biino, H., Campbell, D'Adamo, ADAMO PIO, N. D., Hastie, T., Nutile, O., Polasek, L., Porta, I., Rudan, S., Ulivi, T., Zemunik, A. F., Wright, M., Ciullo, C., Hayward, M., Pirastu, and Gasparini, Paolo

Subjects
Male, Hearing Loss: genetics, hearing, GWAs, isolated populations, new loci, Genetic Linkage, Receptor-Like Protein Tyrosine Phosphatases, Genome-wide association study, Protein-Serine-Threonine Kinase, Receptors, Metabotropic Glutamate, Mice, Doublecortin-Like Kinases, genetic [Hearing Loss], 0302 clinical medicine, Animals, Auditory Threshold, Carrier Proteins, Carrier Proteins: genetics, Class 2, Class 2: genetics, Databases, Europe, Europe: epidemiology, European Continental Ancestry Group, European Continental Ancestry Group: genetics, Female, Founder Effect, Genetic, Genome-Wide Association Study, Genome-Wide Association Study: methods, Hearing, Hearing Loss, Hearing Loss: ethnology, Hearing: genetics, Humans, Intracellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins: gen, Metabotropic Glutamate, Metabotropic Glutamate: genetics, Phenotype, Polymorphism, Protein-Serine-Threonine Kinases, Protein-Serine-Threonine Kinases: genetics, Receptors, Single Nucleotide, Databases, Genetic, genetic [Carrier Proteins], Genetic epidemiology, Molecular genetics, Genetics (clinical), Genetics, 0303 health sciences, Receptor-Like Protein Tyrosine Phosphatases, Class 2, epidemiology [Europe], genetic [European Continental Ancestry Group], ethnology [Hearing Loss], genetic [Class 2], gen [Intracellular Signaling Peptides and Proteins], medicine.symptom, Human, Receptor, medicine.medical_specialty, Hearing loss, genetic [Hearing], genetic [Metabotropic Glutamate], Single-nucleotide polymorphism, Protein Serine-Threonine Kinases, Biology, Polymorphism, Single Nucleotide, White People, Genetic determinism, Database, method [Genome-Wide Association Study], 03 medical and health sciences, Genetic linkage, medicine, otorhinolaryngologic diseases, SNP, Hearing Lo, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Animal, Receptor-Like Protein Tyrosine Phosphatase, genetic [Protein-Serine-Threonine Kinases], Intracellular Signaling Peptides and Protein, Carrier Protein, 030217 neurology & neurosurgery
Abstract

BACKGROUND: Hearing is a complex trait, but until now only a few genes are known to contribute to variability of this process. In order to discover genes and pathways that underlie auditory function, a genome-wide association study was carried out within the International Consortium G-EAR. METHODS: Meta-analysis of genome-wide association study's data from six isolated populations of European ancestry for an overall number of 3417 individuals. RESULTS: Eight suggestive significant loci (p

Published
2011
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48. History, geography and population structure influence the distribution and heritability of blood and anthropometric quantitative traits in nine Sardinian genetic isolates

Author

Laura Portas, Bruno Frongia, Stefania Milia, Debora Parracciani, Ginevra Biino, Federico Murgia, Simona Vaccargiu, Massimiliano Cosso, Michael B. Whalen, Maria Pina Concas, Mario Pirastu, Laura Casula, Portas, Laura, Murgia, Federico, Biino, Ginevra, Concas, MARIA PINA, Casula, Laura, Milia, Stefania, Whalen, Michael B., Vaccargiu, Simona, Cosso, Massimiliano, Parracciani, Debora, Frongia, Bruno, and Pirastu, Mario

Subjects
Male, Rural Population, Range (biology), Population, Biology, Quantitative trait locus, Environment, Analysis of Variance, Anthropometry, Blood Proteins, Child, Cross-Sectional Studies, DNA, Female, Genetic Variation, Geography, Humans, Italy, Phenotype, Thalassemia, Genetics, Population, Quantitative Trait, Heritable, Genetics, Quantitative Trait, Blood Protein, education, Heritable, Genetic association, Cross-Sectional Studie, education.field_of_study, General Medicine, Heritability, Evolutionary biology, Endogamy, Trait, Human
Abstract

SummaryIsolated founder populations which exhibit great genetic and environmental homogeneity provide an attractive setting for the study of quantitative traits (QTs). Geneticists have repeatedly turned to population isolates and the past successes have prompted increased interest among medical researchers. We studied nine small isolated villages of a secluded area of Sardinia (Ogliastra), all of them characterized by a few founders, high endogamy rates, slow population expansion and a distinct genetic makeup. Anthropometric and blood parameters, 43 QTs in all, were analysed in about 9000 voluntary subjects for whom extended genealogical information was available. We explored the distribution and examined mean differences of each trait among villages by analysis of variance (ANOVA). A heritability analysis with the variance component (VC) method was performed. Results show significant differences in the distribution of most traits between groups of villages located in two distinct geographical areas already identified by a previous population structure analysis, thus supporting the existence of differentiation among sub-populations in the same region. Heritability estimates range between 30 and 89%, demonstrating that genetic effects substantially contribute to phenotypic variation of all investigated traits and that this population provides excellent research conditions for gene-mapping projects. Results suggest that history, geographic location and population structure may have influenced the genetic and phenotypic features of these isolates. Our findings may be useful for the ongoing linkage and association studies in these isolates and suggest that a thorough characterization of population is valuable to better identify genes or variants that may be rare in the population at large and peculiar to single villages.

Published
2010

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