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1. Metabolite and protein associations with general health in the population-based CHRIS study

Author

Essi Hantikainen, Christian X. Weichenberger, Nikola Dordevic, Vinicius Verri Hernandes, Luisa Foco, Martin Gögele, Roberto Melotti, Cristian Pattaro, Markus Ralser, Fatma Amari, Vadim Farztdinov, Michael Mülleder, Peter P. Pramstaller, Johannes Rainer, and Francisco S. Domingues

Subjects
Health status, Metabolomics, Proteomics, Comorbidity, Aging, CHRIS study, Medicine, Science
Abstract

Abstract Identifying biomarkers able to discriminate individuals on different health trajectories is crucial to understand the molecular basis of age-related morbidity. We investigated multi-omics signatures of general health and organ-specific morbidity, as well as their interconnectivity. We examined cross-sectional metabolome and proteome data from 3,142 adults of the Cooperative Health Research in South Tyrol (CHRIS) study, an Alpine population study designed to investigate how human biology, environment, and lifestyle factors contribute to people’s health over time. We had 174 metabolites and 148 proteins quantified from fasting serum and plasma samples. We used the Cumulative Illness Rating Scale (CIRS) Comorbidity Index (CMI), which considers morbidity in 14 organ systems, to assess health status (any morbidity vs. healthy). Omics-signatures for health status were identified using random forest (RF) classifiers. Linear regression models were fitted to assess directionality of omics markers and health status associations, as well as to identify omics markers related to organ-specific morbidity. Next to age, we identified 21 metabolites and 10 proteins as relevant predictors of health status and results confirmed associations for serotonin and glutamate to be age-independent. Considering organ-specific morbidity, several metabolites and proteins were jointly related to endocrine, cardiovascular, and renal morbidity. To conclude, circulating serotonin was identified as a potential novel predictor for overall morbidity.

Published
2024
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2. Genome‐Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants

Author

William J. Young, Peter J. van der Most, Traci M. Bartz, Maxime M. Bos, Ginevra Biino, ThuyVy Duong, Luisa Foco, Jesus T. Lominchar, Martina Müller‐Nurasyid, Giuseppe Giovanni Nardone, Alessandro Pecori, Julia Ramirez, Linda Repetto, Katharina Schramm, Xia Shen, Stefan van Duijvenboden, Diana van Heemst, Stefan Weiss, Jie Yao, Jan‐Walter Benjamins, Alvaro Alonso, Beatrice Spedicati, Mary L. Biggs, Jennifer A. Brody, Marcus Dörr, Christian Fuchsberger, Martin Gögele, Xiuqing Guo, M. Arfan Ikram, J. Wouter Jukema, Stefan Kääb, Jørgen K. Kanters, Henry J. Lin, Allan Linneberg, Matthias Nauck, Ilja M. Nolte, Giulia Pianigiani, Aurora Santin, Elsayed Z. Soliman, Paola Tesolin, Simona Vaccargiu, Melanie Waldenberger, Pim van der Harst, Niek Verweij, Dan E. Arking, Maria Pina Concas, Alessandro De Grandi, Giorgia Girotto, Niels Grarup, Maryam Kavousi, Dennis O. Mook‐Kanamori, Pau Navarro, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Mario Pirastu, Peter P. Pramstaller, Susan R. Heckbert, Mortiz Sinner, Harold Snieder, Uwe Völker, James F. Wilson, W. James Gauderman, Pier D. Lambiase, Nona Sotoodehnia, Andrew Tinker, Helen R. Warren, Raymond Noordam, and Patricia B. Munroe

Subjects
calcium, ECG intervals, gene‐lifestyle interaction, genome‐wide association study, ventricular repolarization, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

Published
2024
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3. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Rosalie B. T. M. Sterenborg, Inga Steinbrenner, Yong Li, Melissa N. Bujnis, Tatsuhiko Naito, Eirini Marouli, Tessel E. Galesloot, Oladapo Babajide, Laura Andreasen, Arne Astrup, Bjørn Olav Åsvold, Stefania Bandinelli, Marian Beekman, John P. Beilby, Jette Bork-Jensen, Thibaud Boutin, Jennifer A. Brody, Suzanne J. Brown, Ben Brumpton, Purdey J. Campbell, Anne R. Cappola, Graziano Ceresini, Layal Chaker, Daniel I. Chasman, Maria Pina Concas, Rodrigo Coutinho de Almeida, Simone M. Cross, Francesco Cucca, Ian J. Deary, Alisa Devedzic Kjaergaard, Justin B. Echouffo Tcheugui, Christina Ellervik, Johan G. Eriksson, Luigi Ferrucci, Jan Freudenberg, GHS DiscovEHR, Regeneron Genetics Center, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E. Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N. Harding, Sarah E. Harris, Stig Haunsø, Caroline Hayward, Jennie Hui, Till Ittermann, J. Wouter Jukema, Eero Kajantie, Jørgen K. Kanters, Line L. Kårhus, Lambertus A. L. M. Kiemeney, Margreet Kloppenburg, Brigitte Kühnel, Jari Lahti, Claudia Langenberg, Bruno Lapauw, Graham Leese, Shuo Li, David C. M. Liewald, Allan Linneberg, Jesus V. T. Lominchar, Jian’an Luan, Nicholas G. Martin, Antonela Matana, Marcel E. Meima, Thomas Meitinger, Ingrid Meulenbelt, Braxton D. Mitchell, Line T. Møllehave, Samia Mora, Silvia Naitza, Matthias Nauck, Romana T. Netea-Maier, Raymond Noordam, Casia Nursyifa, Yukinori Okada, Stefano Onano, Areti Papadopoulou, Colin N. A. Palmer, Cristian Pattaro, Oluf Pedersen, Annette Peters, Maik Pietzner, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Ante Punda, Debashree Ray, Paul Redmond, J. Brent Richards, Paul M. Ridker, Tom C. Russ, Kathleen A. Ryan, Morten Salling Olesen, Ulla T. Schultheiss, Elizabeth Selvin, Moneeza K. Siddiqui, Carlo Sidore, P. Eline Slagboom, Thorkild I. A. Sørensen, Enrique Soto-Pedre, Tim D. Spector, Beatrice Spedicati, Sundararajan Srinivasan, John M. Starr, David J. Stott, Toshiko Tanaka, Vesela Torlak, Stella Trompet, Johanna Tuhkanen, André G. Uitterlinden, Erik B. van den Akker, Tibbert van den Eynde, Melanie M. van der Klauw, Diana van Heemst, Charlotte Verroken, W. Edward Visser, Dina Vojinovic, Henry Völzke, Melanie Waldenberger, John P. Walsh, Nicholas J. Wareham, Stefan Weiss, Cristen J. Willer, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Hanneke J. C. M. Wouters, Margaret J. Wright, Qiong Yang, Tatijana Zemunik, Wei Zhou, Gu Zhu, Sebastian Zöllner, Johannes W. A. Smit, Robin P. Peeters, Anna Köttgen, Alexander Teumer, and Marco Medici

Subjects
Science
Abstract

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Published
2024
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4. Smoking and salivary microbiota: a cross-sectional analysis of an Italian alpine population

Author

Giacomo Antonello, Freida Blostein, Deesha Bhaumik, Elyse Davis, Martin Gögele, Roberto Melotti, Peter Pramstaller, Cristian Pattaro, Nicola Segata, Betsy Foxman, and Christian Fuchsberger

Subjects
Medicine, Science
Abstract

Abstract The oral microbiota plays an important role in the exogenous nitrate reduction pathway and is associated with heart and periodontal disease and cigarette smoking. We describe smoking-related changes in oral microbiota composition and resulting potential metabolic pathway changes that may explain smoking-related changes in disease risk. We analyzed health information and salivary microbiota composition among 1601 Cooperative Health Research in South Tyrol participants collected 2017–2018. Salivary microbiota taxa were assigned from amplicon sequences of the 16S-V4 rRNA and used to describe microbiota composition and predict metabolic pathways. Aerobic taxa relative abundance decreased with daily smoking intensity and increased with years since cessation, as did inferred nitrate reduction. Former smokers tended to be more similar to Never smokers than to Current smokers, especially those who had quit for longer than 5 years. Cigarette smoking has a consistent, generalizable association on oral microbiota composition and predicted metabolic pathways, some of which associate in a dose-dependent fashion. Smokers who quit for longer than 5 years tend to have salivary microbiota profiles comparable to never smokers.

Published
2023
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5. Genetic determinants of complement activation in the general population

Author

Damia Noce, Luisa Foco, Dorothea Orth-Höller, Eva König, Giulia Barbieri, Maik Pietzner, Dariush Ghasemi-Semeskandeh, Stefan Coassin, Christian Fuchsberger, Martin Gögele, Fabiola Del Greco M., Alessandro De Grandi, Monika Summerer, Eleanor Wheeler, Claudia Langenberg, Cornelia Lass-Flörl, Peter Paul Pramstaller, Florian Kronenberg, Reinhard Würzner, and Cristian Pattaro

Subjects
CP: Genomics, CP: Immunology, Biology (General), QH301-705.5
Abstract

Summary: Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement’s genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways’ genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.

Published
2024
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6. Cluster analysis of angiotensin biomarkers to identify antihypertensive drug treatment in population studies

Author

Maeregu Woldeyes Arisido, Luisa Foco, Robin Shoemaker, Roberto Melotti, Christian Delles, Martin Gögele, Stefano Barolo, Stephanie Baron, Michel Azizi, Anna F. Dominiczak, Maria-Christina Zennaro, Peter P. Pramstaller, Marko Poglitsch, and Cristian Pattaro

Subjects
Angiotensin, Aldosterone, Antihypertensive drugs, Cluster analysis, Lasso regression, CHRIS study, Medicine (General), R5-920
Abstract

Abstract Background The recent progress in molecular biology generates an increasing interest in investigating molecular biomarkers as markers of response to treatments. The present work is motivated by a study, where the objective was to explore the potential of the molecular biomarkers of renin-angiotensin-aldosterone system (RAAS) to identify the undertaken antihypertensive treatments in the general population. Population-based studies offer an opportunity to assess the effectiveness of treatments in real-world scenarios. However, lack of quality documentation, especially when electronic health record linkage is unavailable, leads to inaccurate reporting and classification bias. Method We present a machine learning clustering technique to determine the potential of measured RAAS biomarkers for the identification of undertaken treatments in the general population. The biomarkers were simultaneously determined through a novel mass-spectrometry analysis in 800 participants of the Cooperative Health Research In South Tyrol (CHRIS) study with documented antihypertensive treatments. We assessed the agreement, sensitivity and specificity of the resulting clusters against known treatment types. Through the lasso penalized regression, we identified clinical characteristics associated with the biomarkers, accounting for the effects of cluster and treatment classifications. Results We identified three well-separated clusters: cluster 1 (n = 444) preferentially including individuals not receiving RAAS-targeting drugs; cluster 2 (n = 235) identifying angiotensin type 1 receptor blockers (ARB) users (weighted kappa κw = 74%; sensitivity = 73%; specificity = 83%); and cluster 3 (n = 121) well discriminating angiotensin-converting enzyme inhibitors (ACEi) users (κw = 81%; sensitivity = 55%; specificity = 90%). Individuals in clusters 2 and 3 had higher frequency of diabetes as well as higher fasting glucose and BMI levels. Age, sex and kidney function were strong predictors of the RAAS biomarkers independently of the cluster structure. Conclusions Unsupervised clustering of angiotensin-based biomarkers is a viable technique to identify individuals on specific antihypertensive treatments, pointing to a potential application of the biomarkers as useful clinical diagnostic tools even outside of a controlled clinical setting.

Published
2023
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7. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author

William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, and Patricia B. Munroe

Subjects
Science
Abstract

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.

Published
2022
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8. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author

Thomas W. Winkler, Humaira Rasheed, Alexander Teumer, Mathias Gorski, Bryce X. Rowan, Kira J. Stanzick, Laurent F. Thomas, Adrienne Tin, Anselm Hoppmann, Audrey Y. Chu, Bamidele Tayo, Chris H. L. Thio, Daniele Cusi, Jin-Fang Chai, Karsten B. Sieber, Katrin Horn, Man Li, Markus Scholz, Massimiliano Cocca, Matthias Wuttke, Peter J. van der Most, Qiong Yang, Sahar Ghasemi, Teresa Nutile, Yong Li, Giulia Pontali, Felix Günther, Abbas Dehghan, Adolfo Correa, Afshin Parsa, Agnese Feresin, Aiko P. J. de Vries, Alan B. Zonderman, Albert V. Smith, Albertine J. Oldehinkel, Alessandro De Grandi, Alexander R. Rosenkranz, Andre Franke, Andrej Teren, Andres Metspalu, Andrew A. Hicks, Andrew P. Morris, Anke Tönjes, Anna Morgan, Anna I. Podgornaia, Annette Peters, Antje Körner, Anubha Mahajan, Archie Campbell, Barry I. Freedman, Beatrice Spedicati, Belen Ponte, Ben Schöttker, Ben Brumpton, Bernhard Banas, Bernhard K. Krämer, Bettina Jung, Bjørn Olav Åsvold, Blair H. Smith, Boting Ning, Brenda W. J. H. Penninx, Brett R. Vanderwerff, Bruce M. Psaty, Candace M. Kammerer, Carl D. Langefeld, Caroline Hayward, Cassandra N. Spracklen, Cassianne Robinson-Cohen, Catharina A. Hartman, Cecilia M. Lindgren, Chaolong Wang, Charumathi Sabanayagam, Chew-Kiat Heng, Chiara Lanzani, Chiea-Chuen Khor, Ching-Yu Cheng, Christian Fuchsberger, Christian Gieger, Christian M. Shaffer, Christina-Alexandra Schulz, Cristen J. Willer, Daniel I. Chasman, Daniel F. Gudbjartsson, Daniela Ruggiero, Daniela Toniolo, Darina Czamara, David J. Porteous, Dawn M. Waterworth, Deborah Mascalzoni, Dennis O. Mook-Kanamori, Dermot F. Reilly, E. Warwick Daw, Edith Hofer, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, E-Shyong Tai, Eulalia Catamo, Federica Rizzi, Feng Guo, Fernando Rivadeneira, Franco Guilianini, Gardar Sveinbjornsson, Georg Ehret, Gerard Waeber, Ginevra Biino, Giorgia Girotto, Giorgio Pistis, Girish N. Nadkarni, Graciela E. Delgado, Grant W. Montgomery, Harold Snieder, Harry Campbell, Harvey D. White, He Gao, Heather M. Stringham, Helena Schmidt, Hengtong Li, Hermann Brenner, Hilma Holm, Holgen Kirsten, Holly Kramer, Igor Rudan, Ilja M. Nolte, Ioanna Tzoulaki, Isleifur Olafsson, Jade Martins, James P. Cook, James F. Wilson, Jan Halbritter, Janine F. Felix, Jasmin Divers, Jaspal S. Kooner, Jeannette Jen-Mai Lee, Jeffrey O’Connell, Jerome I. Rotter, Jianjun Liu, Jie Xu, Joachim Thiery, Johan Ärnlöv, Johanna Kuusisto, Johanna Jakobsdottir, Johanne Tremblay, John C. Chambers, John B. Whitfield, John M. Gaziano, Jonathan Marten, Josef Coresh, Jost B. Jonas, Josyf C. Mychaleckyj, Kaare Christensen, Kai-Uwe Eckardt, Karen L. Mohlke, Karlhans Endlich, Katalin Dittrich, Kathleen A. Ryan, Kenneth M. Rice, Kent D. Taylor, Kevin Ho, Kjell Nikus, Koichi Matsuda, Konstantin Strauch, Kozeta Miliku, Kristian Hveem, Lars Lind, Lars Wallentin, Laura M. Yerges-Armstrong, Laura M. Raffield, Lawrence S. Phillips, Lenore J. Launer, Leo-Pekka Lyytikäinen, Leslie A. Lange, Lorena Citterio, Lucija Klaric, M. Arfan Ikram, Marcus Ising, Marcus E. Kleber, Margherita Francescatto, Maria Pina Concas, Marina Ciullo, Mario Piratsu, Marju Orho-Melander, Markku Laakso, Markus Loeffler, Markus Perola, Martin H. de Borst, Martin Gögele, Martina La Bianca, Mary Ann Lukas, Mary F. Feitosa, Mary L. Biggs, Mary K. Wojczynski, Maryam Kavousi, Masahiro Kanai, Masato Akiyama, Masayuki Yasuda, Matthias Nauck, Melanie Waldenberger, Miao-Li Chee, Miao-Ling Chee, Michael Boehnke, Michael H. Preuss, Michael Stumvoll, Michael A. Province, Michele K. Evans, Michelle L. O’Donoghue, Michiaki Kubo, Mika Kähönen, Mika Kastarinen, Mike A. Nalls, Mikko Kuokkanen, Mohsen Ghanbari, Murielle Bochud, Navya Shilpa Josyula, Nicholas G. Martin, Nicholas Y. Q. Tan, Nicholette D. Palmer, Nicola Pirastu, Nicole Schupf, Niek Verweij, Nina Hutri-Kähönen, Nina Mononen, Nisha Bansal, Olivier Devuyst, Olle Melander, Olli T. Raitakari, Ozren Polasek, Paolo Manunta, Paolo Gasparini, Pashupati P. Mishra, Patrick Sulem, Patrik K. E. Magnusson, Paul Elliott, Paul M. Ridker, Pavel Hamet, Per O. Svensson, Peter K. Joshi, Peter Kovacs, Peter P. Pramstaller, Peter Rossing, Peter Vollenweider, Pim van der Harst, Rajkumar Dorajoo, Ralene Z. H. Sim, Ralph Burkhardt, Ran Tao, Raymond Noordam, Reedik Mägi, Reinhold Schmidt, Renée de Mutsert, Rico Rueedi, Rob M. van Dam, Robert J. Carroll, Ron T. Gansevoort, Ruth J. F. Loos, Sala Cinzia Felicita, Sanaz Sedaghat, Sandosh Padmanabhan, Sandra Freitag-Wolf, Sarah A. Pendergrass, Sarah E. Graham, Scott D. Gordon, Shih-Jen Hwang, Shona M. Kerr, Simona Vaccargiu, Snehal B. Patil, Stein Hallan, Stephan J. L. Bakker, Su-Chi Lim, Susanne Lucae, Suzanne Vogelezang, Sven Bergmann, Tanguy Corre, Tarunveer S. Ahluwalia, Terho Lehtimäki, Thibaud S. Boutin, Thomas Meitinger, Tien-Yin Wong, Tobias Bergler, Ton J. Rabelink, Tõnu Esko, Toomas Haller, Unnur Thorsteinsdottir, Uwe Völker, Valencia Hui Xian Foo, Veikko Salomaa, Veronique Vitart, Vilmantas Giedraitis, Vilmundur Gudnason, Vincent W. V. Jaddoe, Wei Huang, Weihua Zhang, Wen Bin Wei, Wieland Kiess, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Xin Gao, Xueling Sim, Ya Xing Wang, Yechiel Friedlander, Yih-Chung Tham, Yoichiro Kamatani, Yukinori Okada, Yuri Milaneschi, Zhi Yu, Lifelines cohort study, DiscovEHR/MyCode study, VA Million Veteran Program, Klaus J. Stark, Kari Stefansson, Carsten A. Böger, Adriana M. Hung, Florian Kronenberg, Anna Köttgen, Cristian Pattaro, and Iris M. Heid

Subjects
Biology (General), QH301-705.5
Abstract

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Published
2022
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9. Trends and symptoms of SARS-CoV-2 infection: a longitudinal study on an Alpine population representative sample

Author

Rebecca Lundin, Daniele Giardiello, Peter P Pramstaller, Martin Gögele, Cristian Pattaro, Giulia Barbieri, Massimo Pizzato, Christian X Weichenberger, Luisa Foco, Daniele Bottigliengo, Cinzia Bertelli, Laura Barin, and Roberto Melotti

Subjects
Medicine
Abstract

Objectives The continuous monitoring of SARS-CoV-2 infection waves and the emergence of novel pathogens pose a challenge for effective public health surveillance strategies based on diagnostics. Longitudinal population representative studies on incident events and symptoms of SARS-CoV-2 infection are scarce. We aimed at describing the evolution of the COVID-19 pandemic during 2020 and 2021 through regular monitoring of self-reported symptoms in an Alpine community sample.Design To this purpose, we designed a longitudinal population representative study, the Cooperative Health Research in South Tyrol COVID-19 study.Participants and outcome measures A sample of 845 participants was retrospectively investigated for active and past infections with swab and blood tests, by August 2020, allowing adjusted cumulative incidence estimation. Of them, 700 participants without previous infection or vaccination were followed up monthly until July 2021 for first-time infection and symptom self-reporting: COVID-19 anamnesis, social contacts, lifestyle and sociodemographic data were assessed remotely through digital questionnaires. Temporal symptom trajectories and infection rates were modelled through longitudinal clustering and dynamic correlation analysis. Negative binomial regression and random forest analysis assessed the relative importance of symptoms.Results At baseline, the cumulative incidence of SARS-CoV-2 infection was 1.10% (95% CI 0.51%, 2.10%). Symptom trajectories mimicked both self-reported and confirmed cases of incident infections. Cluster analysis identified two groups of high-frequency and low-frequency symptoms. Symptoms like fever and loss of smell fell in the low-frequency cluster. Symptoms most discriminative of test positivity (loss of smell, fatigue and joint-muscle aches) confirmed prior evidence.Conclusions Regular symptom tracking from population representative samples is an effective screening tool auxiliary to laboratory diagnostics for novel pathogens at critical times, as manifested in this study of COVID-19 patterns. Integrated surveillance systems might benefit from more direct involvement of citizens’ active symptom tracking.

Published
2023
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10. Structural equation modeling (SEM) of kidney function markers and longitudinal CVD risk assessment

Author

Ryosuke Fujii, Roberto Melotti, Martin Gögele, Laura Barin, Dariush Ghasemi-Semeskandeh, Giulia Barbieri, Peter P. Pramstaller, and Cristian Pattaro

Subjects
Medicine, Science
Abstract

Lower kidney function is known to enhance cardiovascular disease (CVD) risk. It is unclear which estimated glomerular filtration rate (eGFR) equation best predict an increased CVD risk and if prediction can be improved by integration of multiple kidney function markers. We performed structural equation modeling (SEM) of kidney markers and compared the performance of the resulting pooled indexes with established eGFR equations to predict CVD risk in a 10-year longitudinal population-based design. We split the study sample into a set of participants with only baseline data (n = 647; model-building set) and a set with longitudinal data (n = 670; longitudinal set). In the model-building set, we fitted five SEM models based on serum creatinine or creatinine-based eGFR (eGFRcre), cystatin C or cystatin-based eGFR (eGFRcys), uric acid (UA), and blood urea nitrogen (BUN). In the longitudinal set, 10-year incident CVD risk was defined as a Framingham risk score (FRS)>5% and a pooled cohort equation (PCE)>5%. Predictive performances of the different kidney function indexes were compared using the C-statistic and the DeLong test. In the longitudinal set, a SEM-based estimate of latent kidney function based on eGFRcre, eGFRcys, UA, and BUN showed better prediction performance for both FRS>5% (C-statistic: 0.70; 95% CI: 0.65–0.74) and PCE>5% (C-statistic: 0.75; 95%CI: 0.71–0.79) than other SEM models and different eGFR formulas (DeLong test p-values5% and 5%, respectively). However, the new derived marker could not outperform eGFRcys (DeLong test p-values = 0.88 for FRS>5% and 0.20 for PCE>5%, respectively). SEM is a promising approach to identify latent kidney function signatures. However, for incident CVD risk prediction, eGFRcys could still be preferrable given its simpler derivation.

Published
2023

11. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Ioanna Ntalla, Lu-Chen Weng, James H. Cartwright, Amelia Weber Hall, Gardar Sveinbjornsson, Nathan R. Tucker, Seung Hoan Choi, Mark D. Chaffin, Carolina Roselli, Michael R. Barnes, Borbala Mifsud, Helen R. Warren, Caroline Hayward, Jonathan Marten, James J. Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolcic, Ozren Polasek, Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Fabiola Del Greco M, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli T. Raitakari, Catriona L. K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Kenneth Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, and Patricia B. Munroe

Subjects
Science
Abstract

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Published
2020
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12. Development and evaluation of a kidney health questionnaire and estimates of chronic kidney disease prevalence in the Cooperative Health Research In South Tyrol (CHRIS) study

Author

Giulia, Barbieri, primary, Lucia, Cazzoletti, additional, Roberto, Melotti, additional, Essi, Hantikainen, additional, Rebecca, Lundin, additional, Laura, Barin, additional, Martin, Gögele, additional, Peter, Riegler, additional, Manuel, Ferraro Pietro, additional, Paul, Pramstaller Peter, additional, Giovanni, Gambaro, additional, Elisabetta, Zanolin Maria, additional, and Cristian, Pattaro, additional

Published
2024
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13. Microbiota, type 2 diabetes and non-alcoholic fatty liver disease: protocol of an observational study

Author

Benedetta M. Motta, Christoph Grander, Martin Gögele, Luisa Foco, Vladimir Vukovic, Roberto Melotti, Christian Fuchsberger, Alessandro De Grandi, Chiara Cantaloni, Anne Picard, Deborah Mascalzoni, Alessandra Rossini, Cristian Pattaro, Herbert Tilg, and Peter P. Pramstaller

Subjects
Microbiota, Type 2 diabetes, NAFLD, Cooperative Health Research In South Tyrol, Medicine
Abstract

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride accumulation in the hepatocytes in the absence of alcohol overconsumption, commonly associated with insulin resistance and obesity. Both NAFLD and type 2 diabetes (T2D) are characterized by an altered microbiota composition, however the role of the microbiota in NAFLD and T2D is not well understood. To assess the relationship between alteration in the microbiota and NAFLD while dissecting the role of T2D, we established a nested study on T2D and non-T2D individuals within the Cooperative Health Research In South Tyrol (CHRIS) study, called the CHRIS-NAFLD study. Here, we present the study protocol along with baseline and follow-up characteristics of study participants. Methods Among the first 4979 CHRIS study participants, 227 individuals with T2D were identified and recalled, along with 227 age- and sex-matched non-T2D individuals. Participants underwent ultrasound and transient elastography examination to evaluate the presence of hepatic steatosis and liver stiffness. Additionally, sampling of saliva and faeces, biochemical measurements and clinical interviews were carried out. Results We recruited 173 T2D and 183 non-T2D participants (78% overall response rate). Hepatic steatosis was more common in T2D (63.7%) than non-T2D (36.3%) participants. T2D participants also had higher levels of liver stiffness (median 4.8 kPa, interquartile range (IQR) 3.7, 5.9) than non-T2D participants (median 3.9 kPa, IQR 3.3, 5.1). The non-invasive scoring systems like the NAFLD fibrosis score (NFS) suggests an increased liver fibrosis in T2D (mean − 0.55, standard deviation, SD, 1.30) than non-T2D participants (mean − 1.30, SD, 1.17). Discussion Given the comprehensive biochemical and clinical characterization of study participants, once the bioinformatics classification of the microbiota will be completed, the CHRIS-NAFLD study will become a useful resource to further our understanding of the relationship between microbiota, T2D and NAFLD.

Published
2019
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14. Associations of autozygosity with a broad range of human phenotypes

Author

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

Subjects
Science
Abstract

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

Published
2019
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15. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, and Anna Köttgen

Subjects
Science
Abstract

Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.

Published
2019
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16. Frequency of Heterozygous Parkin (PRKN) Variants and Penetrance of Parkinson's Disease Risk Markers in the Population-Based CHRIS Cohort

Author

Maria Paulina Castelo Rueda, Athina Raftopoulou, Martin Gögele, Max Borsche, David Emmert, Christian Fuchsberger, Essi M. Hantikainen, Vladimir Vukovic, Christine Klein, Peter P. Pramstaller, Irene Pichler, and Andrew A. Hicks

Subjects
Parkin, heterozygote mutation, Parkinson's disease, risk markers, penetrance, population, Neurology. Diseases of the nervous system, RC346-429
Abstract

Mutations in the Parkin (PRKN) gene are the most frequent cause of autosomal recessive early-onset Parkinson's disease (PD). Heterozygous PRKN mutation carriers might also be at increased risk for developing clinical symptoms of PD. Given the high frequency of heterozygous mutations in the general population, it is essential to have better estimates of the penetrance of these variants, and to investigate, which clinical and biochemical markers are present in carriers and thus potentially useful for identifying those individuals at greater risk of developing clinical symptoms later in life. In the present study, we ascertained the frequency of heterozygous PRKN mutation carriers in a large population sample of the Cooperative Health Research in South Tyrol (CHRIS) study, and screened for reported PD risk markers. 164 confirmed heterozygous PRKN mutation carriers were compared with 2,582 controls. A higher number of heterozygous mutation carriers reported a detectable increase in an akinesia-related phenotype, and a higher percentage of carriers had manifested diabetes. We also observed lower resting heart rate in the PRKN mutation carriers. Extending our risk analyses to a larger number of potential carriers and non-carriers using genotype imputation (n = 299 carriers and n = 7,127 non-carriers), from previously published biomarkers we also observed a higher neutrophil-to-lymphocyte ratio (NLR) and lower serum albumin and sodium levels in the heterozygous PRKN variant carriers. These results identify a set of biomarkers that might be useful either individually or as an ensemble to identify variant carriers at greater risk of health issues due to carrier status.

Published
2021
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17. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Alexander Teumer, Layal Chaker, Stefan Groeneweg, Yong Li, Celia Di Munno, Caterina Barbieri, Ulla T. Schultheiss, Michela Traglia, Tarunveer S. Ahluwalia, Masato Akiyama, Emil Vincent R. Appel, Dan E. Arking, Alice Arnold, Arne Astrup, Marian Beekman, John P. Beilby, Sofie Bekaert, Eric Boerwinkle, Suzanne J. Brown, Marc De Buyzere, Purdey J. Campbell, Graziano Ceresini, Charlotte Cerqueira, Francesco Cucca, Ian J. Deary, Joris Deelen, Kai-Uwe Eckardt, Arif B. Ekici, Johan G. Eriksson, Luigi Ferrrucci, Tom Fiers, Edoardo Fiorillo, Ian Ford, Caroline S. Fox, Christian Fuchsberger, Tessel E. Galesloot, Christian Gieger, Martin Gögele, Alessandro De Grandi, Niels Grarup, Karin Halina Greiser, Kadri Haljas, Torben Hansen, Sarah E. Harris, Diana van Heemst, Martin den Heijer, Andrew A. Hicks, Wouter den Hollander, Georg Homuth, Jennie Hui, M. Arfan Ikram, Till Ittermann, Richard A. Jensen, Jiaojiao Jing, J. Wouter Jukema, Eero Kajantie, Yoichiro Kamatani, Elisa Kasbohm, Jean-Marc Kaufman, Lambertus A. Kiemeney, Margreet Kloppenburg, Florian Kronenberg, Michiaki Kubo, Jari Lahti, Bruno Lapauw, Shuo Li, David C. M. Liewald, Lifelines Cohort Study, Ee Mun Lim, Allan Linneberg, Michela Marina, Deborah Mascalzoni, Koichi Matsuda, Daniel Medenwald, Christa Meisinger, Ingrid Meulenbelt, Tim De Meyer, Henriette E. Meyer zu Schwabedissen, Rafael Mikolajczyk, Matthijs Moed, Romana T. Netea-Maier, Ilja M. Nolte, Yukinori Okada, Mauro Pala, Cristian Pattaro, Oluf Pedersen, Astrid Petersmann, Eleonora Porcu, Iris Postmus, Peter P. Pramstaller, Bruce M. Psaty, Yolande F. M. Ramos, Rajesh Rawal, Paul Redmond, J. Brent Richards, Ernst R. Rietzschel, Fernando Rivadeneira, Greet Roef, Jerome I. Rotter, Cinzia F. Sala, David Schlessinger, Elizabeth Selvin, P. Eline Slagboom, Nicole Soranzo, Thorkild I. A. Sørensen, Timothy D. Spector, John M. Starr, David J. Stott, Youri Taes, Daniel Taliun, Toshiko Tanaka, Betina Thuesen, Daniel Tiller, Daniela Toniolo, Andre G. Uitterlinden, W. Edward Visser, John P. Walsh, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Qiong Yang, Hou-Feng Zheng, Anne Cappola, Robin P. Peeters, Silvia Naitza, Henry Völzke, Serena Sanna, Anna Köttgen, Theo J. Visser, and Marco Medici

Subjects
Science
Abstract

Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Published
2018
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18. Age, Sex, Body Mass Index, Diet and Menopause Related Metabolites in a Large Homogeneous Alpine Cohort

Author

Vinicius Verri Hernandes, Nikola Dordevic, Essi Marjatta Hantikainen, Baldur Bragi Sigurdsson, Sigurður Vidir Smárason, Vanessa Garcia-Larsen, Martin Gögele, Giulia Caprioli, Ilaria Bozzolan, Peter P. Pramstaller, and Johannes Rainer

Subjects
metabolomics, menopause, gender differences, diet, aging, body mass index, Microbiology, QR1-502
Abstract

Metabolomics in human serum samples provide a snapshot of the current metabolic state of an individuum. Metabolite concentrations are influenced by both genetic and environmental factors. Concentrations of certain metabolites can further depend on age, sex, menopause, and diet of study participants. A better understanding of these relationships is pivotal for the planning of metabolomics studies involving human subjects and interpretation of their results. We generated one of the largest single-site targeted metabolomics data sets consisting of 175 quantified metabolites in 6872 study participants. We identified metabolites significantly associated with age, sex, body mass index, diet, and menopausal status. While most of our results agree with previous large-scale studies, we also found novel associations including serotonin as a sex and BMI-related metabolite and sarcosine and C2 carnitine showing significantly higher concentrations in post-menopausal women. Finally, we observed strong associations between higher consumption of food items and certain metabolites, mostly phosphatidylcholines and lysophosphatidylcholines. Most, and the strongest, relationships were found for habitual meat intake while no significant relationships were found for most fruits, vegetables, and grain products. Summarizing, our results reconfirm findings from previous population-based studies on an independent cohort. Together, these findings will ultimately enable the consolidation of sets of metabolites which are related to age, sex, BMI, and menopause as well as to participants’ diet.

Published
2022
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19. Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

Author

David B. Emmert, Vladimir Vukovic, Nikola Dordevic, Christian X. Weichenberger, Chiara Losi, Yuri D’Elia, Claudia Volpato, Vinicius V. Hernandes, Martin Gögele, Luisa Foco, Giulia Pontali, Deborah Mascalzoni, Francisco S. Domingues, Rupert Paulmichl, Peter P. Pramstaller, Cristian Pattaro, Alessandra Rossini, Johannes Rainer, Christian Fuchsberger, and Marzia De Bortoli

Subjects
atrial fibrillation, GWAS, rare alleles, familial aggregation, metabolomics, Cooperative Health Research in South Tyrol, Microbiology, QR1-502
Abstract

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.

Published
2021
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20. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Author

Peter K. Joshi, Nicola Pirastu, Katherine A. Kentistou, Krista Fischer, Edith Hofer, Katharina E. Schraut, David W. Clark, Teresa Nutile, Catriona L. K. Barnes, Paul R. H. J. Timmers, Xia Shen, Ilaria Gandin, Aaron F. McDaid, Thomas Folkmann Hansen, Scott D. Gordon, Franco Giulianini, Thibaud S. Boutin, Abdel Abdellaoui, Wei Zhao, Carolina Medina-Gomez, Traci M. Bartz, Stella Trompet, Leslie A. Lange, Laura Raffield, Ashley van der Spek, Tessel E. Galesloot, Petroula Proitsi, Lisa R. Yanek, Lawrence F. Bielak, Antony Payton, Federico Murgia, Maria Pina Concas, Ginevra Biino, Salman M. Tajuddin, Ilkka Seppälä, Najaf Amin, Eric Boerwinkle, Anders D. Børglum, Archie Campbell, Ellen W. Demerath, Ilja Demuth, Jessica D. Faul, Ian Ford, Alessandro Gialluisi, Martin Gögele, MariaElisa Graff, Aroon Hingorani, Jouke-Jan Hottenga, David M. Hougaard, Mikko A. Hurme, M. Arfan Ikram, Marja Jylhä, Diana Kuh, Lannie Ligthart, Christina M. Lill, Ulman Lindenberger, Thomas Lumley, Reedik Mägi, Pedro Marques-Vidal, Sarah E. Medland, Lili Milani, Reka Nagy, William E. R. Ollier, Patricia A. Peyser, Peter P. Pramstaller, Paul M. Ridker, Fernando Rivadeneira, Daniela Ruggiero, Yasaman Saba, Reinhold Schmidt, Helena Schmidt, P. Eline Slagboom, Blair H. Smith, Jennifer A. Smith, Nona Sotoodehnia, Elisabeth Steinhagen-Thiessen, Frank J. A. van Rooij, André L. Verbeek, Sita H. Vermeulen, Peter Vollenweider, Yunpeng Wang, Thomas Werge, John B. Whitfield, Alan B. Zonderman, Terho Lehtimäki, Michele K. Evans, Mario Pirastu, Christian Fuchsberger, Lars Bertram, Neil Pendleton, Sharon L. R. Kardia, Marina Ciullo, Diane M. Becker, Andrew Wong, Bruce M. Psaty, Cornelia M. van Duijn, James G. Wilson, J. Wouter Jukema, Lambertus Kiemeney, André G. Uitterlinden, Nora Franceschini, Kari E. North, David R. Weir, Andres Metspalu, Dorret I. Boomsma, Caroline Hayward, Daniel Chasman, Nicholas G. Martin, Naveed Sattar, Harry Campbell, Tōnu Esko, Zoltán Kutalik, and James F. Wilson

Subjects
Science
Abstract

Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Published
2017
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21. Association of dietary proteins with serum creatinine and estimated glomerular filtration rate in a general population sample: the CHRIS study

Author

Vladimir Vukovic, Essi Hantikainen, Athina Raftopoulou, Martin Gögele, Johannes Rainer, Francisco S. Domingues, Peter P. Pramstaller, Vanessa Garcia-Larsen, and Cristian Pattaro

Subjects
Nephrology
Abstract

Background Diet is known to affect kidney function. However, population-based studies provide contrasting evidence, resulting in a poor understanding of the effect of proteins from specific foods on kidney health. Methods We analyzed the effect of total daily protein intake (TDPI) and source-specific daily protein intake (DPI) on fasting serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) in the Cooperative Health Research In South Tyrol (CHRIS) cross-sectional study (n = 5889), using the GA2LEN food frequency questionnaire for TDPI and DPI estimation. We fitted multivariable adjusted mixed models of SCr and eGFR on TDPI and DPI quartiles (Q1-Q4) in the overall sample, and after removing individuals with known hypertension, diabetes or chronic kidney disease (CKD). Results Higher TDPI as well as DPI from overall animal sources, fish, and poultry, were associated with higher SCr (trend test p, ptrend 2; 95% CI − 2.5, − 0.7; ptrend = 3e−4) and DPI from fish (Q4 vs Q1: − 2.1 ml/min/1.73 m2; 95% CI − 2.9, − 1.20; ptrend = 4.3e−6), overall animal source (Q4 vs Q1: − 1.6 ml/min/1.73 m2; 95% CI −2.5, − 0.8), processed meat (Q4 vs Q1: − 1.4 ml/min/1.73 m2; ptrend = 0.027), red meat, offal and processed meat (Q4 vs Q1: − 1.4 ml/min/1.73 m2; ptrend = 0.015) and poultry (Q4 vs Q1: − 0.9 ml/min/1.73 m2; ptrend = 0.015). Conclusions TDPI and DPI from specific animal sources were positively associated with SCr and negatively associated with eGFR. Lacking an alternative marker of kidney function, confounding involving muscle mass metabolism cannot be fully excluded. Graphical abstract

Published
2022
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22. Systematic mediation and interaction analyses in an individual population study help characterize kidney function genetic loci

Author

Dariush Ghasemi-Semeskandeh, David Emmert, Eva König, Luisa Foco, Martin Gögele, Laura Barin, Ryosuke Fujii, Christian Fuchsberger, Dorien J.M. Peters, Peter P. Pramstaller, and Cristian Pattaro

Abstract

Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental effects. To identify molecular targets for treatment, genome-wide association study meta-analyses (GWAMAs) of CKD-defining traits have identified hundreds of genetic loci in aggregated populations. However, while GWAMAs estimate the average allelic effect across studies, single population studies may be relevant to unravel specific mechanisms. To assess whether an individual study from a specific population could extend existing knowledge on kidney function genetics, we selected 147 kidney function relevant loci identified by a large European ancestry GWAMA, assessing their association with the glomerular filtration rate estimated from serum creatinine (eGFRcrea) in the Cooperative Health Research In South Tyrol (CHRIS) study (n=10,146), conducted in an Alpine region where thyroid dysfunction is common. We replicated associations with single nucleotide polymorphisms (SNPs) at 11 loci, showing up-to-5.4 times larger effect sizes than in the corresponding GWAMA, not explainable by minor allele frequency differences. Systematic mediation analysis across 70 quantitative traits identified serum magnesium, the activated partial thromboplastin time, and serum urate as partial mediators of the eGFRcrea associations atSHROOM3,SLC34A1, andIGF1R, respectively. Given that free triiodothyronine and thyroxine were effect modifiers across all loci, we conducted SNP-by-thyroid stimulating hormone (TSH) interaction analyses, identifying significant interactions atSTC1: SNPs had larger effects on eGFRcrea at higher TSH levels, possibly reflecting stanniocalcin-1 autocrine and paracrine role. Individual population studies can help characterize genetic associations. The interplay between phenotypes atSHROOM3andSLC34A1and the role of thyroid function as a genetic effect modifier warrant further investigations.

Published
2023
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23. Effects of smoking status, history and intensity on heart rate variability in the general population: The CHRIS study.

Author

Federico Murgia, Roberto Melotti, Luisa Foco, Martin Gögele, Viviana Meraviglia, Benedetta Motta, Alexander Steger, Michael Toifl, Daniel Sinnecker, Alexander Müller, Giampiero Merati, Georg Schmidt, Alessandra Rossini, Peter P Pramstaller, and Cristian Pattaro

Subjects
Medicine, Science
Abstract

BackgroundHeart rate variability (HRV) reflects the autonomous nervous system modulation on heart rate and is associated with several pathologies, including cardiac mortality. While mechanistic studies show that smoking is associated with lower HRV, population-based studies present conflicting results.MethodsWe assessed the mutual effects of active smoking status, cumulative smoking history, and current smoking intensity, on HRV among 4751 adults from the Cooperative Health Research In South Tyrol (CHRIS) study. The HRV metrics standard deviation of normal-to-normal (NN) inter-beat intervals (SDNN), square root of the mean squared differences of consecutive NN intervals (RMSSD), total power (TP), low (LF) and high frequency (HF) power, and their ratio (LF/HF), were derived from 20-minute electrocardiograms. Smoking status, pack-years (PY), and tobacco grams/day from standardized questionnaires were the main exposures. We fitted linear mixed models to account for relatedness, non-linearity, and moderating effects, and including fractional polynomials.ResultsPast smokers had higher HRV levels than never smokers, independently of PY. The association of HRV with current smoking became apparent when accounting for the interaction between smoking status and PY. In current smokers, but not in past smokers, we observed HRV reductions between 2.0% (SDNN) and 4.9% (TP) every 5 PY increase. Furthermore, current smokers were characterized by dose-response reductions of 9.8% (SDNN), 8.9% (RMSSD), 20.1% (TP), 17.7% (LF), and 19.1% (HF), respectively, every 10 grams/day of smoked tobacco, independently of common cardiometabolic conditions and HRV-modifying drugs. The LF/HF ratio was not associated with smoking status, history, or intensity.ConclusionsSmoking cessation was associated with higher HRV levels. In current smokers, heavier smoking intensity appears gradually detrimental on HRV, corroborating previous evidence. By affecting both the sympathetic and parasympathetic nervous system indexes, but not the LF/HF balance, smoking intensity seems to exert a systemic dysautonomic effect.

Published
2019
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24. Determinants of SARS-CoV-2 nasopharyngeal testing in a rural community sample susceptible of first infection: the CHRIS COVID-19 study

Author

Daniele Giardiello, Roberto Melotti, Giulia Barbieri, Martin Gögele, Christian X. Weichenberger, Luisa Foco, Daniele Bottigliengo, Laura Barin, Rebecca Lundin, Peter P. Pramstaller, and Cristian Pattaro

Subjects
Infectious Diseases, PCR, SARS-CoV-2, swab, Public Health, Environmental and Occupational Health, cooperative health research in south tyrol, COVID-19, Parasitology, General Medicine, Microbiology, testing
Abstract

To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandemic intensity and public health interventions, COVID-19-related symptoms (odds ratio, OR:8.26; 95% confidence interval, CI:6.04–11.31), contacts with infected individuals within home (OR:7.47, 95%CI:3.81–14.62) or outside home (OR:9.87, 95%CI:5.78–16.85), and being retired (OR:0.50, 95%CI:0.34-0.73). Symptoms and next within- and outside-home contacts were the leading determinants of swab testing predisposition in the most acute phase of the pandemics. Testing was not associated with age, sex, education, comorbidities, or lifestyle factors. In the study area, contextual determinants reflecting the course of the pandemic were predominant compared to individual sociodemographic characteristics in explaining the SARS-CoV-2 probability of testing. Decision makers should evaluate whether the intended target groups were correctly prioritized by the testing campaign.

Published
2023
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25. Prospective epidemiological, molecular, and genetic characterization of a novel coronavirus disease in the Val Venosta/Vinschgau: the CHRIS COVID-19 study protocol

Author

Andrew A. Hicks, Cristian Pattaro, Giulia Barbieri, Horand Meier, Christian Dejaco, Roberto Melotti, Francisco S. Domingues, Peter P. Pramstaller, Luisa Foco, Michael Mian, Vera S C Amon, Alessandro De Grandi, Clemens Egger, Stefano Lombardo, Angelika Mahlknecht, Martin Gögele, Robert Rainer, Massimo Pizzato, Christian Fuchsberger, Deborah Mascalzoni, Andrea Crisanti, Christian X. Weichenberger, Roberta Biasiotto, Helmuth Weiss, Günter Weiss, and Enrico Lavezzo

Subjects
Adult, Infectious Medicine, medicine.medical_specialty, Population, novel coronavirus, Infektionsmedicin, Disease, Microbiology, general population, COVID-19, Cooperative Health Research In South Tyrol (CHRIS) study, SARS-CoV-2, COVID-19 Testing, Humans, Pandemics, Prospective Studies, Health care, Epidemiology, Pandemic, medicine, education, Prospective cohort study, Socioeconomic status, education.field_of_study, business.industry, Incidence (epidemiology), Public Health, Environmental and Occupational Health, General Medicine, Infectious Diseases, Family medicine, Parasitology, business, Research Article
Abstract

The COVID-19 pandemic has been threatening the healthcare and socioeconomic systems of entire nations. While population-based surveys to assess the distribution of SARS-CoV-2 infection have become a priority, pre-existing longitudinal studies are ideally suited to assess the determinants of COVID-19 onset and severity.The Cooperative Health Research In South Tyrol (CHRIS) study completed the baseline recruitment of 13,393 adults from the Venosta/Vinschgau rural district in 2018, collecting extensive phenotypic and biomarker data, metabolomic data, densely imputed genotype and whole-exome sequencing data.Based on CHRIS, we designed a prospective study, called CHRIS COVID-19, aimed at: 1) estimating the incidence of SARS-CoV-2 infections; 2) screening for and investigating the determinants of incident infection among CHRIS participants and their household members; 3) monitoring the immune response of infected participants prospectively.An online screening questionnaire was sent to all CHRIS participants and their household members. A random sample of 1450 participants representative of the district population was invited to assess active (nasopharyngeal swab) or past (serum antibody test) infections. We prospectively invited for complete SARS-CoV-2 testing all questionnaire completers gauged as possible cases of past infection and their household members. In positive tested individuals, antibody response is monitored quarterly for one year. Untested and negative participants receive the screening questionnaire every four weeks until gauged as possible incident cases or till the study end.Originated from a collaboration between researchers and community stakeholders, the CHRIS COVID-19 study aims at generating knowledge about the epidemiological, molecular, and genetic characterization of COVID-19 and its long-term sequelae.

Published
2021

26. Task matters - challenging the motor system allows distinguishing unaffected Parkin mutation carriers from mutation-free controls

Author

Martin Gögele, Maria Paulina Castelo-Rueda, Max Borsche, Irene Pichler, Christine Klein, Meike Kasten, Cleo Kritzinger, Clemens Egger, Norbert Brüggemann, Peter P. Pramstaller, Deborah Mascalzoni, Jannik Prasuhn, Andrew A. Hicks, and Lynn Langlott

Subjects
Adult, Male, 0301 basic medicine, Heterozygote, medicine.medical_specialty, Ubiquitin-Protein Ligases, Substantia nigra, Disease, Audiology, Parkin, 03 medical and health sciences, 0302 clinical medicine, Accelerometry, Motor system, Humans, Medicine, Postural Balance, Aged, business.industry, Posturography, Parkinson Disease, Middle Aged, Gait, 030104 developmental biology, Neurology, Gait analysis, Mutation, Mutation (genetic algorithm), Female, Neurology (clinical), Geriatrics and Gerontology, Gait Analysis, business, Psychomotor Performance, 030217 neurology & neurosurgery
Abstract

Background Heterozygous carriers of Parkin mutations are suggested to be at risk of developing Parkinson's disease, while biallelic variants are associated with typical autosomal recessive early-onset PD. Investigating unaffected heterozygous mutation carriers holds the potential of a deeper understanding of monogenic PD and has implications for PD in general, in particular regarding the prodromal phase. Objectives To discriminate healthy Parkin mutation carriers from healthy non-mutation carriers using a multimodal approach. Methods Twenty-seven healthy heterozygous Parkin mutation carriers (13 female. age: 48 ± 13 years) and 24 healthy non-mutation carriers (14 female. age: 48 ± 15 years) from the CHRIS study (Cooperative Health Research in South Tyrol) were recalled based on their genetic profile and underwent a blinded assessment of motor and non-motor PD symptoms, transcranial sonography and sensor-based posturography and gait analyses under different conditions with increasing difficulty. For the latter, gradient-boosted trees were used to discriminate between carriers and non-carriers. The classification accuracy and the area under the curve of the receiver-operator characteristics curve were calculated. Results We observed no differences concerning motor or non-motor symptoms and substantia nigra hyperechogenicity. The best gradient-boosted trees-based model on posturography measurements (tandem feet, eyes closed, firm surface), however, showed a classification accuracy of up to 86%. The best-performing gradient-boosted trees-based model for gait analyses showed a balanced accuracy of up to 87% (dual-tasking). Conclusions Sensor-based quantification of movements allows to discriminate unaffected heterozygous mutation carriers from mutation-free controls. Thereby, it is crucial to challenge the motor system with more difficult tasks to unmask subtle motor alterations.

Published
2021
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27. MO383: Structural Equation Modelling to Improve Kidney Function Assessment in The General Population

Author

Ryosuke Fujii, Giulia Barbieri, Dariush Ghasemi, Martin Gögele, Pramstaller Peter, and Cristian Pattaro

Subjects
Transplantation, Nephrology
Abstract

BACKGROUND AND AIMS In order to identify behavioral, environmental, biological or genetic determinants of kidney function, population-based epidemiological studies rely on approximate estimates of the glomerular filtration rate (eGFR) based on measured markers such as serum creatinine, cystatin C, and a few other [1,2]. Since none of these markers is the exclusive reflection of the kidney function, results should always be interpreted with caution to disentangle determinants of kidney function from those that are specific to the marker metabolism. A structural equation modelling (SEM) approach could overcome these limitations allowing to estimate the unobservable kidney function based on a larger number of markers, improving the possibilities of conducting more specific inferential studies [3]. We implemented SEM to identify a latent kidney function trait in a general population sample and validated this derived biomarker against 10-year incidence of kidney disease using an independent dataset. METHOD In the population-based MICROS study (South Tyrol, Italy) [4], we measured serum creatinine (SCr), uric acid (UA), blood urea nitrogen (BUN), cystatin C (CysC), and serum albumin in 1317 study participants. We split the sample into a model-building (n = 647) and a validation set (n = 670). The model-building set was used for SEM analysis and estimation of factor loadings for each biomarker, using the R package ‘lavaan’. Participants in the validation set were submitted a 10-year follow-up interview on kidney disease within the Cooperative Health Research In South Tyrol (CHRIS) study [5]. We fitted logistic regression models to assess the predictivity of the estimated latent kidney function trait versus each individual marker, CKD-EPI eGFR estimates based on serum creatinine and cystatin C (CKD-EPI 2009; CKD-EPI 2021; CKD-EPI Cys; and CKD-EPI CreCys), as well as MDRD-4 and MDRD-6. We estimated odds ratios (ORs) for 10-year kidney disease incidence per standard deviation (SD) change in each marker. RESULTS In the model-building set (mean age 49 years, SD = 19; 58% females; mean eGFRCKD-EPI 2021 = 85.9, SD = 20.9), we identified factor loadings for SCr, UA, BUN, and CysC (Figure 1) achieving acceptable goodness of fit (Chi-square = 14.7; CFI = 0.98; TLI = 0.93; and RMSEA = 0.099). The validation set (baseline mean age = 40 years, SD = 13; 55% females; mean eGFRCKD-EPI 2021 = 100.8, SD = 16.1) had a 10-year kidney disease incidence of 7.8%. For the latent kidney function trait, we observed an OR of 2.1 (95% CI: 1.4–3.2) for incidence per each SD change. This was lower than the ORs (95% CI) associated with the eGFRMDRD4 (2.3, 1.4–4.1) and eGFRMDRD6 (2.5, 1.5–4.2), but larger than the ORs (95% CI) observed for all other markers (SCr: 1.8, 1.3–2.6; UA: 1.2, 0.9–1.8; BUN: 1.3, 0.9–1.8; and CysC: 1.3, 1.0–1.7) or eGFR estimates (eGFRCKD-EPI2009: 1.8, 1.2–2.7; eGFRCKD-EPI2021: 1.7, 1.2–2.5; eGFRCKD-EPI Cys: 1.4, 1.0–1.9; and eGFRCKD-EPI CreCys: 1.8, 1.2–2.6). CONCLUSION A latent kidney function trait derived from SEM performed similarly and often better than conventional eGFR estimates in a 10-year kidney disease incidence prediction. The method warrants validation in independent general population samples with large sample size.

Published
2022
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28. Ten years of dynamic consent in the CHRIS study : informed consent as a dynamic process

Author

Deborah Mascalzoni, Roberto Melotti, Cristian Pattaro, Peter Paul Pramstaller, Martin Gögele, Alessandro De Grandi, and Roberta Biasiotto

Subjects
Ethics, Informed Consent, Communication, Genetics, Humans, Etik, Longitudinal Studies, Trust, Medical Genetics, Genetics (clinical), Research Personnel, Medicinsk genetik
Abstract

The Cooperative Health Research in South Tyrol (CHRIS) is a longitudinal study in Northern Italy, using dynamic consent since its inception in 2011. The CHRIS study collects health data and biosamples for research, and foresees regular follow-ups over time. We describe the experience with the CHRIS study dynamic consent, providing an overview of its conceptualization and implementation, and of the participant-centered strategies used to assess and improve the process, directly linked to participation and communication. In order to comply with high ethical standards and to allow broadness in the areas of research, CHRIS dynamic consent was conceived as an interactive process: based on a strong governance and an ongoing tailored communication with participants, it aims to promote autonomy and to develop a trust-based engaged relationship with participants, also relevant for retention. Built within an online platform, the consent allows granular choices, which can be changed over time. In a process of co-production, participants views have been investigated and kept into account in policy development. Participants showed a high degree of participation, thus enabling the consolidation of the CHRIS resources. Even though a low change rate was reported in the baseline, participants valued the possibility of changing their informed consent choices. Communication (language-tailored, ongoing, multimedia) was important for participants, and for participation and retention. In our experience, dynamic consent was proven to be a flexible consent model, which allowed to meet ethical and legal standards for participation in research, and to accommodate participants’ and researchers’ needs.

Published
2022

29. Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Author

Peter W. Macfarlane, Niels Grarup, Ruth J. F. Loos, Marcus Dörr, Peter P. Pramstaller, Torben Hansen, James F. Wilson, Lu-Chen Weng, Eduardo Tarazona-Santos, Honghuang Lin, Yong Qian, Jeffrey R. O'Connell, Maria Pina Concas, Claudia Schurmann, Michele Orini, Joshua C. Bis, Archie Campbell, Susan R. Heckbert, Jie Yao, Eulalia Catamo, Claus Graff, James G. Wilson, Pashupati P. Mishra, Massimo Mangino, Martina Müller-Nurasyid, Borbala Mifsud, Linda Repetto, Stephan B. Felix, Julia Ramirez, Rebecca D. Jackson, Eric Boerwinkle, Monika Stoll, Elsayed Z. Soliman, Maryam Kavousi, David J. Porteous, Nina Mononen, Dan E. Arking, Laura Andreasen, Lorenz Risch, Antonio Luiz Pinho Ribeiro, Pier D. Lambiase, Mika Kähönen, Xia Shen, Kenneth Rice, Eric A. Whitsel, Nona Sotoodehnia, Victor Nauffal, Konstantin Strauch, Jørgen K. Kanters, Henry Völzke, Daniel S. Evans, Jonas L. Isaksen, Alessandro De Grandi, Hao Mei, Alexander P. Reiner, Christy L. Avery, Thiago P. Leal, Alanna C. Morrison, Christian Fuchsberger, M. Arfan Ikram, Moritz Sinner, Yongmei Liu, Bruno H. Stricker, Francesco Cucca, Allan Linneberg, Patricia B. Munroe, Christina Ellervik, Olli T. Raitakari, Melanie Waldenberger, Reem Salman, Xiuqing Guo, Sandosh Padmanabhan, ThuyVy Duong, Dawood Darbar, Stefan Weiss, Arden Moscati, Alvaro Alonso, Cornelia M. van Duijn, Gianfranco Sinagra, Luisa Foco, Matthias Nauck, Kathleen A. Ryan, Kjell Nikus, Gustav Ahlberg, Helen R. Warren, Kent D. Taylor, Niek Verweij, Rebecca Freudling, Cristian Pattaro, Michael Preuss, Charles Kooperberg, Anne Richmond, David Conen, Oliver Hines, Juhani Junttila, Leo-Pekka Lyytikäinen, Nina Hutri-Kähönen, Kirill V. Tarasov, Ulrich Schotten, M. Benjamin Shoemaker, Marten E. van den Berg, Jerome I. Rotter, Michael J. Cutler, Adolfo Correa, Bruce M. Psaty, Caroline Hayward, Yalda Jamshidi, Pau Navarro, J W Benjamins, Patrick T. Ellinor, Massimo Mezzavilla, William J Young, Stefan Kääb, Lars Lind, Antonio De Luca, Heikki V. Huikuri, Marjo-Riitta Järvelin, Guillaume Paré, Stefan van Duijvenboden, Uwe Völker, Maria Fernanda Lima-Costa, Philippe Froguel, Jan A. Kors, Annette Peters, David Schlessinger, Christopher Newton-Cheh, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Antoine R Baldassari, Stefanie Aeschbacher, Mariaelisa Graff, Najim Lahrouchi, Henry J. Lin, Giorgia Girotto, Giulia Pelliccione, Jeffrey Haessler, Aaron Isaacs, Rebecca N. Mitchell, Carolina Roselli, Massimiliano Cocca, Sina A. Gharib, Rozenn N. Lemaitre, Raymond Noordam, Morten S. Olesen, Steven A. Lubitz, Jun Ding, May E. Montasser, Jennifer A. Brody, Stella Trompet, Traci M. Bartz, Dania Raza, Thomas Meitinger, Andrew P. Morris, James P. Cook, Sébastien Thériault, Martin Gögele, André G. Uitterlinden, Pim van der Harst, Alan Pittman, Farah Ahmed, Simin Liu, Casia Nursyifa, Paul L. Huang, Kristen K. Patton, and Terho Lehtimäki

Subjects
medicine.medical_specialty, business.industry, Locus (genetics), Atrial fibrillation, medicine.disease, QT interval, Genetic architecture, Sudden cardiac death, QRS complex, Internal medicine, cardiovascular system, medicine, Cardiology, Repolarization, cardiovascular diseases, business, Ventricular depolarization
Abstract

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Published
2021

31. Abstract P136: Reference Ranges And Cut-Off Values For Simultaneous Monitoring Of RAS-Blocker Efficacy And Screening For Secondary Hypertension Using RAAS Triple-A Profiling

Author

Luisa Foco, Cristian Pattaro, Martin Gögele, Peter P. Pramstaller, and Marko Poglitsch

Subjects
medicine.medical_specialty, Aldosterone, business.industry, Urology, Secondary hypertension, Patient specific, Precision medicine, medicine.disease, Angiotensin II, Drug uptake, Compliance (physiology), chemistry.chemical_compound, chemistry, Internal Medicine, Medicine, business
Abstract

Uncontrolled hypertension is caused by various factors including compliance issues, patient specific drug uptake and elimination profiles or secondary forms of hypertension, resulting in blood pressure control rates of less that 50%. RAAS Triple-A profiling is a high-throughput mass-spectrometry based assay for Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone in serum samples. Hormone levels are used to calculate markers for plasma-renin-activity (PRA-S), plasma angiotensin-converting-enzyme activity (ACE-S) and adrenal aldosterone secretion (AA2-Ratio). The integrated analysis of these molecular markers together with drug prescription information allows to identify the underlying cause of uncontrolled hypertension, including primary aldosteronism and insufficiency in drug adherence or dosing for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs). 500 participants with prescribed antihypertensive drugs were selected from the “Cooperative Health Research in South Tyrol” (CHRIS) study, a population-based study from an Alpine rural environment. Five age- and sex-matched groups (N=100 each) selected were individuals on single therapy with ARBs, ACEi or beta blockers, and on single pill dual therapy of ACEi or ARBs in combination with diuretics. Three age and sex-matched control groups of 100 participants each were included, being normotensive, hypertensive (treated with non-antihypertensive drugs) and hypertensive participants without any prescribed medication. RAAS Triple-A analysis was performed in all individuals and reference values for Ang I, Ang II, Aldosterone, PRA-S, ACE-S and AA2-Ratio were established in appropriate sub-populations. Drug monitoring by LC-MS/MS based quantification of anti-hypertensive drugs in serum was used as a gold standard to determine cut-off values for compliance with ARB and ACEi therapy and ROC analysis was performed using angiotensin-based biomarkers.

Published
2021
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33. Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample : The CHRIS Study

Author

Marzia De Bortoli, Nikola Dordevic, David B. Emmert, Vladimir Vukovic, Luisa Foco, Deborah Mascalzoni, Francisco S. Domingues, Johannes Rainer, Rupert Paulmichl, Peter P. Pramstaller, Alessandra Rossini, Vinicius Veri Hernandes, Christian X. Weichenberger, Cristian Pattaro, Chiara Losi, Claudia B. Volpato, Martin Gögele, Christian Fuchsberger, Yuri D’Elia, and Giulia Pontali

Subjects
Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Biochemistry, Microbiology, Polymorphism, Single Nucleotide, Article, symbols.namesake, Genotype, Humans, GWAS, Cooperative Health Research in South Tyrol, Genetic Predisposition to Disease, atrial fibrillation, rare alleles, Cardiac and Cardiovascular Systems, Allele, education, Molecular Biology, Gene, Medicinsk genetik, Genetics, Sanger sequencing, education.field_of_study, Kardiologi, Family aggregation, Middle Aged, metabolomics, QR1-502, familial aggregation, symbols, Medical Genetics, Genome-Wide Association Study
Abstract

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value &lt, 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.

Published
2021

34. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

Author

Eleonora Porcu, Marco Medici, Giorgio Pistis, Claudia B Volpato, Scott G Wilson, Anne R Cappola, Steffan D Bos, Joris Deelen, Martin den Heijer, Rachel M Freathy, Jari Lahti, Chunyu Liu, Lorna M Lopez, Ilja M Nolte, Jeffrey R O'Connell, Toshiko Tanaka, Stella Trompet, Alice Arnold, Stefania Bandinelli, Marian Beekman, Stefan Böhringer, Suzanne J Brown, Brendan M Buckley, Clara Camaschella, Anton J M de Craen, Gail Davies, Marieke C H de Visser, Ian Ford, Tom Forsen, Timothy M Frayling, Laura Fugazzola, Martin Gögele, Andrew T Hattersley, Ad R Hermus, Albert Hofman, Jeanine J Houwing-Duistermaat, Richard A Jensen, Eero Kajantie, Margreet Kloppenburg, Ee M Lim, Corrado Masciullo, Stefano Mariotti, Cosetta Minelli, Braxton D Mitchell, Ramaiah Nagaraja, Romana T Netea-Maier, Aarno Palotie, Luca Persani, Maria G Piras, Bruce M Psaty, Katri Räikkönen, J Brent Richards, Fernando Rivadeneira, Cinzia Sala, Mona M Sabra, Naveed Sattar, Beverley M Shields, Nicole Soranzo, John M Starr, David J Stott, Fred C G J Sweep, Gianluca Usala, Melanie M van der Klauw, Diana van Heemst, Alies van Mullem, Sita H Vermeulen, W Edward Visser, John P Walsh, Rudi G J Westendorp, Elisabeth Widen, Guangju Zhai, Francesco Cucca, Ian J Deary, Johan G Eriksson, Luigi Ferrucci, Caroline S Fox, J Wouter Jukema, Lambertus A Kiemeney, Peter P Pramstaller, David Schlessinger, Alan R Shuldiner, Eline P Slagboom, André G Uitterlinden, Bijay Vaidya, Theo J Visser, Bruce H R Wolffenbuttel, Ingrid Meulenbelt, Jerome I Rotter, Tim D Spector, Andrew A Hicks, Daniela Toniolo, Serena Sanna, Robin P Peeters, and Silvia Naitza

Subjects
Genetics, QH426-470
Abstract

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Published
2013
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35. Age- and sex-related variations in platelet count in Italy: a proposal of reference ranges based on 40987 subjects' data.

Author

Ginevra Biino, Iolanda Santimone, Cosetta Minelli, Rossella Sorice, Bruno Frongia, Michela Traglia, Sheila Ulivi, Augusto Di Castelnuovo, Martin Gögele, Teresa Nutile, Marcella Francavilla, Cinzia Sala, Nicola Pirastu, Chiara Cerletti, Licia Iacoviello, Paolo Gasparini, Daniela Toniolo, Marina Ciullo, Peter Pramstaller, Mario Pirastu, Giovanni de Gaetano, and Carlo L Balduini

Subjects
Medicine, Science
Abstract

Background and objectivesAlthough several studies demonstrated that platelet count is higher in women, decreases with age, and is influenced by genetic background, most clinical laboratories still use the reference interval 150-400×10(9) platelets/L for all subjects. The present study was to identify age- and sex-specific reference intervals for platelet count.MethodsWe analysed electronic records of subjects enrolled in three population-based studies that investigated inhabitants of seven Italian areas including six geographic isolates. After exclusion of patients with malignancies, liver diseases, or inherited thrombocytopenias, which could affect platelet count, reference intervals were estimated from 40,987 subjects with the non parametric method computing the 2.5° and 97.5° percentiles.ResultsPlatelet count was similar in men and women until the age of 14, but subsequently women had steadily more platelets than men. The number of platelets decreases quickly in childhood, stabilizes in adulthood, and further decreases in oldness. The final result of this phenomenon is that platelet count in old age was reduced by 35% in men and by 25% in women compared with early infancy. Based on these findings, we estimated reference intervals for platelet count ×10(9)/L in children (176-452), adult men (141-362), adult women (156-405), old men (122-350) and, old women (140-379). Moreover, we calculated an "extended" reference interval that takes into account the differences in platelet count observed in different geographic areas.ConclusionsThe age-, sex-, and origin-related variability of platelet count is very wide, and the patient-adapted reference intervals we propose change the thresholds for diagnosing both thrombocytopenia and thrombocytosis in Italy.

Published
2013
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36. Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.

Author

Irene Pichler, Fabiola Del Greco M, Martin Gögele, Christina M Lill, Lars Bertram, Chuong B Do, Nicholas Eriksson, Tatiana Foroud, Richard H Myers, PD GWAS Consortium, Michael Nalls, Margaux F Keller, International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium, Beben Benyamin, John B Whitfield, Genetics of Iron Status Consortium, Peter P Pramstaller, Andrew A Hicks, John R Thompson, and Cosetta Minelli

Subjects
Medicine
Abstract

BackgroundAlthough levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.Methods and findingsWe used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron.ConclusionsOur study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.

Published
2013
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38. Evidence of inbreeding depression on human height.

Author

Ruth McQuillan, Niina Eklund, Nicola Pirastu, Maris Kuningas, Brian P McEvoy, Tõnu Esko, Tanguy Corre, Gail Davies, Marika Kaakinen, Leo-Pekka Lyytikäinen, Kati Kristiansson, Aki S Havulinna, Martin Gögele, Veronique Vitart, Albert Tenesa, Yurii Aulchenko, Caroline Hayward, Asa Johansson, Mladen Boban, Sheila Ulivi, Antonietta Robino, Vesna Boraska, Wilmar Igl, Sarah H Wild, Lina Zgaga, Najaf Amin, Evropi Theodoratou, Ozren Polašek, Giorgia Girotto, Lorna M Lopez, Cinzia Sala, Jari Lahti, Tiina Laatikainen, Inga Prokopenko, Mart Kals, Jorma Viikari, Jian Yang, Anneli Pouta, Karol Estrada, Albert Hofman, Nelson Freimer, Nicholas G Martin, Mika Kähönen, Lili Milani, Markku Heliövaara, Erkki Vartiainen, Katri Räikkönen, Corrado Masciullo, John M Starr, Andrew A Hicks, Laura Esposito, Ivana Kolčić, Susan M Farrington, Ben Oostra, Tatijana Zemunik, Harry Campbell, Mirna Kirin, Marina Pehlic, Flavio Faletra, David Porteous, Giorgio Pistis, Elisabeth Widén, Veikko Salomaa, Seppo Koskinen, Krista Fischer, Terho Lehtimäki, Andrew Heath, Mark I McCarthy, Fernando Rivadeneira, Grant W Montgomery, Henning Tiemeier, Anna-Liisa Hartikainen, Pamela A F Madden, Pio d'Adamo, Nicholas D Hastie, Ulf Gyllensten, Alan F Wright, Cornelia M van Duijn, Malcolm Dunlop, Igor Rudan, Paolo Gasparini, Peter P Pramstaller, Ian J Deary, Daniela Toniolo, Johan G Eriksson, Antti Jula, Olli T Raitakari, Andres Metspalu, Markus Perola, Marjo-Riitta Järvelin, André Uitterlinden, Peter M Visscher, James F Wilson, and ROHgen Consortium

Subjects
Genetics, QH426-470
Abstract

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

Published
2012
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39. KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Author

Christian P. Müller, Patricia B. Munroe, Philipp S. Wild, Teresa Trenkwalder, Christian Hengstenberg, Georg Schmidt, Yalda Jamshidi, Stephan B. Felix, Renate B. Schnabel, Nilesh J. Samani, Jan A. Kors, Peter S. Braund, Bruno H. Stricker, Bernhard M. Kaess, Solmaz Assa, C. Pattaro, Uwe Völker, Matthias Nauck, M. Arfan Ikram, Thomas Münzel, Mobeen Zafar, Isabel Deisenhofer, Niek Verweij, Alexander Teumer, Alessandra Rossini, Christopher P. Nelson, Thorsten Kessler, Anna F. Dominiczak, Tim D. Spector, Harold Snieder, Marten E. van den Berg, André G. Uitterlinden, Rachel Bastiaenen, Maryam Kavousi, Christian Fuchsberger, Sandosh Padmanabhan, Claudia P. Cabrera, Leanne M. Hall, Klaus Stark, Helen R. Warren, Norbert Pfeiffer, Heribert Schunkert, Karl J. Lackner, Ilja M. Nolte, Elijah R. Behr, Marcus Dörr, Peter P. Pramstaller, Marzia De Bortoli, Martin Gögele, Pim van der Harst, Wibke Reinhard, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Epidemiology, and Medical Informatics

Subjects
Male, 0301 basic medicine, Genotype, Heart Ventricles, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, White People, Sudden cardiac death, Electrocardiography, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Genetic predisposition, Humans, SNP, GWAS, Genetic Predisposition to Disease, J-POINT ELEVATION, S422L, Allele, GENOME-WIDE ASSOCIATION, Gene, MUTATION, Alleles, METAANALYSIS, Genetics, General Medicine, medicine.disease, ddc, Death, Sudden, Cardiac, Shal Potassium Channels, 030104 developmental biology, Genetic Loci, 030220 oncology & carcinogenesis, Ventricular Fibrillation, CORONARY-ARTERY-DISEASE, Female, VENTRICULAR-FIBRILLATION, Clinical Medicine, Transcriptome, Genome-Wide Association Study
Abstract

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS: We identified a genome-wide significant (P < 5 × 10(–8)) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10(–)12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. CONCLUSIONS: In this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies. FUNDING: This project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 – STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Published
2019

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

Author

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

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

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

Published
2019
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41. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author

Lorenz Risch, Igor Rudan, Hilma Holm, Christopher P. Nelson, Jan A. Kors, Stefanie Aeschbacher, Stefan Kääb, Peter W. Macfarlane, Lars Lind, Amanda A. Seyerle, Ozren Polasek, Daniel F. Gudbjartsson, Xiuqing Guo, Nilesh J. Samani, Bruce M. Psaty, Rosa B. Thorolfsdottir, Elsayed Z. Soliman, Yong Qian, Mary L. Biggs, Antti Jula, Vilmundur Gudnason, Paul L. Huang, Tamara B. Harris, Gianfranco Sinagra, Luisa Foco, Anubha Mahajan, Mika Kähönen, Lu-Chen Weng, Borbala Mifsud, Stefan van Duijvenboden, Terho Lehtimäki, Jennifer A. Brody, Paolo Gasparini, Kathleen A. Ryan, Marten E. van den Berg, James J. Cranley, Eric Boerwinkle, Cathy C. Laurie, Annette Peters, Joshua C. Bis, Raymond Noordam, Andrew P. Morris, Johan Sundström, Lenore J. Launer, Stefan Weiss, Rebecca D. Jackson, Alison D. Murray, Jeffrey R. O'Connell, Aki S. Havulinna, Dennis O. Mook-Kanamori, Sheila Ulivi, Renée de Mutsert, Eric A. Whitsel, Adrienne M. Stilp, James P. Cook, Nona Sotoodehnia, Antonio Luiz Pinho Ribeiro, Seung Hoan Choi, Mark J. Caulfield, Sébastien Thériault, Henry J. Lin, Dan M. Roden, J. Wouter Jukema, James F. Wilson, Veikko Salomaa, Honghuang Lin, Andrew A. Hicks, Christy L. Avery, Nina Mononen, Dan E. Arking, Ruth J. F. Loos, Yalda Jamshidi, André G. Uitterlinden, Nina Hutri-Kähönen, Andrew Tinker, Gudmar Thorleifsson, Daniel Levy, Martina Müller-Nurasyid, Alexander P. Reiner, Bruno H. Stricker, Caroline Hayward, Yordi J. van de Vegte, Ioanna Ntalla, Tim D. Spector, Niek Verweij, Michael R. Barnes, Martin Gögele, Nathan R. Tucker, Arie C. Maan, Eduardo Tarazona-Santos, Katri Sääksjärvi, Maria Pina Concas, Pim van der Harst, Georg Ehret, Cecilia M. Lindgren, David Conen, Cornelia M. van Duijn, Muhammad B. Riaz, Leo-Pekka Lyytikäinen, Amelia W. Hall, Peter P. Pramstaller, Maria Fernanda Lima-Costa, Vilmantas Giedraitis, Emelia J. Benjamin, M. Fabiola Del Greco, Thomas Meitinger, Erwin P. Bottinger, Francesco Cucca, Aaron Isaacs, Carolina Roselli, James H. Cartwright, Massimo Mangino, Adolfo Correa, Patrick Sulem, Thibaud Boutin, Michiel Rienstra, Stephan B. Felix, Julia Ramirez, Kathleen F. Kerr, Jonathan Marten, David J. Porteous, Kent D. Taylor, Patrick T. Ellinor, Michele Orini, Susan R. Heckbert, Olli T. Raitakari, Girish N. Nadkarni, Edward G. Lakatta, Anna F. Dominiczak, Jie Yao, Erik Ingelsson, Christopher Newton-Cheh, Katharina Schramm, Jerome I. Rotter, Michael J. Cutler, Pashupati P. Mishra, Diane Fatkin, Marcus Dörr, Ulrike Peters, Solmaz Assa, Christian Fuchsberger, M. Abdullah Said, Catriona L. K. Barnes, Peter K. Joshi, M. Yldau van der Ende, Alvaro Alonso, James G. Wilson, Jun Ding, Kathryn L. Lunetta, Kjell Nikus, Helen R. Warren, Charles Kooperberg, Moritz F. Sinner, Sandosh Padmanabhan, Patricia B. Munroe, Jeffrey Haessler, Albert V. Smith, Alan R. Shuldiner, Morten S. Olesen, Konstantin Strauch, Steven A. Lubitz, J. Gustav Smith, Renan P. Souza, Michael Preuss, Kirill V. Tarasov, M. Benjamin Shoemaker, Barry London, Melanie Waldenberger, Cristian Pattaro, David O. Arnar, Gardar Sveinbjornsson, Alessandro De Grandi, Ian Ford, Kenneth Rice, Mark Chaffin, Kari Stefansson, Hao Mei, Uwe Völker, Blair H. Smith, Nathalia M. Araujo, Harry Campbell, Pier D. Lambiase, Stephanie M. Gogarten, May E. Montasser, Unnur Thorsteinsdottir, Ivana Kolcic, and Stella Trompet

Subjects
0303 health sciences, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cardiomyopathy, Atrial fibrillation, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Endophenotype, Cardiac conduction, medicine, Cardiology, PR interval, business, education, 030304 developmental biology
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Published
2019
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42. KCND3 is a novel susceptibility locus for early repolarization

Author

Jan A. Kors, Renate B. Schnabel, Rachel Bastiaenen, Philipp S. Wild, Marcus Dörr, Cristian Pattaro, Matthias Nauck, Muller Christian, Claudia P. Cabrera, Arfan Ikram, Patricia B. Munroe, Harold Snieder, Bernhard M. Kaess, Isabel Deisenhofer, Thomas Münzel, Uwe Völker, Christopher P. Nelson, Sandosh Padmanabhan, Mobeen Zafar, Ilja M. Nolte, Christian Hengstenberg, Georg Schmidt, Leanne M. Hall, Stephan B. Felix, Marten E. van den Berg, Helen R. Warren, Yalda Jamshidi, Alessandra Rossini, Anna F. Dominiczak, Martin Gögele, Klaus Stark, Christian Fuchsberger, Pim van der Harst, Wibke Reinhard, Niek Verweij, Peter P. Pramstaller, Maryam Kavousi, Peter S. Braund, Teresa Trenkwalder, Bruno H. Stricker, Thorsten Kessler, Solmaz Assa, André G. Uitterlinden, Norbert Pfeiffer, Heribert Schunkert, Alexander Teumer, Elijah R. Behr, Marzia De Bortoli, Nilesh J. Samani, Karl J. Lackner, and Tim D. Spector

Subjects
medicine.medical_specialty, Benign early repolarization, Early Repolarization Pattern, business.industry, Genome-wide association study, medicine.disease, Sudden cardiac death, Family studies, Internal medicine, Ventricular fibrillation, medicine, Susceptibility locus, Cardiology, business, Genetic association
Abstract

The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (pKCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D’=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

Published
2019
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43. REFERENCE RANGES AND CUT-OFF VALUES FOR SIMULTANEOUS MONITORING OF RAS BLOCKER EFFICACY AND SCREENING FOR SECONDARY HYPERTENSION USING RAAS TRIPLE-A PROFILING

Author

Peter P. Pramstaller, Cristian Pattaro, Luisa Foco, Marko Poglitsch, and Martin Gögele

Subjects
Oncology, Profiling (computer programming), medicine.medical_specialty, Physiology, business.industry, Internal medicine, Internal Medicine, Medicine, Secondary hypertension, Cardiology and Cardiovascular Medicine, business, medicine.disease
Published
2021
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44. DISTRIBUTION OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BIOMARKERS IN TREATED HYPERTENSIVE INDIVIDUALS FROM THE GENERAL POPULATION: THE CHRIS STUDY

Author

Luisa Foco, Martin Gögele, Marko Poglitsch, Cristian Pattaro, and Peter P. Pramstaller

Subjects
medicine.medical_specialty, education.field_of_study, Physiology, business.industry, Population, Endocrinology, Internal medicine, Renin–angiotensin system, Internal Medicine, medicine, Distribution (pharmacology), Cardiology and Cardiovascular Medicine, business, education
Published
2021
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45. Effects of Calcium, Magnesium, and Potassium concentrations on ventricular repolarization in unselected individuals

Author

Pedro Guatimosim Vidigal, Yongmei Liu, Alice Stanton, Kent D. Taylor, Thomas Meitinger, Vilmundur Gudnason, Massimo Mangino, Mario Pirastu, Nilesh J. Samani, Christopher Newton-Cheh, Xiuqing Guo, Bruno H. Stricker, Mortiz F. Sinner, Steven R. Cummings, Jennifer A. Brody, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Bryan Kestenbaum, Dennis O. Mook-Kanamori, Jørgen K. Kanters, Kirill V. Tarasov, Martina Müller-Nurasyid, Luana Giatti, Elsayed Z. Soliman, Christian R. Juhl, Nuno R. Zilhão, Harold Snieder, Eric Campana, Mika Kähönen, Ginevra Biino, Raymond Noordam, Jun Ding, Chris H. L. Thio, Jerome I. Rotter, Torben Hansen, M. Abdullah Said, Francesco Cucca, Allan Linneberg, Nona Sotoodehnia, Niels Grarup, Peter S. Sever, James F. Wilson, André G. Uitterlinden, Xia Shen, Luisa Foco, Yong Qian, Christina Ellervik, Diana van Heemst, Antonietta Robino, Henry J. Lin, Konstantin Strauch, Patricia B. Munroe, Nabi Shah, Claus Graff, Daniel S. Evans, Peter J. van der Most, Stefan Weiss, Maria Pina Concas, Reem Salman, Hao Mei, Linda Repetto, Helen R. Warren, Peter K. Joshi, Susan R. Heckbert, Tim D. Spector, Sandhi Maria Barreto, Jie Yao, Marcus Dörr, Eulalia Catamo, Anna F. Dominiczak, Leo-Pekka Lyytikäinen, Giorgia Girotto, Peter P. Pramstaller, Gudny Eiriksdottir, J. Wouter Jukema, Paulo A. Lotufo, Colin N. A. Palmer, Andrew Tinker, James G. Wilson, Mary L. Biggs, Astrid Petersmann, Arie C. Maan, Peter S. Braund, Maria Fernanda Lima-Costa, Paraskevi Christofidou, Sandosh Padmanabhan, Adolfo Correa, Melanie Waldenberger, Alessandro De Grandi, Stefan Kääb, Cristian Pattaro, Annette Peters, William J Young, Alex S. F. Doney, Katharina Schramm, Terho Lehtimäki, Christopher P. Nelson, Martin Gögele, Marten E. van den Berg, Marco Brumat, Pim van der Harst, Niek Verweij, Simona Vaccargiu, Noordam, R, Young, Wj, Salman, R, Kanters, Jk, van den Berg, Me, van Heemst, D, Lin, Hj, Barreto, Sm, Biggs, Ml, Biino, G, Catamo, E, Concas, Mp, Ding, J, Evans, D, Foco, L, Grarup, N, Lyytikäinen, Lp, Mangino, M, Mei, H, van der Most, Pj, Müller-Nurasyid, M, Nelson, Cp, Qian, Y, Repetto, L, Said, Ma, Shah, N, Schramm, K, Vidigal, Pg, Weiss, S, Yao, J, Zilhao, Nr, Brody, Ja, Braund, P, Brumat, M, Campana, E, Christofidou, P, Caulfield, Mj, De Grandi, A, Dominiczak, Af, Doney, Asf, Eiriksdottir, G, Ellervik, C, Giatti, L, Gögele, M, Graff, C, Guo, X, van der Harst, P, Joshi, Pk, Kähönen, M, Kestenbaum, B, Lima-Costa, Mf, Linneberg, A, Maan, Ac, Meitinger, T, Padmanabhan, S, Pattaro, C, Peters, A, Petersmann, A, Sever, P, Sinner, Mf, Shen, X, Stanton, A, Strauch, K, Soliman, Ez, Tarasov, Kv, Taylor, Kd, Thio, Chl, Uitterlinden, Ag, Vaccargiu, S, Waldenberger, M, Robino, A, Correa, A, Cucca, F, Cummings, Sr, Dörr, M, Girotto, G, Gudnason, V, Hansen, T, Heckbert, Sr, Juhl, Cr, Kääb, S, Lehtimäki, T, Liu, Y, Lotufo, Pa, Palmer, Cna, Pirastu, M, Pramstaller, Pp, Ribeiro, Alp, Rotter, Ji, Samani, Nj, Snieder, H, Spector, Td, Stricker, Bh, Verweij, N, Wilson, Jf, Wilson, Jg, Jukema, Jw, Tinker, A, Newton-Cheh, Ch, Sotoodehnia, N, Mook-Kanamori, Do, Munroe, Pb, Warren, Hr., Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), and Epidemiology

Subjects
Male, Cardiac & Cardiovascular Systems, 030204 cardiovascular system & hematology, ELECTROCARDIOGRAM, Electrocardiography, 0302 clinical medicine, cohort studies, Risk Factors, Medicine, Magnesium, 030212 general & internal medicine, Correlation of Data, 1102 Cardiorespiratory Medicine and Haematology, RISK, education.field_of_study, medicine.diagnostic_test, ACTION-POTENTIAL DURATION, ASSOCIATION, Middle Aged, COUNCIL, electrocardiographic intervals, Cardiovascular Diseases, Cardiology, Female, epidemiology, Electrical conduction system of the heart, Cardiology and Cardiovascular Medicine, Electrophysiologic Techniques, Cardiac, Life Sciences & Biomedicine, medicine.medical_specialty, Population, electrolytes epidemiology, meta-analysis, chemistry.chemical_element, electrolytes, Calcium, QT interval, 1117 Public Health and Health Services, 03 medical and health sciences, QRS complex, DISPERSION, Heart Conduction System, Internal medicine, Humans, PR interval, education, Science & Technology, Cohort Studies, Electrocardiographic Intervals, Electrolytes, Epidemiology, Meta-analysis, business.industry, QT INTERVAL, RESTING HEART-RATE, Confidence interval, REDUCTION, chemistry, Cardiovascular System & Hematology, CONDUCTION, Asymptomatic Diseases, Potassium, Cardiovascular System & Cardiology, electrocardiographic interval, business, cohort studie
Abstract

BACKGROUND Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.OBJECTIVES This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.METHODS Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 +/- 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.RESULTS Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.CONCLUSIONS The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms. (C) 2019 by the American College of Cardiology Foundation.

Published
2019
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46. Effects of smoking status, history and intensity on heart rate variability in the general population: The CHRIS study

Author

Benedetta Maria Motta, Martin Gögele, Cristian Pattaro, Daniel Sinnecker, Roberto Melotti, Federico Murgia, Alessandra Rossini, Luisa Foco, Michael Toifl, Alexander Steger, Georg Schmidt, Alexander Müller, Giampiero Merati, Peter P. Pramstaller, and Viviana Meraviglia

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Aged, Aged, 80 and over, Arrhythmias, Cardiac, Female, Germany, Heart Rate, Humans, Middle Aged, Prognosis, Smokers, Smoking, Tobacco Use Disorder, Young Adult, medicine.medical_treatment, Science, Population, Arrhythmias, Internal medicine, Diabetes mellitus, Heart rate, 80 and over, Medicine, Heart rate variability, Young adult, education, education.field_of_study, Multidisciplinary, medicine.diagnostic_test, business.industry, medicine.disease, ddc, Intensity (physics), Cardiology, Smoking cessation, business, Electrocardiography, Cardiac, circulatory and respiratory physiology
Abstract

BackgroundHeart rate variability (HRV) reflects the autonomous nervous system modulation on heart rate and is associated with several pathologies, including cardiac mortality. While mechanistic studies show that smoking is associated with lower HRV, population-based studies present conflicting results.MethodsWe assessed the mutual effects of active smoking status, cumulative smoking history, and current smoking intensity, on HRV among 4751 adults from the Cooperative Health Research In South Tyrol (CHRIS) study. The HRV metrics standard deviation of normal-to-normal (NN) inter-beat intervals (SDNN), square root of the mean squared differences of consecutive NN intervals (RMSSD), total power (TP), low (LF) and high frequency (HF) power, and their ratio (LF/HF), were derived from 20-minute electrocardiograms. Smoking status, pack-years (PY), and tobacco grams/day from standardized questionnaires were the main exposures. We fitted linear mixed models to account for relatedness, non-linearity, and moderating effects, and including fractional polynomials.ResultsPast smokers had higher HRV levels than never smokers, independently of PY. The association of HRV with current smoking became apparent when accounting for the interaction between smoking status and PY. In current smokers, but not in past smokers, we observed HRV reductions between 2.0% (SDNN) and 4.9% (TP) every 5 PY increase. Furthermore, current smokers were characterized by dose-response reductions of 9.8% (SDNN), 8.9% (RMSSD), 20.1% (TP), 17.7% (LF), and 19.1% (HF), respectively, every 10 grams/day of smoked tobacco, independently of common cardiometabolic conditions and HRV-modifying drugs. The LF/HF ratio was not associated with smoking status, history, or intensity.ConclusionsSmoking cessation was associated with higher HRV levels. In current smokers, heavier smoking intensity appears gradually detrimental on HRV, corroborating previous evidence. By affecting both the sympathetic and parasympathetic nervous system indexes, but not the LF/HF balance, smoking intensity seems to exert a systemic dysautonomic effect.

Published
2019

47. 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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48. Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease

Author

Tammy Gillis, Yuri D’Elia, Peter P. Pramstaller, Irene Pichler, Isabel Alonso, Marcy E. MacDonald, Martin Gögele, Eliana Marisa Ramos, Jorge Sequeiros, James F. Gusella, Jayalakshmi S. Mysore, and Jong-Min Lee

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, Choreiform movement, Biology, Delta 2642 allele, Polymorphism, Single Nucleotide, Genetic diversity, Genomic Instability, 03 medical and health sciences, Cellular and Molecular Neuroscience, Huntington's disease, mental disorders, Haplotype analysis, medicine, Humans, Family, Allele, Base Pairing, Genetics (clinical), Research Articles, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, Portugal, 030305 genetics & heredity, Haplotype, Chromosome, Instability, medicine.disease, Penetrance, 3. Good health, nervous system diseases, Pedigree, Psychiatry and Mental health, Chromosome 4, Huntington Disease, Haplotypes, Female, Chromosomes, Human, Pair 4, Trinucleotide repeat expansion, Trinucleotide Repeat Expansion, Research Article
Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary choreic movements, cognitive impairment, and behavioral changes, caused by the expansion of an unstable CAG repeat in HTT. We characterized the genetic diversity of the HD mutation by performing an extensive haplotype analysis of ∼1Mb region flanking HTT in over 300 HD families of Portuguese origin. We observed that haplotype A, marked by HTT delta2642, was enriched in HD chromosomes and carried the two largest expansions reported in the Portuguese population. However, the most frequent HD haplotype B carried one of the largest (+12 CAGs) expansions, which resulted in an allele class change to full penetrance. Despite having a normal CAG distribution skewed to the higher end of the range, these two core haplotypes had similar expanded CAG repeat sizes compared to the other major core haplotypes (C and D) and there was no statistical difference in transmitted repeat instability across haplotypes. We observed a diversity of HTT region haplotypes in both normal and expanded chromosomes, representative of more than one ancestral chromosome underlying HD in Portugal, where multiple independent events on distinct chromosome 4 haplotypes have given rise to expansion into the pathogenic range. © 2015 Wiley Periodicals, Inc.

Published
2015

49. NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality

Author

Carsten A. Böger, Mathias Gorski, Gearoid M. McMahon, Huichun Xu, Yen-Pei C. Chang, Peter J. van der Most, Gerjan Navis, Ilja M. Nolte, Martin H. de Borst, Weihua Zhang, Benjamin Lehne, Marie Loh, Sian-Tsung Tan, Eric Boerwinkle, Morgan E. Grams, Peggy Sekula, Man Li, Beth Wilmot, James G. Moon, Paul Scheet, Francesco Cucca, Xiangjun Xiao, Leo-Pekka Lyytikäinen, Graciela Delgado, Tanja B. Grammer, Marcus E. Kleber, Sanaz Sedaghat, Fernando Rivadeneira, Tanguy Corre, Zoltan Kutalik, Sven Bergmann, Carrie M. Nielson, Priya Srikanth, Alexander Teumer, Martina Müller-Nurasyid, Anne Catharina Brockhaus, Arne Pfeufer, Wolfgang Rathmann, Annette Peters, Martha Matsumoto, Mariza de Andrade, Elizabeth J. Atkinson, Cassianne Robinson-Cohen, Ian H. de Boer, Shih-Jen Hwang, Iris M. Heid, Martin Gögele, Maria Pina Concas, Toshiko Tanaka, Stefania Bandinelli, Mike A. Nalls, Andrew Singleton, Salman M. Tajuddin, Adebowale Adeyemo, Jie Zhou, Ayo Doumatey, Shannon McWeeney, Joanne Murabito, Nora Franceschini, Michael Flessner, Michael Shlipak, James G. Wilson, Guanjie Chen, Charles N. Rotimi, Alan B. Zonderman, Michele K. Evans, Luigi Ferrucci, Olivier Devuyst, Mario Pirastu, Alan Shuldiner, Andrew A. Hicks, Peter Paul Pramstaller, Bryan Kestenbaum, Sharon L.R. Kardia, Stephen T. Turner, LifeLines Cohort Study, Tamara Ellefson Briske, Christian Gieger, Konstantin Strauch, Christa Meisinger, Thomas Meitinger, Uwe Völker, Matthias Nauck, Henry Völzke, Peter Vollenweider, Murielle Bochud, Gerard Waeber, Mika Kähönen, Terho Lehtimäki, Winfried März, Abbas Dehghan, Oscar H. Franco, Andre G. Uitterlinden, Albert Hofman, Herman A. Taylor, John C. Chambers, Jaspal S. Kooner, Caroline S. Fox, Robert Hitzemann, Eric S. Orwoll, Cristian Pattaro, David Schlessinger, Anna Köttgen, Harold Snieder, Afshin Parsa, David M. Cohen, Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Life Course Epidemiology (LCE), Value, Affordability and Sustainability (VALUE), Groningen Institute for Organ Transplantation (GIOT), Böger, Carsten A., Gorski, Mathia, Mcmahon, Gearoid M., Xu, Huichun, Chang, Yen Pei C., Van Der Most, Peter J., Navis, Gerjan, Nolte, Ilja M., De Borst, Martin H., Zhang, Weihua, Lehne, Benjamin, Loh, Marie, Tan, Sian Tsung, Boerwinkle, Eric, Grams, Morgan E., Sekula, Peggy, Li, Man, Wilmot, Beth, Moon, James G., Scheet, Paul, Cucca, Francesco, Xiao, Xiangjun, Lyytikäinen, Leo Pekka, Delgado, Graciela, Grammer, Tanja B., Kleber, Marcus E., Sedaghat, Sanaz, Rivadeneira, Fernando, Corre, Tanguy, Kutalik, Zoltan, Bergmann, Sven, Nielson, Carrie M., Srikanth, Priya, Teumer, Alexander, Müller Nurasyid, Martina, Brockhaus, Anne Catharina, Pfeufer, Arne, Rathmann, Wolfgang, Peters, Annette, Matsumoto, Martha, De Andrade, Mariza, Atkinson, Elizabeth J., Robinson Cohen, Cassianne, De Boer, Ian H., Hwang, Shih Jen, Heid, Iris M., Gögele, Martin, Concas, MARIA PINA, Tanaka, Toshiko, Bandinelli, Stefania, Nalls, Mike A., Singleton, Andrew, Tajuddin, Salman M., Adeyemo, Adebowale, Zhou, Jie, Doumatey, Ayo, Mcweeney, Shannon, Murabito, Joanne, Franceschini, Nora, Flessner, Michael, Shlipak, Michael, Wilson, James G., Chen, Guanjie, Rotimi, Charles N., Zonderman, Alan B., Evans, Michele K., Ferrucci, Luigi, Devuyst, Olivier, Pirastu, Mario, Shuldiner, Alan, Hicks, Andrew A., Pramstaller, Peter Paul, Kestenbaum, Bryan, Kardia, Sharon L. R., Turner, Stephen T., Study, Lifelines Cohort, Briske, Tamara Ellefson, Gieger, Christian, Strauch, Konstantin, Meisinger, Christa, Meitinger, Thoma, Völker, Uwe, Nauck, Matthia, Völzke, Henry, Vollenweider, Peter, Bochud, Murielle, Waeber, Gerard, Kähönen, Mika, Lehtimäki, Terho, März, Winfried, Dehghan, Abba, Franco, Oscar H., Uitterlinden, Andre G., Hofman, Albert, Taylor, Herman A., Chambers, John C., Kooner, Jaspal S., Fox, Caroline S., Hitzemann, Robert, Orwoll, Eric S., Pattaro, Cristian, Schlessinger, David, Köttgen, Anna, Snieder, Harold, Parsa, Afshin, and Cohen, David M.

Subjects
0301 basic medicine, medicine.medical_specialty, hyponatremia, Body water, Water-Electrolyte Imbalance, PROTEIN, human genetics, Genome-wide association study, Biology, 03 medical and health sciences, Plasma, NFAT5, Internal medicine, Gene expression, Genetic variation, Transcriptional regulation, medicine, Humans, human genetic, CELL-TYPES, GENE-EXPRESSION, Genetics, IDENTIFICATION, hypernatremia, Sodium-Bicarbonate Symporter, Sodium-Bicarbonate Symporters, Sodium, PRIMARY-CARE, 1103 Clinical Sciences, General Medicine, Urology & Nephrology, water-electrolyte balance, Plasma osmolality, Human Genetics, Hypernatremia, Hyponatremia, Water-electrolyte Balance, 030104 developmental biology, Endocrinology, Basic Research, NEPHROGENIC DIABETES-INSIPIDUS, Genome-Wide Association Study, Genetic Loci, Nephrology, Expression quantitative trait loci, TRANSCRIPTION FACTOR-BINDING, INAPPROPRIATE ANTIDIURESIS, INTRONIC ENHANCERS, Human
Abstract

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P-6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 3 x 10-5), with combined stages 1 and 2 genomewide significance of P=5.6 x 10-10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous systemand relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Published
2017

50. Importance of Different Types of Prior Knowledge in Selecting Genome-Wide Findings for Follow-Up

Author

Mirko Modenese, Francisco S. Domingues, Arne Pfeufer, Christian X. Weichenberger, Andrew A. Hicks, Fabio Marroni, Martin Gögele, John Attia, Alessandro De Grandi, Thomas Freina, Christine Schwienbacher, Giuseppe Borsani, Michael Boehnke, John R. Thompson, Fabrizio Ruggeri, Cristian Pattaro, Giorgio Casari, Peter P. Pramstaller, Cosetta Minelli, Andrea Pastore, Giovanni Parmigiani, Daniel Taliun, Jennifer H. Barrett, and Caroline S. Fox

Subjects
Genetics, Epidemiology, Delphi method, Trait, SNP, Genome-wide association study, Single-nucleotide polymorphism, Biological plausibility, Computational biology, Biology, Empirical evidence, Genetics (clinical), Weighting
Abstract

Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts' opinions and empirical evidence to estimate the relative importance of 15 types of information at the single-nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from 10 experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, whereas previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, although location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.

Published
2013
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