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1. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: Yordi J. van de Vegte, Ruben N. Eppinga, M. Yldau van der Ende, Yanick P. Hagemeijer, Yuvaraj Mahendran, Elias Salfati, Albert V. Smith, Vanessa Y. Tan, Dan E. Arking, Ioanna Ntalla, Emil V. Appel, Claudia Schurmann, Jennifer A. Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian’an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U. Jackson, Lawrence F. Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E. Kleber, Xiuqing Guo, Henry J. Lin, Francesca Pavani, Tessel E. Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E. Schraut, Marcel den Hoed, Frauke Degenhardt, Stella Trompet, Marten E. van den Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S. Sim, Hengtong L. Li, Peter J. van der Most, Ilja M. Nolte, Leo-Pekka Lyytikäinen, M. Abdullah Said, Daniel R. Witte, Carlos Iribarren, Lenore Launer, Susan M. Ring, Paul S. de Vries, Peter Sever, Allan Linneberg, Erwin P. Bottinger, Sandosh Padmanabhan, Bruce M. Psaty, Nona Sotoodehnia, Ivana Kolcic, The DCCT/EDIC Research Group, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T. Silva, Christopher H. Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L. Mohlke, Patricia A. Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C. Rao, Marilyn C. Cornelis, Jessica D. Faul, Jennifer A. Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F. Sinner, Konstantin Strauch, Graciela E. Delgado, Kent D. Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline de Graaf, Renée de Mutsert, Eco J. C. de Geus, Åsa Johansson, Peter K. Joshi, Lars Lind, Andre Franke, Peter W. Macfarlane, Kirill V. Tarasov, Nicholas Tan, Stephan B. Felix, E-Shyong Tai, Debra Q. Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P. Morris, Olli T. Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J. Timpson, Alanna C. Morrison, Patricia B. Munroe, David P. Strachan, Niels Grarup, Ruth J. F. Loos, Susan R. Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J. Wareham, Cornelia M. van Duijn, Mary F. Feitosa, Christopher J. O’Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L. R. Kardia, Jeanette Erdmann, Colin N. A. Palmer, Claes Ohlsson, David J. Porteous, Johan G. Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R. Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C. Chambers, Jaspal S. Kooner, Winfried März, Jerome I. Rotter, Andrew A. Hicks, J. Gustav Smith, Lambertus A. L. M. Kiemeney, Dennis O. Mook-Kanamori, Brenda W. J. H. Penninx, Ulf Gyllensten, James F. Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J. Wouter Jukema, Mark Eijgelsheim, Edward L. M. Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J. Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij, and Pim van der Harst
Subjects: Science
Abstract: Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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2. Case Report: Two cases of apparent discordance between non-invasive prenatal testing (NIPT) and amniocentesis resulting in feto-placental mosaicism of trisomy 21. Issues in diagnosis, investigation and counselling

Author: Agnese Feresin, Tamara Stampalija, Stefania Cappellani, Rossana Bussani, Flavio Faletra, Flora Murru, Sheila Ulivi, Sarah Suergiu, Pasquale Savarese, Antonio Pedicini, Margherita Policicchio, Raffaella Ruggiero, Barbara Bosio, Giovanni Savarese, and Carmela Ardisia
Subjects: NIPT, false negative cffDNA, feto-placental mosaicism, trisomy 21, SNP array, autopsy, Genetics, QH426-470
Abstract: The sequencing of cell-free fetal DNA in the maternal plasma through non-invasive prenatal testing (NIPT) is an accurate genetic screening test to detect the most common fetal aneuploidies during pregnancy. The extensive use of NIPT, as a screening method, has highlighted the limits of the technique, including false positive and negative results. Feto-placental mosaicism is a challenging biological issue and is the most frequent cause of false positive and negative results in NIPT screening, and of discrepancy between NIPT and invasive test results. We are reporting on two cases of feto-placental mosaicism of trisomy 21, both with a low-risk NIPT result, identified by ultrasound signs and a subsequent amniocentesis consistent with a trisomy 21. In both cases, after the pregnancy termination, cytogenetic and/or cytogenomic analyses were performed on the placenta and fetal tissues, showing in the first case a mosaicism of trisomy 21 in both the placenta and the fetus, but a mosaicism in the placenta and a complete trisomy 21 in the fetus in the second case. These cases emphasize the need for accurate and complete pre-test NIPT counselling, as well as to identify situations at risk for a possible false negative NIPT result, which may underestimate a potential pathological condition, such as feto-placental mosaicism or fetal trisomy. Post-mortem molecular autopsy may discriminate between placental, fetal and feto-placental mosaicism, and between complete or mosaic fetal chromosomal anomalies. A multidisciplinary approach in counselling, as well as in the interpretation of biological events, is essential for the clarification of complex cases, such as feto-placental mosaicisms.
Published: 2022
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3. 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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4. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author: Jessica van Setten, Jennifer A. Brody, Yalda Jamshidi, Brenton R. Swenson, Anne M. Butler, Harry Campbell, Fabiola M. Del Greco, Daniel S. Evans, Quince Gibson, Daniel F. Gudbjartsson, Kathleen F. Kerr, Bouwe P. Krijthe, Leo-Pekka Lyytikäinen, Christian Müller, Martina Müller-Nurasyid, Ilja M. Nolte, Sandosh Padmanabhan, Marylyn D. Ritchie, Antonietta Robino, Albert V. Smith, Maristella Steri, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sheila Ulivi, Niek Verweij, Xiaoyan Yin, David O. Arnar, Folkert W. Asselbergs, Joel S. Bader, John Barnard, Josh Bis, Stefan Blankenberg, Eric Boerwinkle, Yuki Bradford, Brendan M. Buckley, Mina K. Chung, Dana Crawford, Marcel den Hoed, Josh C. Denny, Anna F. Dominiczak, Georg B. Ehret, Mark Eijgelsheim, Patrick T. Ellinor, Stephan B. Felix, Oscar H. Franco, Lude Franke, Tamara B. Harris, Hilma Holm, Gandin Ilaria, Annamaria Iorio, Mika Kähönen, Ivana Kolcic, Jan A. Kors, Edward G. Lakatta, Lenore J. Launer, Honghuang Lin, Henry J. Lin, Ruth J. F. Loos, Steven A. Lubitz, Peter W. Macfarlane, Jared W. Magnani, Irene Mateo Leach, Thomas Meitinger, Braxton D. Mitchell, Thomas Munzel, George J. Papanicolaou, Annette Peters, Arne Pfeufer, Peter P. Pramstaller, Olli T. Raitakari, Jerome I. Rotter, Igor Rudan, Nilesh J. Samani, David Schlessinger, Claudia T. Silva Aldana, Moritz F. Sinner, Jonathan D. Smith, Harold Snieder, Elsayed Z. Soliman, Timothy D. Spector, David J. Stott, Konstantin Strauch, Kirill V. Tarasov, Unnur Thorsteinsdottir, Andre G. Uitterlinden, David R. Van Wagoner, Uwe Völker, Henry Völzke, Melanie Waldenberger, Harm Jan Westra, Philipp S. Wild, Tanja Zeller, Alvaro Alonso, Christy L. Avery, Stefania Bandinelli, Emelia J. Benjamin, Francesco Cucca, Marcus Dörr, Luigi Ferrucci, Paolo Gasparini, Vilmundur Gudnason, Caroline Hayward, Susan R. Heckbert, Andrew A. Hicks, J. Wouter Jukema, Stefan Kääb, Terho Lehtimäki, Yongmei Liu, Patricia B. Munroe, Afshin Parsa, Ozren Polasek, Bruce M. Psaty, Dan M. Roden, Renate B. Schnabel, Gianfranco Sinagra, Kari Stefansson, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, James F. Wilson, Sina A. Gharib, Paul I. W. de Bakker, Aaron Isaacs, Dan E. Arking, and Nona Sotoodehnia
Subjects: Science
Abstract: Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.
Published: 2018
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5. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author: Bram P. Prins, Timothy J. Mead, Jennifer A. Brody, Gardar Sveinbjornsson, Ioanna Ntalla, Nathan A. Bihlmeyer, Marten van den Berg, Jette Bork-Jensen, Stefania Cappellani, Stefan Van Duijvenboden, Nikolai T. Klena, George C. Gabriel, Xiaoqin Liu, Cagri Gulec, Niels Grarup, Jeffrey Haessler, Leanne M. Hall, Annamaria Iorio, Aaron Isaacs, Ruifang Li-Gao, Honghuang Lin, Ching-Ti Liu, Leo-Pekka Lyytikäinen, Jonathan Marten, Hao Mei, Martina Müller-Nurasyid, Michele Orini, Sandosh Padmanabhan, Farid Radmanesh, Julia Ramirez, Antonietta Robino, Molly Schwartz, Jessica van Setten, Albert V. Smith, Niek Verweij, Helen R. Warren, Stefan Weiss, Alvaro Alonso, David O. Arnar, Michiel L. Bots, Rudolf A. de Boer, Anna F. Dominiczak, Mark Eijgelsheim, Patrick T. Ellinor, Xiuqing Guo, Stephan B. Felix, Tamara B. Harris, Caroline Hayward, Susan R. Heckbert, Paul L. Huang, J. W. Jukema, Mika Kähönen, Jan A. Kors, Pier D. Lambiase, Lenore J. Launer, Man Li, Allan Linneberg, Christopher P. Nelson, Oluf Pedersen, Marco Perez, Annette Peters, Ozren Polasek, Bruce M. Psaty, Olli T. Raitakari, Kenneth M. Rice, Jerome I. Rotter, Moritz F. Sinner, Elsayed Z. Soliman, Tim D. Spector, Konstantin Strauch, Unnur Thorsteinsdottir, Andrew Tinker, Stella Trompet, André Uitterlinden, Ilonca Vaartjes, Peter van der Meer, Uwe Völker, Henry Völzke, Melanie Waldenberger, James G. Wilson, Zhijun Xie, Folkert W. Asselbergs, Marcus Dörr, Cornelia M. van Duijn, Paolo Gasparini, Daniel F. Gudbjartsson, Vilmundur Gudnason, Torben Hansen, Stefan Kääb, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Henry J. Lin, Steven A. Lubitz, Dennis O. Mook-Kanamori, Francesco J. Conti, Christopher H. Newton-Cheh, Jonathan Rosand, Igor Rudan, Nilesh J. Samani, Gianfranco Sinagra, Blair H. Smith, Hilma Holm, Bruno H. Stricker, Sheila Ulivi, Nona Sotoodehnia, Suneel S. Apte, Pim van der Harst, Kari Stefansson, Patricia B. Munroe, Dan E. Arking, Cecilia W. Lo, and Yalda Jamshidi
Subjects: Exome chip, Conduction, ADAMTS6, Meta-analysis, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract Background Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Published: 2018
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6. Identification of a New Mutation in RSK2, the Gene for Coffin–Lowry Syndrome (CLS), in Two Related Patients with Mild and Atypical Phenotypes

Author: Mariateresa Di Stazio, Stefania Bigoni, Nicola Iuso, Josef Vuch, Rita Selvatici, Sheila Ulivi, and Pio Adamo d’Adamo
Subjects: RSK2 gene, Coffin–Lowry syndrome, intellectual disability, kinase assay, functional assay, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Background: Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. Methods: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. Results: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. Conclusions: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.
Published: 2021
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7. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox
Subjects: Science
Abstract: Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
Published: 2016
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8. Genome-wide association studies on Northern Italy isolated populations provide further support concerning genetic susceptibility for major depressive disorder

Author: Vincenzo Dattilo, Sheila Ulivi, Alessandra Minelli, Martina La Bianca, Edoardo Giacopuzzi, Marco Bortolomasi, Stefano Bignotti, Massimo Gennarelli, Paolo Gasparini, Maria Pina Concas, Dattilo, Vincenzo, Ulivi, Sheila, Minelli, Alessandra, La Bianca, Martina, Giacopuzzi, Edoardo, Bortolomasi, Marco, Bignotti, Stefano, Gennarelli, Massimo, Gasparini, Paolo, and Concas, Maria Pina
Subjects: genetic isolates, Psychiatry and Mental health, genome-wide association study, genetic isolate, Major depressive disorder, CTNNA2, KCNQ5, Biological Psychiatry
Abstract: Objectives: Major depressive disorder (MDD) is a psychiatric disorder with pathogenesis influenced by both genetic and environmental factors. To date, the molecular-level understanding of its aetiology remains unclear. Thus, we aimed to identify genetic variants and susceptibility genes for MDD with a genome-wide association study (GWAS) approach. Methods: We performed a meta-analysis of GWASs and a gene-based analysis on two Northern Italy isolated populations (cases/controls n = 166/472 and 33/320), followed by replication and polygenic risk score (PRS) analyses in Italian independent samples (cases n = 464, controls n = 339). Results: We identified two novel MDD-associated genes, KCNQ5 (lead SNP rs867262, p = 3.82 × 10-9) and CTNNA2 (rs6729523, p = 1.25 × 10-8). The gene-based analysis revealed another six genes (p < 2.703 × 10-6): GRM7, CTNT4, SNRK, SRGAP3, TRAPPC9, and FHIT. No replication of the genome-wide significant SNPs was found in the independent cohort, even if 14 SNPs around CTNNA2 showed association with MDD and related phenotypes at the nominal level of p (
Published: 2023

9. Genetic determinants of circulating VEGF levels in major depressive disorder and electroconvulsive therapy response

Author: Massimo Gennarelli, Sheila Ulivi, Marco Bortolomasi, Elisabetta Maffioletti, Alessandra Minelli, Cristian Bonvicini, Chiara Magri, Luigi Trabucchi, Luisella Bocchio-Chiavetto, and Maria Abate
Subjects: Adult, Male, Vascular Endothelial Growth Factor A, Oncology, medicine.medical_specialty, Genotype, medicine.medical_treatment, convulsive therapy, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, electric, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Electroconvulsive therapy, Internal medicine, Drug Discovery, medicine, Humans, SNP, Allele, Electroconvulsive Therapy, genome wide association study, Aged, Depressive Disorder, Major, major depressive disorder, vascular endothelial growth factor, business.industry, convulsive therapy, electric, single-nucleotide polymorphism, Middle Aged, medicine.disease, Vascular endothelial growth factor, chemistry, 030220 oncology & carcinogenesis, Major depressive disorder, Female, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome-wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome-wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy-one patients with treatment-resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR-corrected p = 2.4 × 10-5 ) and in patients with major depressive disorder (best SNP: FDR-corrected p = 2.6 × 10-3 ). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.
Published: 2020
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10. Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Author: Christina B. Joseph, Marta Mariniello, Ayumi Yoshifuji, Guglielmo Schiano, Jennifer Lake, Jonathan Marten, Anne Richmond, Jennifer E. Huffman, Archie Campbell, Sarah E. Harris, Stephan Troyanov, Massimiliano Cocca, Antonietta Robino, Sébastien Thériault, Kai-Uwe Eckardt, Matthias Wuttke, Yurong Cheng, Tanguy Corre, Ivana Kolcic, Corrinda Black, Vanessa Bruat, Maria Pina Concas, Cinzia Sala, Stefanie Aeschbacher, Franz Schaefer, Sven Bergmann, Harry Campbell, Matthias Olden, Ozren Polasek, David J. Porteous, Ian J. Deary, Francois Madore, Philip Awadalla, Giorgia Girotto, Sheila Ulivi, David Conen, Elke Wuehl, Eric Olinger, James F. Wilson, Murielle Bochud, Anna Köttgen, Caroline Hayward, Olivier Devuyst, Joseph, C. B., Mariniello, M., Yoshifuji, A., Schiano, G., Lake, J., Marten, J., Richmond, A., Huffman, J. E., Campbell, A., Harris, S. E., Troyanov, S., Cocca, M., Robino, A., Theriault, S., Eckardt, K. -U., Wuttke, M., Cheng, Y., Corre, T., Kolcic, I., Black, C., Bruat, V., Concas, M. P., Sala, C., Aeschbacher, S., Schaefer, F., Bergmann, S., Campbell, H., Olden, M., Polasek, O., Porteous, D. J., Deary, I. J., Madore, F., Awadalla, P., Girotto, G., Ulivi, S., Conen, D., Wuehl, E., Olinger, E., Wilson, J. F., Bochud, M., Kottgen, A., Hayward, C., and Devuyst, O.
Subjects: KRT40, Tamm-Horsfall protein, WDR72, cytokeratin, loop of Henle, thick ascending limb, Creatinine, Humans, Polymorphism, Single Nucleotide, Protein Disulfide-Isomerases, Uromodulin, Genome-Wide Association Study, Kidney, Protein Disulfide-Isomerases/genetics, Single Nucleotide, General Medicine, Uromodulin/genetics, Nephrology, Up Front Matters, Polymorphism, Human, Protein Disulfide-Isomerase
Abstract: BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus ( P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus ( P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
Published: 2022
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11. Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism

Author: Davide Carlino, Ruggiero Francavilla, Gabriele Baj, Karolina Kulak, Pio d’Adamo, Sheila Ulivi, Stefania Cappellani, Paolo Gasparini, and Enrico Tongiorgi
Subjects: Neurotrophins, Brain-derived neurotrophic factor, Serum biomarkers, Val66Met polymorphism, Genome wide analysis, Anxiety, Medicine, Biology (General), QH301-705.5
Abstract: Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.
Published: 2015
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12. Modulation of genetic associations with serum urate levels by body-mass-index in humans.

Author: Jennifer E Huffman, Eva Albrecht, Alexander Teumer, Massimo Mangino, Karen Kapur, Toby Johnson, Zoltán Kutalik, Nicola Pirastu, Giorgio Pistis, Lorna M Lopez, Toomas Haller, Perttu Salo, Anuj Goel, Man Li, Toshiko Tanaka, Abbas Dehghan, Daniela Ruggiero, Giovanni Malerba, Albert V Smith, Ilja M Nolte, Laura Portas, Amanda Phipps-Green, Lora Boteva, Pau Navarro, Asa Johansson, Andrew A Hicks, Ozren Polasek, Tõnu Esko, John F Peden, Sarah E Harris, Federico Murgia, Sarah H Wild, Albert Tenesa, Adrienne Tin, Evelin Mihailov, Anne Grotevendt, Gauti K Gislason, Josef Coresh, Pio D'Adamo, Sheila Ulivi, Peter Vollenweider, Gerard Waeber, Susan Campbell, Ivana Kolcic, Krista Fisher, Margus Viigimaa, Jeffrey E Metter, Corrado Masciullo, Elisabetta Trabetti, Cristina Bombieri, Rossella Sorice, Angela Döring, Eva Reischl, Konstantin Strauch, Albert Hofman, Andre G Uitterlinden, Melanie Waldenberger, H-Erich Wichmann, Gail Davies, Alan J Gow, Nicola Dalbeth, Lisa Stamp, Johannes H Smit, Mirna Kirin, Ramaiah Nagaraja, Matthias Nauck, Claudia Schurmann, Kathrin Budde, Susan M Farrington, Evropi Theodoratou, Antti Jula, Veikko Salomaa, Cinzia Sala, Christian Hengstenberg, Michel Burnier, Reedik Mägi, Norman Klopp, Stefan Kloiber, Sabine Schipf, Samuli Ripatti, Stefano Cabras, Nicole Soranzo, Georg Homuth, Teresa Nutile, Patricia B Munroe, Nicholas Hastie, Harry Campbell, Igor Rudan, Claudia Cabrera, Chris Haley, Oscar H Franco, Tony R Merriman, Vilmundur Gudnason, Mario Pirastu, Brenda W Penninx, Harold Snieder, Andres Metspalu, Marina Ciullo, Peter P Pramstaller, Cornelia M van Duijn, Luigi Ferrucci, Giovanni Gambaro, Ian J Deary, Malcolm G Dunlop, James F Wilson, Paolo Gasparini, Ulf Gyllensten, Tim D Spector, Alan F Wright, Caroline Hayward, Hugh Watkins, Markus Perola, Murielle Bochud, W H Linda Kao, Mark Caulfield, Daniela Toniolo, Henry Völzke, Christian Gieger, Anna Köttgen, and Veronique Vitart
Subjects: Medicine, Science
Abstract: We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
Published: 2015
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13. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021
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14. Identification of a New Mutation in RSK2, the Gene for Coffin–Lowry Syndrome (CLS), in Two Related Patients with Mild and Atypical Phenotypes

Author: Rita Selvatici, Josef Vuch, Mariateresa Di Stazio, Stefania Bigoni, Sheila Ulivi, Pio D'Adamo, Nicola Iuso, Di Stazio, Mariateresa, Bigoni, Stefania, Iuso, Nicola, Vuch, Josef, Selvatici, Rita, Ulivi, Sheila, and D’Adamo, Pio Adamo
Subjects: kinase assay, Socio-culturale, coffin, RSK2 gene, Neurosciences. Biological psychiatry. Neuropsychiatry, Biology, functional assay, intellectual disability, lowry syndrome, rsk2 gene, medicine.disease_cause, Coffin–Lowry syndrome, Ribosomal s6 kinase, Intellectual disability, medicine, Missense mutation, Kinase activity, Gene, Genetics, Mutation, General Neuroscience, medicine.disease, Phenotype, biology.protein, Functional assay, Kinase assay, RC321-571
Abstract: Background: Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. Methods: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. Results: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. Conclusions: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.
Published: 2021

15. A general approach for haplotype phasing across the full spectrum of relatedness.

Author: Jared O'Connell, Deepti Gurdasani, Olivier Delaneau, Nicola Pirastu, Sheila Ulivi, Massimiliano Cocca, Michela Traglia, Jie Huang, Jennifer E Huffman, Igor Rudan, Ruth McQuillan, Ross M Fraser, Harry Campbell, Ozren Polasek, Gershim Asiki, Kenneth Ekoru, Caroline Hayward, Alan F Wright, Veronique Vitart, Pau Navarro, Jean-Francois Zagury, James F Wilson, Daniela Toniolo, Paolo Gasparini, Nicole Soranzo, Manjinder S Sandhu, and Jonathan Marchini
Subjects: Genetics, QH426-470
Abstract: Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
Published: 2014
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16. Genetic insights into the biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Daniel I. Chasman, Rehannah Borup, Anne B. Newman, Kristina W. Olsen, Lude Franke, Stefania Bandinelli, Nora Franceschini, Celine M. Vachon, Nicholas J. Timpson, James F. Wilson, Micaella Joaquim, Christa Meisinger, Felix R. Day, Charles Kooperberg, Qin Wang, Pascal Timshel, Dennis O. Mook-Kanamori, Luigi Ferrucci, Jennifer A. Smith, Miriam Dwek, Pascal Guénel, Claus Yding Andersen, Peter A. Fasching, Sven Bergmann, Thomas Meitinger, Nicholas Bowker, Jane L. Tarry-Adkins, Jeremy A. Daniel, Katharina E. Schraut, Mikael Eriksson, Amruta Shrikhande, Jacques E. Rossouw, Amber N. Wilcox, Simon S. Cross, Stasa Stankovic, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Annette Peters, David Schlessinger, Sheila Ulivi, Mònica Ferrer-Roda, Immaculata De Vivo, Michela Traglia, Jessica Tyrrell, Paul R. H. J. Timmers, Rico Rueedi, Ko Willems van Dijk, N. Charlotte Onland-Moret, Doris Stöckl, Anthony J. Swerdlow, Paul M. Ridker, Zoltán Kutalik, Patrick Deelen, Gerardo Heiss, Marie Louise Grøndahl, Alison M. Dunning, Dale R. Nyholt, Nicholas J. Wareham, Reedik Mägi, Stephen J. Chanock, Martina La Bianca, Ozren Polasek, Daniel F. Gudbjartsson, Rebecca D. Jackson, Alison D. Murray, Lynda M. Rose, Hironori Abe, Joanne M. Murabito, Henry Völzke, Daniela Ruggiero, Dorret I. Boomsma, Harald Grallert, Stefania Benonisdottir, Javier Martin Gonzalez, Esther M. John, Natalia Perjakova, Georgia Chenevix-Trench, John R. B. Perry, Jenny Chang-Claude, Archie Campbell, Teresa Nutile, Ellen W. Demerath, Robin N Beaumont, Jouke J. Hottenga, Albert V. Smith, David Karasik, Linda Broer, Raymond Noordam, Wei He, Niclas Håkansson, Catherine E. Aiken, Robert Karlsson, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Sharon L.R. Kardia, Nicholas G. Martin, Jodie N. Painter, Peter K. Joshi, Gonneke Willemsen, Lenore J. Launer, Alicja Wolk, Konstantin Strauch, Stig E. Bojesen, Manjeet K. Bolla, Allison W. Kurian, Renée de Mutsert, Joop S.E. Laven, Antonella Mulas, Igor Rudan, Vallari Shukla, Kathyrn L Lunetta, Susan E. Ozanne, Loic Le Marchand, Jenny A. Visser, Gad Rennert, Jennifer A. Brody, Paul D.P. Pharoah, Tune H. Pers, Sara Lindström, Ignasi Roig, Angela Cox, Unnur Þorsteinsdottir, Graham G. Giles, Toshiko Tanaka, Eva Hoffmann, Melissa A. Troester, Claudia Langenberg, Serena Sanna, Julie E. Buring, Anna Pujol, Mike A. Nalls, Kamila Czene, Tõnu Esko, Jian'an Luan, Lili Milani, Iffat Rahman, Sarah E. Medland, Caterina Barbieri, Emil Peter Trane Hertz, Behrooz Z. Alizadeh, David G. Hunter, Sandra Turon, Antonietta Robino, Marina Ciullo, Barbara McKnight, Chunyan He, Bruce H. R. Wolffenbuttel, David R. Weir, Daniela Toniolo, Ulrike Peters, George Davey-Smith, Saleh Shekari, Caroline Hayward, Elinor J. Sawyer, Patrick Sulem, Simin Liu, Tanguy Corre, Susan M. Ring, Peter Kraft, Alexander Teumer, Marjanka K. Schmidt, André G. Uitterlinden, Arto Mannermaa, Kristan J. Aronson, Heiko Becher, John L. Hopper, Alpa V. Patel, Joyce B. J. van Meurs, kConFab Investigators, Hamdi Mbarek, Frits R. Rosendaal, Minouk J. Schoemaker, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Nancy L. Pedersen, Jessica D. Faul, Patrik K. E. Magnusson, Jingmei Li, Christopher G. Scott, Joe Dennis, Genevieve Lachance, Ajuna Azad, Yongmei Liu, Elnaz Naderi, Andrew R. Wood, Yan Huang, Anna Murray, Annique Claringbould, Stephen Burgess, Jose E. Castelao, Brumat Marco, Eco J. C. de Geus, Veronique Vitart, Ken K. Ong, Kari Stefansson, Blair H. Smith, Francesco Cucca, Grant W. Montgomery, Emmanouil Saloustros, Andrés J. López-Contreras, Jonathan Marten, Håkan Olsson, Dale P. Sandler, Alice M. Arnold, Ana Martínez-Marchal, Tim D. Spector, Chloé Sarnowski, John J. Spinelli, Vilmundur Gudnason, Frank B. Hu, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Eric Boerwinkle, Matthias W. Beckmann, Jazib Hussain, Uwe Völker, Peter Vollenweider, Douglas F. Easton, Irene L. Andrulis, Harry Campbell, Manuela Gago-Dominguez, Cari M. Kitahara, Yvonne T. van der Schouw, Eleonora Porcu, Annika Lindblom, Martha S. Linet, Meir J. Stampfer, Eulalia Catamo, Roger L. Milne, Ivana Kolcic, Annelie Augustinsson, Cinzia Sala, Debbie A Lawlor, Cristina Menni, Timothy M. Frayling, Lauren R. Teras, Marek Zygmunt, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Per Hall, Rossella Sorice, Wei Zhao, Andres Metspalu, Katherine S. Ruth, Andrew F. Olshan, Massimo Mezzavilla, Murielle Bochud, and Christian Gieger
Subjects: media_common.quotation_subject, Genetic predisposition, Longevity, Fertility, Disease, Biology, Premature ovarian insufficiency, Bioinformatics, Ovarian reserve, FMR1, Human genetics, media_common
Abstract: Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021
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17. 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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18. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Author: Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud
Subjects: Genetics, QH426-470
Abstract: Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Published: 2013
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19. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.
Published: 2020
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20. Genome-wide association and functional follow-up reveals new loci for kidney function.

Author: Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, Man Li, Xiaoyi Gao, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Conall M O'Seaghdha, Nicole Glazer, Aaron Isaacs, Ching-Ti Liu, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Andrew D Johnson, Hinco J Gierman, Mary Feitosa, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Åsa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Chouraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tõnu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Margherita Cavalieri, Madhumathi Rao, Frank B Hu, Ayse Demirkan, Ben A Oostra, Mariza de Andrade, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Ivana Kolcic, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Karlhans Endlich, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polasek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Shamika Ketkar, Helen Colhoun, Alex Doney, Antonietta Robino, Franco Giulianini, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Marie Metzger, Paul Mitchell, Marina Ciullo, Stuart K Kim, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, David S Siscovick, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline C M Witteman, Caroline Hayward, Paul Ridker, Afshin Parsa, Murielle Bochud, Iris M Heid, Wolfram Goessling, Daniel I Chasman, W H Linda Kao, and Caroline S Fox
Subjects: Genetics, QH426-470
Abstract: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Published: 2012
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21. 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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22. Heritability and demographic analyses in the large isolated population of Val Borbera suggest advantages in mapping complex traits genes.

Author: Michela Traglia, Cinzia Sala, Corrado Masciullo, Valeria Cverhova, Francesca Lori, Giorgio Pistis, Silvia Bione, Paolo Gasparini, Sheila Ulivi, Marina Ciullo, Teresa Nutile, Emanuele Bosi, Marcella Sirtori, Giovanna Mignogna, Alessandro Rubinacci, Iwan Buetti, Clara Camaschella, Enrico Petretto, and Daniela Toniolo
Subjects: Medicine, Science
Abstract: Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South.The study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits.The data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations.
Published: 2009
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23. 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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24. Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

Author: Yalda Jamshidi, Paul I.W. de Bakker, J. Wouter Jukema, Ilaria Gandin, Monika Stoll, Christopher P. Nelson, Moritz F. Sinner, Eco J. C. de Geus, André G. Uitterlinden, Jan A. Kors, Vilmundur Gudnason, Sheila Ulivi, Jouke-Jan Hottenga, Terho Lehtimäki, Antonietta Robino, Mark Eijgelsheim, Annamaria Iorio, Niek Verweij, Martina Müller-Nurasyid, Ian Ford, Hao Mei, James G. Wilson, Albert V. Smith, Thomas Meitinger, Gianfranco Sinagra, Claudia T. Silva Aldana, Maartje N. Niemeijer, Torben Hansen, Allan Linneberg, Jennifer A. Brody, Pim van der Harst, Stella Trompet, Paolo Gasparini, Bram P. Prins, Stefan Kääb, Hamdi Mbarek, Alvaro Alonso, Leanne M. Hall, Helen R. Warren, Dan E. Arking, Peter W. Macfarlane, Annette Peters, Olli T. Raitakari, Daiane Hemerich, Mark J. Caulfield, Folkert W. Asselbergs, Dorret I. Boomsma, Aaron Isaacs, Bruno H. Stricker, Tamara B. Harris, Susan R. Heckbert, Jessica van Setten, Niels Grarup, Patricia B. Munroe, Leo-Pekka Lyytikäinen, Nilesh J. Samani, Cornelia M. van Duijn, Elsayed Z. Soliman, Nona Sotoodehnia, Jørgen K. Kanters, Melanie Waldenberger, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, Erasmus MC other, Epidemiology, Medical Informatics, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, van Setten, Jessica, Verweij, Niek, Mbarek, Hamdi, Niemeijer, Maartje N., Trompet, Stella, Arking, Dan E., Brody, Jennifer A., Gandin, Ilaria, Grarup, Niel, Hall, Leanne M., Hemerich, Daiane, Lyytikäinen, Leo-Pekka, Mei, Hao, Müller-Nurasyid, Martina, Prins, Bram P., Robino, Antonietta, Smith, Albert V., Warren, Helen R., Asselbergs, Folkert W., Boomsma, Dorret I., Caulfield, Mark J., Eijgelsheim, Mark, Ford, Ian, Hansen, Torben, Harris, Tamara B., Heckbert, Susan R., Hottenga, Jouke-Jan, Iorio, Anita, Kors, Jan A., Linneberg, Allan, Macfarlane, Peter W., Meitinger, Thoma, Nelson, Christopher P., Raitakari, Olli T., Silva Aldana, Claudia T., Sinagra, Gianfranco, Sinner, Moritz, Soliman, Elsayed Z., Stoll, Monika, Uitterlinden, Andre, van Duijn, Cornelia M., Waldenberger, Melanie, Alonso, Alvaro, Gasparini, Paolo, Gudnason, Vilmundur, Jamshidi, Yalda, Kääb, Stefan, Kanters, Jørgen K., Lehtimäki, Terho, Munroe, Patricia B., Peters, Annette, Samani, Nilesh J., Sotoodehnia, Nona, Ulivi, Sheila, Wilson, James G., de Geus, Eco J. C., Jukema, J. Wouter, Stricker, Bruno, van der Harst, Pim, de Bakker, Paul I. W., Isaacs, Aaron, Cardiovascular Centre (CVC), Biochemie, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Netherlands Twin Register (NTR), Genetics, Genetics (clinical), PROTEIN, Genome-wide association study, Quantitative trait, Genome-wide association studies, ANNOTATION, Gene locus, Electrocardiography, Computer model, Netherlands, Priority journal, Allele, 0303 health sciences, Genome, Rr interval, 030305 genetics & heredity, COMMON VARIANTS, ddc, GLUCOCORTICOID-RECEPTOR, Qrs interval, Female, Cohort analysis, Erfðarannsóknir, PHOSPHOLAMBAN, Human, QT INTERVAL DURATION, Genotype, Heart rate, HEART-RATE, Exon, Single-nucleotide polymorphism, Major clinical study, Biology, Quantitative trait locus, Dutchman, Polymorphism, Single Nucleotide, QT interval, Article, Sample, 03 medical and health sciences, QRS complex, Genetic, SDG 3 - Good Health and Well-being, Humans, PR interval, Gene mapping, Genetic association, MUTATIONS, Follow up, CONTRACTILITY, DNA-rannsóknir, R1, Gene frequency, POLYMORPHISM, Electrocardiogram, Single nucleotide polymorphism, Minor allele frequency, Genetic Loci, Meta analysis, Qt interval, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes., Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre.
Published: 2019
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25. 52 Genetic Loci Influencing Myocardial Mass

Author: Alan F. Wright, Cisca Wijmenga, Bruno H. Stricker, Peter W. Macfarlane, Edward G. Lakatta, Uwe Völker, Lenore J. Launer, Olli T. Raitakari, Stephan B. Felix, Toshiko Tanaka, Osorio Meirelles, Phil Barnett, Thomas Meitinger, Albert Hofman, Bosco Trinh, Tamara B. Harris, Peter M. Okin, Axel Visel, Teresa Nutile, Claudia T. Silva, Harry Campbell, Ilja M. Nolte, M. Fabiola Del Greco, Terho Lehtimäki, Shih-Jen Hwang, Alicia Lundby, Kamil Slowikowski, Luigi Ferrucci, Joshua C. Bis, Jerome I. Rotter, Nona Sotoodehnia, Sebastian Schafer, Igor Rudan, Ozren Polasek, Vinicius Tragante, Kenneth Rice, Connie R. Bezzina, Siegfried Perz, Aravinda Chakravarti, Paul I.W. de Bakker, Jared W. Magnani, Xinchen Wang, Yigal M. Pinto, Carsten Oliver Schmidt, Marcus Dörr, Peter P. Pramstaller, Jobanpreet Sehmi, Susan R. Heckbert, Richard B. Devereux, Jesper V. Olsen, Sheila Ulivi, Shane Neph, Peter M. Visscher, James F. Wilson, Alexander Nord, Tim D. Spector, Stefan Kääb, Elsayed Z. Soliman, Weihua Zhang, Lin Y. Chen, Pim van der Harst, Veronique Vitart, Anna F. Dominiczak, Mark Eijgelsheim, Pieter A. Doevendans, Josef M. Penninger, Jaspal S. Kooner, Georg Vogler, Patricia B. Munroe, Soumya Raychaudhuri, Christian Gieger, Harold Snieder, Annamaria Iorio, Caroline Hayward, Yalda Jamshidi, Mika Kähönen, Jessica van Setten, Wilko Spiering, Ian Ford, Andrew A. Hicks, John C. Chambers, Joel N. Hirschhorn, Matthew T. Maurano, Niek Verweij, Maria Grazia Pilia, Rolf Bodmer, Vilmundur Gudnason, Ben A. Oostra, Megan V. Cannon, Nilesh J. Samani, Bruce H. R. Wolffenbuttel, Annette Peters, David Schlessinger, Daniel Levy, J. Wouter Jukema, Malou van den Boogaard, Brendan M. Buckley, Arne Pfeufer, Michiel E. Adriaens, Rossella Sorice, Matthias Heinig, Jian Yang, Norbert Hubner, Stefania Bandinelli, André G. Uitterlinden, Hans L. Hillege, Martina Müller-Nurasyid, Andres Metspalu, Eric Haugen, Laurie A. Boyer, Ronald P. Stolk, Gonçalo R. Abecasis, Dan E. Arking, Manolis Kellis, Ishminder K. Kooner, Leo-Pekka Lyytikäinen, Dena G. Hernandez, Dirk J. van Veldhuisen, Len A. Pennacchio, Kasper Lage, Gianfranco Sinagra, Bruce M. Psaty, Christopher Newton-Cheh, Cornelia M. van Duijn, Stefania Nappo, Dalit May, Paolo Gasparini, Elizabeth J. Rossin, Rudolf A. de Boer, Alessandro P Delitala, Tõnu Esko, John A. Stamatoyannopoulos, Aaron Isaacs, Kathleen F. Kerr, Sian Tsung Tan, Tune H. Pers, Serena Sanna, Melanie Waldenberger, Marina Ciullo, Jorma Viikari, Vincent M. Christoffels, Bram P. Prins, Alvaro Alonso, Sandosh Padmanabhan, Harm-Jan Westra, Moritz F. Sinner, Albert V. Smith, Kirill V. Tarasov, Konstantin Strauch, Wiek H. van Gilst, Christian X. Weichenberger, Lude Franke, Folkert W. Asselbergs, Herman H W Silljé, Jan A. Kors, Irene Mateo Leach, Karl Andersen, Ivana Kolcic, Stella Trompet, Silvia Naitza, Broad Institute of MIT and Harvard, Raychaudhuri, Soumya, Sciences, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio, Biochemie, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Maastricht Centre for Systems Biology, Fysiologie, RS: Carim - B01 Blood proteins & engineering, Graduate School, ANS - Cellular & Molecular Mechanisms, ANS - Neuroinfection & -inflammation, AGEM - Endocrinology, metabolism and nutrition, Medical Biology, ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Intensive Care Medicine, Other Research, Cardiology, Ophthalmology, ACS - Amsterdam Cardiovascular Sciences, Center of Experimental and Molecular Medicine, AII - Inflammatory diseases, AII - Infectious diseases, ACS - Pulmonary hypertension & thrombosis, Gastroenterology and Hepatology, Experimental Immunology, Erasmus MC other, Epidemiology, Public Health, Medical Informatics, Clinical Genetics, Internal Medicine, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), van der Harst, Pim, van Setten, Jessica, Verweij, Niek, Vogler, Georg, Franke, Lude, Maurano, Matthew T., Wang, Xinchen, Mateo Leach, Irene, Eijgelsheim, Mark, Sotoodehnia, Nona, Hayward, Caroline, Sorice, Rossella, Meirelles, Osorio, Lyytikäinen, Leo Pekka, Polašek, Ozren, Tanaka, Toshiko, Arking, Dan E., Ulivi, Sheila, Trompet, Stella, Müller Nurasyid, Martina, Smith, Albert V., Dörr, Marcu, Kerr, Kathleen F., Magnani, Jared W., Fabiola, Del Greco M., Zhang, Weihua, Nolte, Ilja M., Silva, Claudia T., Padmanabhan, Sandosh, Tragante, Viniciu, Esko, Tõnu, Abecasis, Gonçalo R., Adriaens, Michiel E., Andersen, Karl, Barnett, Phil, Bis, Joshua C., Bodmer, Rolf, Buckley, Brendan M., Campbell, Harry, Cannon, Megan V., Chakravarti, Aravinda, Chen, Lin Y., Delitala, Alessandro, Devereux, Richard B., Doevendans, Pieter A., Dominiczak, Anna F., Ferrucci, Luigi, Ford, Ian, Gieger, Christian, Harris, Tamara B., Haugen, Eric, Heinig, Matthia, Hernandez, Dena G., Hillege, Hans L., Hirschhorn, Joel N., Hofman, Albert, Hubner, Norbert, Hwang, Shih Jen, Iorio, Annamaria, Kähönen, Mika, Kellis, Manoli, Kolcic, Ivana, Kooner, Ishminder K., Kooner, Jaspal S., Kors, Jan A., Lakatta, Edward G., Lage, Kasper, Launer, Lenore J., Levy, Daniel, Lundby, Alicia, Macfarlane, Peter W., May, Dalit, Meitinger, Thoma, Metspalu, Andre, Nappo, Stefania, Naitza, Silvia, Neph, Shane, Nord, Alex S., Nutile, Teresa, Okin, Peter M., Olsen, Jesper V., Oostra, Ben A., Penninger, Josef M., Pennacchio, Len A., Pers, Tune H., Perz, Siegfried, Peters, Annette, Pinto, Yigal M., Pfeufer, Arne, Pilia, Maria Grazia, Pramstaller, Peter P., Prins, Bram P., Raitakari, Olli T., Rice, Ken M., Rossin, Elizabeth J., Rotter, Jerome I., Schafer, Sebastian, Schlessinger, David, Schmidt, Carsten O., Sehmi, Jobanpreet, Silljé, Herman H. W., Sinagra, Gianfranco, Sinner, Moritz F., Slowikowski, Kamil, Soliman, Elsayed Z., Spector, Timothy D., Spiering, Wilko, Stamatoyannopoulos, John A., Stolk, Ronald P., Strauch, Konstantin, Tan, Sian Tsung, Tarasov, Kirill V., Trinh, Bosco, Uitterlinden, Andre G., van den Boogaard, Malou, van Duijn, Cornelia M., van Gilst, Wiek H., Viikari, Jorma S., Visscher, Peter M., Vitart, Veronique, Völker, Uwe, Waldenberger, Melanie, Weichenberger, Christian X., Westra, Harm Jan, Wijmenga, Cisca, Wolffenbuttel, Bruce H., Yang, Jian, Bezzina, Connie R., Munroe, Patricia B., Snieder, Harold, Wright, Alan F., Rudan, Igor, Boyer, Laurie A., Asselbergs, Folkert W., van Veldhuisen, Dirk J., Stricker, Bruno H., Psaty, Bruce M., Ciullo, Marina, Sanna, Serena, Lehtimäki, Terho, Wilson, James F., Bandinelli, Stefania, Alonso, Alvaro, Gasparini, Paolo, Jukema, J. Wouter, Kääb, Stefan, Gudnason, Vilmundur, Felix, Stephan B., Heckbert, Susan R., de Boer, Rudolf A., Newton Cheh, Christopher, Hicks, Andrew A., Chambers, John C., Jamshidi, Yalda, Visel, Axel, Christoffels, Vincent M., Isaacs, Aaron, Samani, Nilesh J., and de Bakker, Paul I. W.
Subjects: 0301 basic medicine, Biological functions, Qrs, Electrocardiogram, Genetic Association Study, Heart Failure, Left Ventricular Hypertrophy, Candidate gene, Cardiac & Cardiovascular Systems, heart failure, Genome-wide association study, ELECTROCARDIOGRAM, 030204 cardiovascular system & hematology, SCN5A gene, Gene locus, DISEASE, Muscle hypertrophy, In vivo study, 0302 clinical medicine, Sodium channel Nav1.5, REGULATORY DNA, Sodium channel Nav1.8, Cardiac muscle, CARDIAC-HYPERTROPHY, Priority journal, RISK, Genetics, Validation study, Heart, Genetic parameters, Reliability, Chromatin, left ventricular hypertrophy, GENOME, Drosophila melanogaster, Phenotype, medicine.anatomical_structure, 1117 Public Health And Health Services, genetic association study, Cardiology, cardiovascular system, HEART, Functional assessment, Histone modification, Cardiology and Cardiovascular Medicine, Genetic trait, Life Sciences & Biomedicine, Human, medicine.medical_specialty, Cardiomegaly, Locus (genetics), Major clinical study, electrocardiogram, European, QRS, 1102 Cardiovascular Medicine And Haematology, Article, 03 medical and health sciences, QRS complex, LEFT-VENTRICULAR HYPERTROPHY, Internal medicine, Journal Article, medicine, Mus musculus, Protein binding, Animals, Humans, SCN10A gene, VOLTAGE, Cardiovascular parameters, Heart ventricle hypertrophy, Science & Technology, Human genome, Animal, business.industry, MORTALITY, In vitro study, ta3121, medicine.disease, DYSFUNCTION, 030104 developmental biology, Gene identification, Cardiovascular System & Hematology, Genetic Loci, Heart failure, Expression quantitative trait loci, Genetic association, Meta analysis (topic), Cardiovascular System & Cardiology, Genetic variability, Transcription factor, Myocardial mass, business
Abstract: BACKGROUND Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.OBJECTIVES This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.METHODS We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.RESULTS We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p CONCLUSIONS Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets. (C) 2016 by the American College of Cardiology Foundation.
Published: 2016
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26. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author: Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.
Published: 2018
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27. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author: Farid Radmanesh, Kenneth Rice, Xiuqing Guo, Jessica van Setten, Konstantin Strauch, Albert V. Smith, Jeffrey Haessler, Stefan Kääb, Folkert W. Asselbergs, Patricia B. Munroe, Steven A. Lubitz, Ching-Ti Liu, Niek Verweij, Aaron Isaacs, Martina Müller-Nurasyid, Allan Linneberg, Jan A. Kors, Ozren Polasek, Kari Stefansson, Caroline Hayward, Daniel F. Gudbjartsson, Jonathan Marten, Olli T. Raitakari, Mark Eijgelsheim, Timothy J. Mead, Nona Sotoodehnia, Elsayed Z. Soliman, Hao Mei, Gianfranco Sinagra, Stefan Weiss, Torben Hansen, Michiel L. Bots, Mika Kähönen, Yalda Jamshidi, Xiaoqin Liu, Stefania Cappellani, Unnur Thorsteinsdottir, Nilesh J. Samani, Cecilia W. Lo, Honghuang Lin, Charles Kooperberg, Moritz F. Sinner, Zhijun Xie, Jennifer A. Brody, Paolo Gasparini, Ruifang Li-Gao, Leo-Pekka Lyytikäinen, Stefan van Duijvenboden, Nikolai Klena, Michele Orini, Stella Trompet, Joop Jukema, Tamara B. Harris, Jerome I. Rotter, Stephan B. Felix, Julia Ramirez, Sheila Ulivi, Ioanna Ntalla, Marcus Dörr, Annette Peters, Paul L. Huang, Dennis O. Mook-Kanamori, Igor Rudan, Cornelia M. van Duijn, Christopher P. Nelson, Anna F. Dominiczak, Henry Völzke, Terho Lehtimäki, Niels Grarup, Henry J. Lin, Bruno H. Stricker, Tim D. Spector, Molly Schwartz, Patrick T. Ellinor, Vilmundur Gudnason, Uwe Völker, Christopher Newton-Cheh, Antonietta Robino, Marten E. van den Berg, Çağrı Güleç, Marco V Perez, Jette Bork-Jensen, Pim van der Harst, Rudolf A. de Boer, Jonathan Rosand, Oluf Pedersen, Susan R. Heckbert, David O Arnar, Dan E. Arking, André G. Uitterlinden, Andrew Tinker, Bram P. Prins, Lenore J. Launer, Alvaro Alonso, Leanne M. Hall, Helen R. Warren, Man Li, Pier D. Lambiase, Jørgen K. Kanters, Ilonca Vaartjes, James G. Wilson, Sandosh Padmanabhan, Melanie Waldenberger, Nathan A. Bihlmeyer, Peter van der Meer, Francesco J. Conti, George C. Gabriel, Hilma Holm, Gardar Sveinbjornsson, Suneel S. Apte, Annamaria Iorio, Blair H. Smith, Bruce M. Psaty, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: CARIM - R1.01 - Blood proteins & engineering, RS: FHML MaCSBio, Biochemie, Jamshidi, Yalda [0000-0003-0151-6482], Apollo - University of Cambridge Repository, Medical Informatics, Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Prins, Bram P, Mead, Timothy J, Brody, Jennifer A, Sveinbjornsson, Gardar, Ntalla, Ioanna, Bihlmeyer, Nathan A, van den Berg, Marten, Bork-Jensen, Jette, Cappellani, Stefania, Van Duijvenboden, Stefan, Klena, Nikolai T, Gabriel, George C, Liu, Xiaoqin, Gulec, Cagri, Grarup, Niel, Haessler, Jeffrey, Hall, Leanne M, Iorio, Annamaria, Isaacs, Aaron, Li-Gao, Ruifang, Lin, Honghuang, Liu, Ching-Ti, Lyytikäinen, Leo-Pekka, Marten, Jonathan, Mei, Hao, Müller-Nurasyid, Martina, Orini, Michele, Padmanabhan, Sandosh, Radmanesh, Farid, Ramirez, Julia, Robino, Antonietta, Schwartz, Molly, van Setten, Jessica, Smith, Albert V, Verweij, Niek, Warren, Helen R, Weiss, Stefan, Alonso, Alvaro, Arnar, David O, Bots, Michiel L, de Boer, Rudolf A, Dominiczak, Anna F, Eijgelsheim, Mark, Ellinor, Patrick T, Guo, Xiuqing, Felix, Stephan B, Harris, Tamara B, Hayward, Caroline, Heckbert, Susan R, Huang, Paul L, Jukema, J W, Kähönen, Mika, Kors, Jan A, Lambiase, Pier D, Launer, Lenore J, Li, Man, Linneberg, Allan, Nelson, Christopher P, Pedersen, Oluf, Perez, Marco, Peters, Annette, Polasek, Ozren, Psaty, Bruce M, Raitakari, Olli T, Rice, Kenneth M, Rotter, Jerome I, Sinner, Moritz F, Soliman, Elsayed Z, Spector, Tim D, Strauch, Konstantin, Thorsteinsdottir, Unnur, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Vaartjes, Ilonca, van der Meer, Peter, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wilson, James G, Xie, Zhijun, Asselbergs, Folkert W, Dörr, Marcu, van Duijn, Cornelia M, Gasparini, Paolo, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hansen, Torben, Kääb, Stefan, Kanters, Jørgen K, Kooperberg, Charle, Lehtimäki, Terho, Lin, Henry J, Lubitz, Steven A, Mook-Kanamori, Dennis O, Conti, Francesco J, Newton-Cheh, Christopher H, Rosand, Jonathan, Rudan, Igor, Samani, Nilesh J, Sinagra, Gianfranco, Smith, Blair H, Holm, Hilma, Stricker, Bruno H, Ulivi, Sheila, Sotoodehnia, Nona, Apte, Suneel S, van der Harst, Pim, Stefansson, Kari, Munroe, Patricia B, Arking, Dan E, Lo, Cecilia W, Jamshidi, Yalda, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AII - Infectious diseases, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam institute for Infection and Immunity, Amsterdam Gastroenterology Endocrinology Metabolism, Radiotherapy, Experimental Immunology, Gastroenterology and Hepatology, Graduate School, Intensive Care Medicine, Cardiology, Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: 0301 basic medicine, ADAMTS6, Conduction, Exome chip, Meta-analysis, Male, Gene Expression, Genome-wide association study, Sudden cardiac death, Electrocardiography, Mice, ADAMTS Proteins, PR INTERVAL, Exome, lcsh:QH301-705.5, Exome sequencing, POPULATION, education.field_of_study, Gen, Ecology, Adamts6, Exome Chip, COMMON VARIANTS, Middle Aged, cardiovascular system, Female, Electrical conduction system of the heart, QRS DURATION, lcsh:QH426-470, Evolution, Population, Black People, Computational biology, Biology, Polymorphism, Single Nucleotide, White People, WORSENING HEART-FAILURE, 03 medical and health sciences, QRS complex, Open Reading Frames, Behavior and Systematics, VENTRICULAR CONDUCTION, Heart Conduction System, Cardiac conduction, Exome Sequencing, medicine, Genetics, Erfðafræði, Animals, Humans, ARRHYTHMIC DEATH, cardiovascular diseases, GENOME-WIDE ASSOCIATION, education, Ecology, Evolution, Behavior and Systematics, Research, Gene Expression Profiling, Myocardium, MORTALITY, Rannsóknir, Cell Biology, medicine.disease, lcsh:Genetics, 030104 developmental biology, lcsh:Biology (General), Genetic Loci, Connexin 43, ELECTROCARDIOGRAPHIC PARAMETERS, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes., Funding This work was funded by a grant to YJ from the British Heart Foundation (PG/12/38/29615). AGES: This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). BRIGHT: The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). This work was also supported by the Medical Research Council of Great Britain (Grant no. G9521010D); and by the British Heart Foundation (Grant no. PG/02/128). AFD was supported by the British Heart Foundation (Grant nos. RG/07/005/23633 and SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant no. LSHM-C7–2006-037093). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Centre staff for their assistance with this project. CHS: This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201800001C, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants R01HL068986, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ERF: The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013)/grant agreement HEALTH-F4–2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). The ERF study was further supported by ENGAGE consortium and CMSB. High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). We are grateful to all study participants and their relatives, general practitioners, and neurologists for their contributions to the ERF study and to P Veraart for her help in genealogy, J Vergeer for the supervision of the laboratory work, and P Snijders for his help in data collection. FHS: The Framingham Heart Study (FHS) research reported in this article was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI), HL120393. Generation Scotland: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the Generation Scotland and Scottish Family Health Study samples was carried out by the Genetics Core Laboratory at the Clinical Research Facility, Edinburgh, Scotland and was funded by the UK’s Medical Research Council. GOCHA: The Genetics of Cerebral Hemorrhage with Anticoagulation was carried out as a collaborative study supported by grants R01NS073344, R01NS059727, and 5K23NS059774 from the NIH–National Institute of Neurological Disorders and Stroke (NIH-NINDS). GRAPHIC: The GRAPHIC Study was funded by the British Heart Foundation (BHF/RG/2000004). NJS and CPN are supported by the British Heart Foundation and is a NIHR Senior Investigator. This work falls under the portfolio of research supported by the NIHR Leicester Cardiovascular Biomedical Research. INGI-FVG: This study has been funded by Regione FVG (L.26.2008). INTER99: The Inter99 was initiated by Torben Jørgensen (PI), Knut Borch-Johnsen (co-PI), Hans Ibsen and Troels F. Thomsen. The steering committee comprises the former two and Charlotta Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). JHS: We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. KORA: The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. Korcula: This work was funded by the Medical Research Council UK, The Croatian Ministry of Science, Education and Sports (grant 216–1080315-0302), the Croatian Science Foundation (grant 8875), the Centre of Excellence in Personalized health care, and the Centre of Competencies for Integrative Treatment, Prevention and Rehabilitation using TMS. LifeLines: The LifeLines Cohort Study and generation and management of GWAS genotype data for the LifeLines Cohort Study are supported by The Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation, and Dutch Diabetes Research Foundation. Niek Verweij is supported by NWO-VENI (016.186.125) and Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395). UHP: Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Ilonca Vaartjes is supported by a Dutch Heart Foundation grant DHF project “Facts and Figures.” MGH-CAMP: Dr. Patrick Ellinor is funded by NIH grants (2R01HL092577, 1R01HL128914, R01HL104156, and K24HL105780) and American Heart Association Established Investigator Award 13EIA14220013 (Ellinor). Dr. Steve Lubitz is funded by NIH grants K23HL114724 and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. NEO: The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants, and all research nurses for collection of the data. We thank the NEO study group, Pat van Beelen, Petra Noordijk, and Ingeborg de Jonge for the coordination, lab, and data management of the NEO study. We also thank Arie Maan for the analyses of the electrocardiograms. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). RS-I: The generation and management of the Illumina Exome Chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array dataset was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050–060-810); the Netherlands Organization for Scientific Research (NWO; project number 184021007); and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl). We thank Ms. Mila Jhamai, Ms. Sarah Higgins, and Mr. Marijn Verkerk for their help in creating the exome chip database, and Carolina Medina-Gomez, MSc, Lennard Karsten, MSc, and Linda Broer PhD for QC and variant calling. Variants were called using the best practice protocol developed by Grove et al. as part of the CHARGE consortium exome chip central calling effort. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The work of Bruno H. Stricker is supported by grants from the Netherlands Organization for Health Research and Development (ZonMw) (Priority Medicines Elderly 113102005 to ME and DoelmatigheidsOnderzoek 80–82500–98-10208 to BHS). The work of Mark Eijgelsheim is supported by grants from the Netherlands Organization for Health Research and Development (ZonMw) (Priority Medicines Elderly 113102005 to ME and DoelmatigheidsOnderzoek 80–82500–98-10208 to BHS). SHIP: SHIP is supported by the BMBF (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]; grant GR 1912/5–1). SHIP and SHIP-TREND are part of the Community Medicine Research net (CMR) of the Ernst-Moritz-Arndt University Greifswald (EMAU) which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. The EMAU is a member of the Center of Knowledge Interchange (CKI) program of the Siemens AG. SNP typing of SHIP and SHIP-TREND using the Illumina Infinium HumanExome BeadChip (version v1.0) was supported by the BMBF (grant 03Z1CN22). We thank all SHIP and SHIP-TREND participants and staff members as well as the genotyping staff involved in the generation of the SNP data. TWINSUK: TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. UKBB: This research has been conducted using the UK Biobank Resource (application 8256 - Understanding genetic influences in the response of the cardiac electrical system to exercise) and is supported by Medical Research Council grant MR/N025083/1. We also wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Unit at Barts and Queen Mary University of London, UK. PD Lambiase acknowledges support from the UCLH Biomedicine NIHR. MO is supported by an IEF 2013 Marie Curie fellowship. JR acknowledges support from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no. 608765. YFS: The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. The expert technical assistance in the statistical analyses by Irina Lisinen is gratefully acknowledged. Cell culture and biochemistry: Funding was provided by the National Institutes of Health (Program of Excellence in Glycoscience award HL107147 to SSA and F32AR063548 to TJM) and the David and Lindsay Morgenthaler Postdoctoral Fellowship (to TJM) and by the Allen Distinguished Investigator Program, through support made by The Paul G. Allen Frontiers Group and the American Heart Association (to SSA). Mutant mouse model: Adamts6 mutant mice were generated and further propagated and analyzed by funding provided by NIH grants HL098180 and HL132024 (to CWL) and by the Allen Distinguished Investigator Program, through support made by The Paul G. Allen Frontiers Group and the American Heart Association (to SSA).
Published: 2018
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28. Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Author: Aaron Isaacs, Sina A. Gharib, Kathleen F. Kerr, Lenore J. Launer, Yuki Bradford, J. Wouter Jukema, Stefan Kääb, Ruth J. F. Loos, Philipp S. Wild, Igor Rudan, Moritz F. Sinner, Annamaria Iorio, David J. Stott, Sheila Ulivi, Martina Müller-Nurasyid, Jerome I. Rotter, Andrew A. Hicks, Leo-Pekka Lyytikäinen, Vilmundur Gudnason, Dan M. Roden, Dana C. Crawford, James F. Wilson, Renate B. Schnabel, Eric Boerwinkle, Mina K. Chung, M. Fabiola Del Greco, Jan A. Kors, Honghuang Lin, Dan E. Arking, Annette Peters, Daniel S. Evans, Kari Stefansson, Francesco Cucca, Harold Snieder, Nona Sotoodehnia, Claudia T. Silva Aldana, Paul I.W. de Bakker, David Schlessinger, Pim van der Harst, Irene Mateo Leach, Kirill V. Tarasov, Marylyn D. Ritchie, Xiaoyan Yin, Marcus Dörr, Jennifer A. Brody, Patrick T. Ellinor, Olli T. Raitakari, Christy L. Avery, Peter W. Macfarlane, Paolo Gasparini, Susan R. Heckbert, John Barnard, Jessica van Setten, Anna F. Dominiczak, Henry Völzke, Edward G. Lakatta, Nilesh J. Samani, Tamara B. Harris, Brenton R. Swenson, Joel S. Bader, Thomas Münzel, Patricia B. Munroe, Hilma Holm, Stefania Bandinelli, Christian Müller, Bruno H. Stricker, Oscar H. Franco, Yongmei Liu, Ivana Kolcic, Peter P. Pramstaller, Josh C. Denny, Maristella Steri, Henry J. Lin, Luigi Ferrucci, Arne Pfeufer, Antonietta Robino, Bruce M. Psaty, Niek Verweij, Lude Franke, Mark Eijgelsheim, Afshin Parsa, Toshiko Tanaka, Folkert W. Asselbergs, Terho Lehtimäki, Stella Trompet, Alvaro Alonso, Harm-Jan Westra, David O. Arnar, Jared W. Magnani, Bouwe P. Krijthe, Cornelia M. van Duijn, Brendan M. Buckley, Jonathan D. Smith, Tim D. Spector, George J. Papanicolaou, Anne M. Butler, Emelia J. Benjamin, Tanja Zeller, Quince Gibson, David R. Van Wagoner, André G. Uitterlinden, Albert V. Smith, Stephan B. Felix, Uwe Völker, Yalda Jamshidi, Ozren Polasek, Daniel F. Gudbjartsson, Harry Campbell, Caroline Hayward, Ilja M. Nolte, Elsayed Z. Soliman, Georg Ehret, Mika Kähönen, Konstantin Strauch, Steven A. Lubitz, Melanie Waldenberger, Alexander Teumer, Sandosh Padmanabhan, Braxton D. Mitchell, Gianfranco Sinagra, Gandin Ilaria, Thomas Meitinger, Marcel den Hoed, Stefan Blankenberg, and J. C. Bis
Subjects: Genetics, QRS complex, Heart block, medicine, cardiovascular system, Missense mutation, Genome-wide association study, Atrial fibrillation, PR interval, Biology, medicine.disease, Genome, Gene
Abstract: Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.
Published: 2018
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29. Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes

Author: Rosa Vargas-Poussou, Igor Rudan, Paolo Gasparini, Ian J. Deary, Joost G. J. Hoenderop, Olivier Devuyst, Aurélien Macé, Menno Pruijm, John M. Starr, Huguette Debaix, Martin Konrad, Jeroen H. F. de Baaij, Stefania Lenarduzzi, Sheila Ulivi, Ozren Polasek, Daniel Ackermann, Rico Rueedi, David Lamparter, Nicholas D. Hastie, Caroline Hayward, Gérard Waeber, Tanguy Corre, Daniela Baptista, Toby W. Hurd, Zoltán Kutalik, Murielle Bochud, Sonia Youhanna, Hendrica Belge, Peter Vollenweider, Sven Bergmann, Maxime G. Blanchard, Michela Traglia, Belen Ponte, René J. M. Bindels, Francisco J. Arjona, Veronique Vitart, Daniela Toniolo, Cinzia Sala, Nadine Nägele, Sarah E. Harris, Georg Ehret, Corre, Tanguy, Arjona, Francisco J., Hayward, Caroline, Youhanna, Sonia, De Baaij, Jeroen H. F., Belge, Hendrica, Nägele, Nadine, Debaix, Huguette, Blanchard, Maxime G., Traglia, Michela, Harris, Sarah E., Ulivi, Sheila, Rueedi, Rico, Lamparter, David, Macé, Aurélien, Sala, Cinzia, Lenarduzzi, Stefania, Ponte, Belen, Pruijm, Menno, Ackermann, Daniel, Ehret, Georg, Baptista, Daniela, Polasek, Ozren, Rudan, Igor, Hurd, Toby W., Hastie, Nicholas D., Vitart, Veronique, Waeber, Geràrd, Kutalik, Zoltán, Bergmann, Sven, Vargas-Poussou, Rosa, Konrad, Martin, Gasparini, Paolo, Deary, Ian J., Starr, John M., Toniolo, Daniela, Vollenweider, Peter, Hoenderop, Joost G. J., Bindels, René J. M., Bochud, Murielle, and Devuyst, Olivier
Subjects: 0301 basic medicine, Magnesium homeostasis, Kidney, Genetic determinants, Mice, Homeostasis, Insulin, Magnesium, 610 Medicine & health, Zebrafish, Adiposity, ddc:616, DOUBLE-BLIND, SECONDARY HYPOCALCEMIA, NONDIABETIC SUBJECTS, INSULIN SENSITIVITY, CONTROLLED-TRIALS, RANDOMIZED-TRIAL, GENETIC-LOCI, ZEBRAFISH, SUPPLEMENTATION, HYPOMAGNESEMIA, education.field_of_study, Gene knockdown, Genetic determinant, ADP-Ribosylation Factors, General Medicine, Metabolic syndrome, Phenotype, Magnesium homeostasi, Nephrology, medicine.medical_specialty, Population, TRPM Cation Channels, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Insulin resistance, GTP-Binding Proteins, Internal medicine, TRPM6, medicine, Tubular transport, Animals, Humans, Obesity, RNA, Messenger, education, Zebrafish Proteins, zebrafish, medicine.disease, biology.organism_classification, Gene-environment interaction, 030104 developmental biology, Endocrinology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 570 Life sciences, biology, Gene-Environment Interaction, Insulin Resistance, Meta-Analysis, Genome-Wide Association Study
Abstract: Contains fulltext : 184156.pdf (Publisher’s version ) (Closed access) Magnesium (Mg(2+)) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg(2+), which is crucial for Mg(2+) homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg(2+) homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4x10(-13)) near TRPM6, which encodes an epithelial Mg(2+) channel, and rs35929 (P=2.1x10(-11)), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg(2+) regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg(2+) wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg(2+) deficiency to insulin resistance and obesity. 01 januari 2018
Published: 2018
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30. 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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31. Evidence of inbreeding depression on human height

Author: Cinzia Sala, Peter P. Pramstaller, Najaf Amin, Brian P. McEvoy, Erkki Vartiainen, Lorna M. Lopez, Nicholas D. Hastie, Andres Metspalu, Susan M. Farrington, Mladen Boban, Marjo-Riitta Järvelin, Vesna Boraska, Seppo Koskinen, Krista Fischer, André G. Uitterlinden, Laura Esposito, Karol Estrada, Ruth McQuillan, Tõnu Esko, Sheila Ulivi, Mart Kals, Harry Campbell, Inga Prokopenko, Peter M. Visscher, Niina Eklund, Markku Heliövaara, Alan F. Wright, Antonietta Robino, Pamela A. F. Madden, Henning Tiemeier, Grant W. Montgomery, Albert Tenesa, Markus Perola, Nicola Pirastu, Albert Hofman, Johan G. Eriksson, Giorgio Pistis, Pio D'Adamo, Ben A. Oostra, Nicholas G. Martin, Terho Lehtimäki, Ivana Kolcic, Igor Rudan, Olli T. Raitakari, Tatijana Zemunik, Ian J. Deary, Giorgia Girotto, Mark I. McCarthy, Veronique Vitart, David J. Porteous, Daniela Toniolo, Malcolm G. Dunlop, Martin Gögele, Anneli Pouta, Jorma Viikari, Åsa Johansson, Tiina Laatikainen, Jari Lahti, Sarah H. Wild, Corrado Masciullo, Elisabeth Widen, Caroline Hayward, Paolo Gasparini, Gail Davies, Antti Jula, Tanguy Corre, John M. Starr, James F. Wilson, Andrew C. Heath, Veikko Salomaa, Aki S. Havulinna, Lina Zgaga, Ulf Gyllensten, Jian Yang, Lili Milani, Fernando Rivadeneira, Kati Kristiansson, Andrew A. Hicks, Leo-Pekka Lyytikäinen, Yurii S. Aulchenko, Marika Kaakinen, Mirna Kirin, Ozren Polasek, Wilmar Igl, Katri Räikkönen, Nelson B. Freimer, Mika Kähönen, Anna-Liisa Hartikainen, Evropi Theodoratou, Maris Kuningas, Flavio Faletra, Cornelia M. van Duijn, Marina Pehlić, Medical Research Council (MRC), Greg, Gibson, Ruth, Mcquillan, Niina, Eklund, Pirastu, Nicola, Maris, Kuninga, Brian P., Mcevoy, Tõnu, Esko, Tanguy, Corre, Gail, Davie, Marika, Kaakinen, Leo Pekka, Lyytikäinen, Kati, Kristiansson, Aki S., Havulinna, Martin, Gögele, Veronique, Vitart, Albert, Tenesa, Yurii, Aulchenko, Caroline, Hayward, Åsa, Johansson, Mladen, Boban, Sheila, Ulivi, Robino, Antonietta, Vesna, Boraska, Wilmar, Igl, Sarah H., Wild, Lina, Zgaga, Najaf, Amin, Evropi, Theodoratou, Ozren, Polašek, Girotto, Giorgia, Lorna M., Lopez, Cinzia, Sala, Jari, Lahti, Tiina, Laatikainen, Inga, Prokopenko, Mart, Kal, 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., Hick, Laura, Esposito, Ivana, Kolčić, Susan M., Farrington, Ben, Oostra, Tatijana, Zemunik, Harry, Campbell, Mirna, Kirin, Marina, Pehlic, Faletra, Flavio, David, Porteou, Giorgio, Pisti, 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, D'Adamo, ADAMO PIO, Nicholas D., Hastie, Ulf, Gyllensten, Alan F., Wright, Cornelia M., van Duijn, Malcolm, Dunlop, Igor, Rudan, Gasparini, Paolo, 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, Epidemiology, Clinical Genetics, Surgery, Internal Medicine, Psychiatry, Department of Surgery, Behavioural Sciences, Institute for Molecular Medicine Finland, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Medicum, Quantitative Genetics, Developmental Psychology Research Group, and Genomic Discoveries and Clinical Translation
Subjects: Male, Cancer Research, Medicin och hälsovetenskap, Genome-wide association study, Runs of Homozygosity, Medical and Health Sciences, PARENTAL CONSANGUINITY, Consanguinity, inbreeding, height, runs of homozygosity, 0302 clinical medicine, Databases, Genetic, Inbreeding depression, GENETICS & HEREDITY, Genetics (clinical), ADULT HEIGHT, Genetics, 0303 health sciences, education.field_of_study, Inbreeding Depression, HERITABILITY, Homozygote, QUANTITATIVE TRAITS, Middle Aged, ROHgen Consortium, Female, PARENTAL, Life Sciences & Biomedicine, Inbreeding, Research Article, Adult, lcsh:QH426-470, Population, Genes, Recessive, Biology, Polymorphism, Single Nucleotide, FOUNDER POPULATION, 03 medical and health sciences, Genetic Heterogeneity, Quantitative Trait, Heritable, Humans, CORONARY-HEART-DISEASE, Family, Human height, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, 0604 Genetics, Science & Technology, Human Genetics, Human Height, ta3121, BRITISH WOMENS HEART, Heritability, Genetic architecture, Body Height, lcsh:Genetics, WIDE ASSOCIATION ANALYSIS, CONSANGUINEOUS MARRIAGE, 3111 Biomedicine, 030217 neurology & neurosurgery, Population Genetics, Developmental Biology, Genome-Wide Association Study
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 (χ2 = 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., Author Summary Studies investigating the extent to which genetics influences human characteristics such as height have concentrated mainly on common variants of genes, where having one or two copies of a given variant influences the trait or risk of disease. This study explores whether a different type of genetic variant might also be important. We investigate the role of recessive genetic variants, where two identical copies of a variant are required to have an effect. By measuring genome-wide homozygosity—the phenomenon of inheriting two identical copies at a given point of the genome—in 35,000 individuals from 21 European populations, and by comparing this to individual height, we found that the more homozygous the genome, the shorter the individual. The offspring of first cousins (who have increased homozygosity) were predicted to be up to 3 cm shorter on average than the offspring of unrelated parents. Height is influenced by the combined effect of many recessive variants dispersed across the genome. This may also be true for other human characteristics and diseases, opening up a new way to understand how genetic variation influences our health.
Published: 2016
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32. Correction: Corrigendum: 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

Author: Albertine J. Oldehinkel, Tõnu Esko, Antonietta Robino, Ingrid B. Borecki, Dragana Vuckovic, Zoltán Kutalik, Douglas M. Ruderfer, Daniel I. Chasman, Daniel Taliun, Henry Völzke, Daniela Ruggiero, Kurt Lohman, Adrienne Tin, Jorma Viikari, Qiong Yang, Martin H. de Borst, Oscar H. Franco, Yongmei Liu, Giorgia Girotto, Vladan Mijatovic, Nicole Probst-Hensch, John Attia, Adamo Pio d. Adamo, Peter P. Pramstaller, Iris M. Heid, Brenda W.J.H. Penninx, Jingzhong Ding, Caroline S. Fox, Edith Hofer, Man Li, Josef Coresh, Frank B. Hu, Abbas Dehghan, Christian Fuchsberger, Albert Hofman, Evelin Mihailov, Elizabeth G. Holliday, Gerjan Navis, Yingchang Lu, Christian Gieger, Murielle Bochud, Lenore J. Launer, Jean-Charles Lambert, Vilmundur Gudnason, Eric Boerwinkle, Paul M. Ridker, Peter Vollenweider, Anna Köttgen, Tamara B. Harris, Ilja M. Nolte, Medea Imboden, Mary F. Feitosa, Ruth J. F. Loos, Simon Höllerer, Massimiliano Cocca, Nina Hutri-Kähönen, Audrey Y. Chu, Karlhans Endlich, Thomas Meitinger, Sylvia Stracke, Cornelia Huth, Reiner Biffar, Cristian Pattaro, Jie Jin Wang, Omri Gottesman, Morris A. Swertz, Shih-Jen Hwang, Marie Metzger, Albert V. Smith, Ming-Huei Chen, Yong Li, Christa Meisinger, Bernhard K. Krämer, Laura Dengler, Daniela Toniolo, Olli T. Raitakari, Rossella Sorice, Bénédicte Stengel, Åsa Johansson, Andres Metspalu, Gerard Tromp, Cinzia Sala, Konstantin Strauch, Stefan Enroth, Helena Schmidt, Sylvia E. Rosas, Vincent Chouraki, Alexander Teumer, Ulf Gyllensten, Mathias Gorski, Giorgio Pistis, Holly Kramer, Gary C. Curhan, Peter J. van der Most, Catherine Helmer, Bamidele O. Tayo, Matthias Olden, Mark McEvoy, André G. Uitterlinden, Rainer Rettig, Rodney J. Scott, Mika Kähönen, Wolfgang König, Georg Homuth, Paolo Gasparini, Sanaz Sedaghat, Matthias Nauck, Carsten A. Böger, Sheila Ulivi, Reinhold E. Schmidt, Leo-Pekka Lyytikäinen, Paul Mitchell, Thor Aspelund, Felicia Gomez, Fernando Rivadeneira, Marilyn C. Cornelis, Yasaman Saba, Gudny Eiriksdottir, Ashok Kumar, Erwin P. Bottinger, Marina Ciullo, Terho Lehtimäki, Harold Snieder, Melanie Waldenberger, Uwe Völker, and Stephen Hancock
Subjects: Genetics, Multidisciplinary, Meta-analysis, Published Erratum, MEDLINE, Genome-wide association study, Computational biology, 1000 Genomes Project, Biology, Typographical error, Spelling
Abstract: Scientific Reports 7: Article number: 45040; published online: 28 April 2017; updated: 26 May 2017 The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2017
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33. Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine

Author: Pascal Houillier, Peter Vollenweider, Olivier Devuyst, Sheila Ulivi, Murielle Bochud, Ozren Polasek, Hendrica Belge, Michela Traglia, Caroline Hayward, Paolo Gasparini, Tanguy Corre, John M. Starr, Stefania Lenarduzzi, Olivier Bonny, Sarah E. Harris, Daniela Toniolo, Eric Olinger, Natsuko Tokonami, Sonia Youhanna, Ian J. Deary, University of Zurich, Devuyst, Olivier, Corre, Tanguy, Olinger, Eric, Harris, Sarah E., Traglia, Michela, Ulivi, Sheila, Lenarduzzi, Stefania, Belge, Hendrica, Youhanna, Sonia, Tokonami, Natsuko, Bonny, Olivier, Houillier, Pascal, Polasek, Ozren, Deary, Ian J., Starr, John M., Toniolo, Daniela, Gasparini, Paolo, Vollenweider, Peter, Hayward, Caroline, and Bochud, Murielle
Subjects: 0301 basic medicine, Claudin-14, GWAS, Mg/Ca ratio, Tubular functions, Animals, Calcium, Claudins, Humans, Kidney Tubules, Magnesium, Polymorphism, Single Nucleotide, Urine, Physiology, Clinical Biochemistry, Physiology (medical), medicine.medical_specialty, Candidate gene, Urinary system, Population, Single-nucleotide polymorphism, Genome-wide association study, 610 Medicine & health, Biology, 1308 Clinical Biochemistry, 10052 Institute of Physiology, Excretion, 03 medical and health sciences, 2737 Physiology (medical), Internal medicine, Tubular function, medicine, Polymorphism, education, education.field_of_study, Animal, Kidney Tubule, nephron, GWAS, Single Nucleotide, 1314 Physiology, medicine.disease, Claudin, 030104 developmental biology, Endocrinology, 570 Life sciences, biology, Kidney stones, Human
Abstract: The nature and importance of genetic factors regulating the differential handling of Ca(2+) and Mg(2+) by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10(-12)), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg(2+) over Ca(2+) in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.
Published: 2017
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34. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author: Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., FernÃ¡ndez Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, AndrÃ© G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P
Published: 2017
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35. SOS2 and ACP1 loci identified through large-scale exome chip analysis regulate kidney development and function

Author: Jacques E. Rossouw, Aldi T. Kraja, Daniel I. Chasman, Jennifer Wessel, Paul Mitchell, Erika Salvi, Adrienne Tin, Paul M. Ridker, David J. Carey, Daniele Braga, Sharon L.R. Kardia, Wolfgang König, Medea Imboden, Antonio Lupo, Paolo Gasparini, Glenn S. Gerhard, David J. Porteous, Karlhans Endlich, Mathias Gorski, Tuomas O. Kilpeläinen, Ivan Brandslund, Jinyan Huang, Min A. Jhun, Alexander P. Reiner, Christine Meisinger, Yong Li, Karen L. Mohlke, Anne U. Jackson, Janina M. Jeff, Iris M. Heid, Gary C. Curhan, Uwe Völker, Marju Orho-Melander, Allan Linneberg, Olli T. Raitakari, Caroline S. Fox, Vilmundur Gudnason, Charlotte Glümer, Ozren Polasek, Annette Kifley, David R. Weir, Konstantin Strauch, Albert V. Smith, Archie Campbell, Annette Peters, Nicole Probst-Hensch, Lu Qi, Rebecca D. Jackson, Eric Boerwinkle, Daniela Toniolo, Laura M. Yerges-Armstrong, Ruifang Li-Gao, Ian H. De Boer, Qiong Yang, Mika Kähönen, Carsten A. Böger, Dan E. Arking, Albert W. Dreisbach, Man Li, Mary F. Feitosa, Stephen T. Turner, Afshin Parsa, Charles Kooperberg, Jennifer E. Huffman, Sanaz Sedaghat, Omri Gottesman, Fernando Rivadeneira, Marit E. Jørgensen, Joshua C. Denny, Olivier Devuyst, Giovanni Malerba, Frank Schmidt, Robert J. Carroll, Michela Traglia, Chunyu Liu, Ruth J. F. Loos, Franco Giulianini, Daniel Levy, Terho Lehtimäki, Tarunveer S. Ahluwalia, Helena Kuivaniemi, Kurt Lohman, Vladan Mijatovic, Matthias Nauck, Henry Völzke, Aiko P. J. de Vries, Torben Hansen, Wolfram Goessling, Lenore J. Launer, Frank B. Hu, Tibor Fülöp, Nathan A. Bihlmeyer, Reedik Mägi, Gerard Tromp, Yingchang Lu, Jessica D. Faul, Nora Franceschini, Lise Lotte N. Husemoen, Leo Pekka Lyytikäinen, Markku Laakso, Dennis O. Mook-Kanamori, Ronit Katz, Dinesh Velayutham, Jennifer A. Smith, Teresa Nutile, David S. Siscovick, Ulrike Peters, Jie Jin Wang, Tamara B. Harris, Christina-Alexandra Schulz, Douglas Ruderfer, Mark O. Goodarzi, Oscar H. Franco, Yongmei Liu, Cramer Christensen, Nicole Soranzo, Audrey Y. Chu, Melanie Waldenberger, Oluf Pedersen, Ingrid B. Borecki, Peter Nürnberg, D. Cusi, Abbas Dehghan, Daniel R. Witte, Niels Grarup, Christian Fuchsberger, Sheila Ulivi, Josef Coresh, Evelin Mihailov, Ashok Kumar, Jennifer Kriebel, Jennifer A. Brody, Erwin P. Bottinger, Marilyn C. Cornelis, Torsten Lauritzen, Albert Hofman, Olivia Weeks, Rainer Rettig, Lynne J. Hocking, Giovanni Gambaro, André G. Uitterlinden, Anna Köttgen, Caroline Hayward, Alexander Teumer, Tõnu Esko, Antonietta Robino, Torben Jørgensen, Bruce M. Psaty, Ursula M. Schick, Rossella Sorice, Wei Zhao, Andres Metspalu, Pamela Linksted, Olle Melander, Jette Bork-Jensen, Errol D. Crook, Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E., Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathia, Lyytikäinen, Leo-Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S., Arking, Dan E., Bihlmeyer, Nathan A., Böger, Carsten A., Carroll, Robert J., Chasman, Daniel I., Cornelis, Marilyn C., Dehghan, Abba, Faul, Jessica D., Feitosa, Mary F., Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iri, Huang, Jinyan, Imboden, Medea, Jackson, Anne U., Jeff, Janina, Jhun, Min A., Katz, Ronit, Kifley, Annette, Kilpeläinen, Tuomas O., Kumar, Ashish, Laakso, Markku, Li-Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Mägi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L., Mook-Kanamori, Dennis O., Robino, Antonietta, Ruderfer, Dougla, Salvi, Erika, Schick, Ursula M., Schulz, Christina-Alexandra, Smith, Albert V., Smith, Jennifer A., Traglia, Michela, Yerges-Armstrong, Laura M., Zhao, Wei, Goodarzi, Mark O., Kraja, Aldi T., Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bottinger, Erwin P., Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A., Campbell, Archie, Carey, David J., Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C., Cusi, Daniele, De Boer, Ian H., De Vries, Aiko P. J., Denny, Joshua C., Devuyst, Olivier, Dreisbach, Albert W., Endlich, Karlhan, Esko, Tõnu, Franco, Oscar H., Fulop, Tibor, Gerhard, Glenn S., Glümer, Charlotte, Gottesman, Omri, Grarup, Niel, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B., Husemoen, Lise Lotte N., Jackson, Rebecca D., Jørgensen, Torben, Jørgensen, Marit E., Kähönen, Mika, Kardia, Sharon L. R., König, Wolfgang, Kooperberg, Charle, Kriebel, Jennifer, Launer, Lenore J., Lauritzen, Torsten, Lehtimäki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F., Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andre, Mitchell, Paul, Nauck, Matthia, Nürnberg, Peter, Orho-Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst-Hensch, Nicole M., Psaty, Bruce M., Qi, Lu, Raitakari, Olli T., Reiner, Alex P., Rettig, Rainer, Ridker, Paul M., Rivadeneira, Fernando, Rossouw, Jacques E., Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T., Uitterlinden, André G., Ulivi, Sheila, Velayutham, Dinesh, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R., Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S., Franceschini, Nora, Goessling, Wolfram, Köttgen, Anna, Chu, Audrey Y., Epidemiology, Erasmus MC other, and Internal Medicine
Subjects: 0301 basic medicine, Nonsynonymous substitution, Nephrology, medicine.medical_specialty, human genetics, Renal function, Genome-wide association study, Single-nucleotide polymorphism, Biology, Kidney, 03 medical and health sciences, 0302 clinical medicine, kidney development, renal function, Clinical Research, Proto-Oncogene Proteins, Internal medicine, Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Protein Tyrosine Phosphatases, Son of Sevenless Proteins, Zebrafish, Journal Article, medicine, Settore MED/14 - NEFROLOGIA, human genetic, Gene, Genetic association, Genetics, Proto-Oncogene Protein, Animal, Son of Sevenless Protein, General Medicine, ta3121, 030104 developmental biology, Human Genetics, Kidney Development, Renal Function, Protein Tyrosine Phosphatase, genome, nephron, 030217 neurology & neurosurgery, Meta-Analysis, Human
Abstract: Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1
Published: 2017
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36. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author: Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. 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W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics
Subjects: Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Published: 2014
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37. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. 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Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. 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Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.
Subjects: 0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
Published: 2016
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38. Genome-wide association study identifies 74 loci associated with educational attainment

Author: K. Petrovic, Massimo Mangino, Daniele Cusi, Ozren Polasek, Rodney J. Scott, Yong Qian, Aysu Okbay, Jari Lahti, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Thomas Meitinger, Frank J. A. van Rooij, Mika Kähönen, Martin Kroh, Ian J. Deary, Neil Pendleton, Pamela A. F. Madden, David J. Porteous, Lambertus A. Kiemeney, Sven Oskarsson, Edith Hofer, Robert F. Krueger, Olga Rostapshova, Georg Homuth, Paolo Gasparini, Aldo Rustichini, Sarah E. Medland, Christian Gieger, Veronique Vitart, Nicholas J. Timpson, George Dedoussis, Joseph K. Pickrell, Christopher Oldmeadow, Aldi T. Kraja, Johan G. Eriksson, Lydia Quaye, William G. Iacono, Danielle Posthuma, George Davey Smith, Karl-Oskar Lindgren, David C. Liewald, Pim van der Harst, Börge Schmidt, Christine Power, Francesco P. Cappuccio, Francesco Cucca, Simona Vaccargiu, Joyce Y. Tung, Aarno Palotie, Natalia Pervjakova, Jonas Bacelis, Jouke-Jan Hottenga, Helena Schmidt, Kari Stefansson, Tamara B. Harris, Momoko Horikoshi, Lude Franke, Wolfgang Hoffmann, Ingrid B. Borecki, William E R Ollier, Johannes Waage, Andreas J. Forstner, Caroline Hayward, Penelope A. Lind, Patricia A. Boyle, Kadri Kaasik, Jian Yang, Gerardus A. Meddens, Antti Latvala, John Attia, Pascal Timshel, Vilmundur Gudnason, Maël Lebreton, Valur Emilsson, James F. Wilson, Jonathan Marten, Ute Bültmann, Erika Salvi, Olli T. Raitakari, Peter M. Visscher, Niek Verweij, Elisabeth Steinhagen-Thiessen, Cristina Venturini, Lili Milani, Tessel E. Galesloot, Kevin Thom, Klaus Berger, Paul Lichtenstein, Tian Liu, Philipp Koellinger, Riccardo E. Marioni, Marjo-Riitta Järvelin, Clemens Baumbach, Unnur Thorsteinsdottir, Magnus Johannesson, Susan M. Ring, David A. Bennett, Anu Loukola, Hans-Jörgen Grabe, Jan A. Staessen, Igor Rudan, Ginevra Biino, Nicholas G. Martin, Jingyun Yang, Anna A. E. Vinkhuyzen, Katri Räikkönen, Zhihong Zhu, Gudmar Thorleifsson, Mary F. Feitosa, Ivana Kolcic, Alexander Teumer, Jaakko Kaprio, David Schlessinger, Katharina E. Schraut, Konstantin Strauch, Ilja Demuth, Albert V. Smith, Juergen Wellmann, Jennifer E. Huffman, Panos Deloukas, Mario Pirastu, Reedik Mägi, Maria Pina Concas, Jaime Derringer, Patrick J. F. Groenen, Henry Völzke, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Nicholas A. Furlotte, Christopher P. Nelson, Barbara Franke, Steven F. Lehrer, Patrick Turley, Tõnu Esko, Jun Ding, Pedro Marques-Vidal, S. Fleur W. Meddens, Zoltán Kutalik, Gonneke Willemsen, Andrew C. Heath, Michelle N. Meyer, James J. Lee, Roy Thurik, Antonietta Robino, Henning Tiemeier, Grant W. Montgomery, C. deLeeuw, Astanand Jugessur, Antti-Pekka Sarin, Veikko Salomaa, Dalton Conley, Tim D. Spector, Sebastian E. Baumeister, Gyda Bjornsdottir, Lavinia Paternoster, Tune H. Pers, Jacob Gratten, Martin D. Tobin, Daniel J. Benjamin, Douglas F. Levinson, Stavroula Kanoni, Elina Hyppönen, David R. Weir, Peter J. van der Most, Terho Lehtimäki, David A. Hinds, Pablo V. Gejman, Uwe Völker, Cornelia M. van Duijn, Karl-Heinz Jöckel, Bjarni V. Halldorsson, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, David Cesarini, Michael A. Province, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Nilesh J. Samani, Sven J. van der Lee, Dorret I. Boomsma, Harry Campbell, Peter Vollenweider, Liisa Keltigangas-Jarvinen, David Laibson, Ronald de Vlaming, Lynne J. Hocking, Christopher F. Chabris, Blair H. Smith, Gail Davies, Niina Eklund, Ioanna P. Kalafati, Bo Jacobsson, Sheila Ulivi, Alan F. Wright, Sarah E. Harris, Mark Alan Fontana, Diego Vozzi, Tomi Mäki-Opas, Albert Hofman, Hans Bisgaard, Andrew Bakshi, Marika Kaakinen, Johannes H. Brandsma, Christa Meisinger, Ilaria Gandin, Tarunveer S. Ahluwalia, Jennifer A. Smith, Beate St Pourcain, Rico Rueedi, Lewin Eisele, Michael B. Miller, Brenda W.J.H. Penninx, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Cornelius A. Rietveld, Peter Lichtner, Dragana Vuckovic, Giorgia Girotto, Behrooz Z. Alizadeh, Reinhold Schmidt, Raymond A. Poot, Judith M. Vonk, Antony Payton, Wouter J. Peyrot, Augustine Kong, Y. Milaneschi, Jessica D. Faul, Patrik K. E. Magnusson, Antonio Terracciano, David M. Evans, Sharon L.R. Kardia, Peter K. Joshi, Michael A. Horan, Matt McGue, Richa Gupta, Jonathan P. Beauchamp, Peter Eibich, Erin B. Ware, Lars Bertram, Philip L. De Jager, Nancy L. Pedersen, Ronny Myhre, Guo-Bo Chen, Harm-Jan Westra, Jan-Emmanuel De Neve, Evelin Mihailov, Leanne M. Hall, Seppo Koskinen, Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Helmholtz-Zentrum München (HZM), University of Queensland [Brisbane], Erasmus University Rotterdam, Universidad de Navarra [Pamplona] (UNAV), National Institute for Health and Welfare [Helsinki], 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, Consiglio Nazionale delle Ricerche (CNR), Montpellier Research in Management (MRM), Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), University of Bristol [Bristol], Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], Medical University Graz, Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), King‘s College London, Tampere University Hospital, University of Turku, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Edinburgh, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Imperial College London, Reykjavík University, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Karolinska Institutet [Stockholm], Department of Health Sciences [Leicester], University of Leicester, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical Epidemiology and Biostatistics (MEB), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Florida State University [Tallahassee] (FSU), IT University of Copenhagen, University of Helsinki-University of Helsinki, Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Faculteit Economie en Bedrijfskunde, Microeconomics (ASE, FEB), LifeLines Cohort Study, Alizadeh, BZ., de Boer, RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw, MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Applied Economics, Cell biology, Epidemiology, Erasmus MC other, Econometrics, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, EMGO+ - Mental Health, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Okbay, Aysu, Beauchamp, Jonathan P., Fontana, Mark Alan, Lee, James J., Pers, Tune H., Rietveld, Cornelius A., Turley, Patrick, Chen, Guo Bo, Emilsson, Valur, Meddens, S. Fleur W., Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, De Vlaming, Ronald, Abdellaoui, Abdel, Ahluwalia, Tarunveer S., Bacelis, Jona, Baumbach, Clemen, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, MARIA PINA, Derringer, Jaime, Furlotte, Nicholas A., Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Van Der Lee, Sven J., Deleeuw, Christiaan, Lind, Penelope A., Lindgren, Karl Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Van Der Most, Peter J., Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J., Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klau, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan Emmanuel, Deloukas, Pano, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Holliday, Elizabeth G., Heath, Andrew C., Hocking, Lynne J., Homuth, Georg, Horan, Michael A., Hottenga, Jouke Jan, De Jager, Philip L., Joshi, Peter K., Jugessur, Astanand, Kaakinen, Marika A., Kähönen, Mika, Kanoni, Stavroula, Keltigangas Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Kutalik, Zoltan, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki Opas, Tomi, Marioni, Riccardo E., Marques Vidal, Pedro, Meddens, Gerardus A., Mcmahon, George, Meisinger, Christa, Meitinger, Thoma, Milaneschi, Yusplitri, Milani, Lili, Montgomery, Grant W., Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Raïkkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Van Rooij, Frank J. A., Venturini, Cristina, Vinkhuyzen, Anna A. E., Völker, Uwe, Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Boomsma, Dorret I., Borecki, Ingrid B., Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Van Duijn, Cornelia M., Eriksson, Johan G., Franke, Barbara, Franke, Lude, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Van Der Harst, Pim, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo Riitta, Jöckel, Karl Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehtimäki, Terho, Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Metspalu, Andre, Pendleton, Neil, Penninx, Brenda W. J. H., Perola, Marku, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Tung, Joyce Y., Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Davey Smith, George, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Yang, Jian, Johannesson, Magnu, Visscher, Peter M., Esko, Toñu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., EMGO - Mental health, IOO, Human genetics, Beauchamp, Jonathan P, Lee, James JJ, Hypponen, Elina, and Benjamin, Daniel J
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Candidate gene, Bipolar Disorder, Medizin, Genome-wide association study, Genome-wide association studies, 0302 clinical medicine, Cognition, Alzheimer Disease, Brain, Computational Biology, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Great Britain, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia, Educational Status, Genome-Wide Association Study, Medicine (all), Multidisciplinary, Fetu, tau, Gene–environment interaction, Soziales und Gesundheit, Genetics, [QFIN]Quantitative Finance [q-fin], HERITABILITY, General Commentary, Alzheimer's disease, Biobank, Phenotype, Multidisciplinary Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], educational attainment, Behavioural genetics, Science & Technology - Other Topics, Bildungsniveau, TRAITS, Human, General Science & Technology, Kultursektor, SNP, ta3111, Polymorphism, Single Nucleotide, Learning and memory, Alzheimer Disease/genetics, Bipolar Disorder/genetics, Brain/metabolism, Fetus/metabolism, Gene Expression Regulation/genetics, Polymorphism, Single Nucleotide/genetics, Schizophrenia/genetics, 03 medical and health sciences, ACHIEVEMENT, MD Multidisciplinary, Non-Profit-Sektor, QH426, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], tauopathies, Data Science, gene, education, school, Heritability, Educational Statu, Educational attainment, United Kingdom, 030104 developmental biology, IQ, Genetische Forschung, Psychiatric disorders, Bildung, 030217 neurology & neurosurgery, LifeLines Cohort Study, Neuroscience
Abstract: Contains fulltext : 167137.pdf (Publisher’s version ) (Closed access) Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
Published: 2016
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39. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Author: W. H. Linda Kao, Nicole Probst-Hensch, Florian Ernst, Paul Mitchell, Christa Meisinger, Florian Kronenberg, Sharon L.R. Kardia, Paul M. Ridker, Vilmundur Gudnason, Jeanette S. Andrews, Ming-Huei Chen, Frank B. Hu, Jean-Charles Lambert, Mario Pirastu, Ozren Polasek, Xiaoyi Gao, Sven Bergmann, Catherine Helmer, Wilmar Igl, Jie Jin Wang, Barry I. Freedman, Anke Tönjes, Jacqueline C. M. Witteman, Sheila Ulivi, Conall M. O'Seaghdha, Mika Kähönen, Mariza de Andrade, Daniel I. Chasman, Meredith C. Foster, Rossella Sorice, Mathias Gorski, Eric Boerwinkle, Karlhans Endlich, Maksim Struchalin, Bernhard K. Krämer, Bénédicte Stengel, Caroline Hayward, Giorgio Pistis, Andres Metspalu, Peter Kovacs, Jorma Viikari, Guo Li, Cristian Pattaro, Adrienne Tin, Igor Rudan, Christian Gieger, Mary F. Feitosa, Stephen T. Turner, Gary C. Curhan, Shamika Ketkar, Ian Ford, Peter Vollenweider, Wolfgang Koenig, Madhumathi Rao, Iris M. Heid, Stuart K. Kim, Heather E. Wheeler, Matthias Olden, Hinco J. Gierman, Alex S. F. Doney, Lenore J. Launer, Mladen Boban, Georg Homuth, Paolo Gasparini, Harshal Deshmukh, Henry Völzke, Daniela Ruggiero, Medea Imboden, Elizabeth J. Atkinson, Ben A. Oostra, Stefan Coassin, Ute Nöthlings, Marilyn C. Cornelis, David S. Siscovick, Yongmei Liu, Gian Andri Thun, Gunnar Jacobs, Franco Giulianini, Uwe Völker, Tõnu Esko, Alexander Teumer, Jeffrey R. O'Connell, Brendan M. Buckley, Heyo K. Kroemer, Albert V. Smith, Ulf Gyllensten, Federico Murgia, Man Li, Harry Campbell, Antonietta Robino, Abbas Dehghan, Inga Prokopenko, Shih-Jen Hwang, Sylvia Stracke, Michael Stumvoll, Alan R. Shuldiner, Christian Fuchsberger, Claudia Hundertmark, Luigi Ferrucci, David Ellinghaus, Laura Portas, Caroline S. Fox, Afshin Parsa, Carsten A. Böger, Toshiko Tanaka, Terho Lehtimäki, Ayse Demirkan, James F. Wilson, Elizabeth G. Holliday, Yurii S. Aulchenko, Murielle Bochud, Helen M. Colhoun, Jingzhong Ding, Nicole L. Glazer, Rainer Rettig, Bernhard Paulweber, Margherita Cavalieri, Andre Franke, Ingrid B. Borecki, Olli T. Raitakari, Josef Coresh, Tamara B. Harris, Sarah H. Wild, Reinhold Schmidt, Ching-Ti Liu, Zoltán Kutalik, André G. Uitterlinden, J. Wouter Jukema, Helena Schmidt, Martin Adam, Audrey Y. Chu, Fernando Rivadeneira, Cornelia M. van Duijn, Braxton D. Mitchell, Gudny Eiriksdottir, Tatijana Zemunik, Andrew D. Johnson, Ghazal Zaboli, Reiner Biffar, Thor Aspelund, Cinzia Sala, Peter P. Pramstaller, Veronique Vitart, Michael A. Province, Anna Köttgen, Nicholas D. Hastie, Daniel Taliun, Marina Ciullo, Cosetta Minelli, Kurt Lohman, Matthias Nauck, Thomas Illig, Alan F. Wright, Albert Hofman, Colin N. A. Palmer, Daniela Toniolo, Qiong Yang, Lina Zgaga, Åsa Johansson, Margot Haun, Stella Trompet, Aaron Isaacs, Reedik Mägi, Tiit Nikopensius, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Internal Medicine, Chasman, Di, Fuchsberger, C, Pattaro, C, Teumer, A, Böger, Ca, Endlich, K, Olden, M, Chen, Mh, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, Mc, O'Seaghdha, Cm, Glazer, N, Isaacs, A, Liu, Ct, Smith, Av, O'Connell, Jr, Struchalin, M, Tanaka, T, Li, G, Johnson, Ad, Gierman, Hj, Feitosa, Mf, Hwang, Sj, Atkinson, Ej, Lohman, K, Cornelis, Mc, Johansson, A, Tönjes, A, Dehghan, A, Lambert, Jc, Holliday, Eg, Sorice, R, Kutalik, Z, Lehtimäki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, Ay, Murgia, F, Trompet, S, Imboden, M, Coassin, S, Pistis, G, Cardiogram, Consortium, Icbp, Consortium, the CARe, Consortium, Wtccc2, Harris, Tb, Launer, Lj, Aspelund, T, Eiriksdottir, G, Mitchell, Bd, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, F, Demirkan, A, Oostra, Ba, de Andrade, M, Turner, St, Ding, J, Andrews, J, Freedman, Bi, Giulianini, F, Koenig, W, Illig, T, Meisinger, C, Gieger, C, Zgaga, L, Zemunik, T, Boban, M, Minelli, C, Wheeler, He, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Ernst, F, Homuth, G, Kroemer, Hk, Nauck, M, Stracke, S, Völker, U, Völzke, H, Kovacs, P, Stumvoll, M, Mägi, R, Hofman, A, Uitterlinden, Ag, Rivadeneira, F, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, Jj, Stengel, B, Ruggiero, D, Bergmann, S, Kähönen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, Antonietta, Krämer, Bk, Portas, L, Ford, I, Buckley, Bm, Adam, M, Thun, Ga, Paulweber, B, Haun, M, Sala, C, Mitchell, P, Ciullo, M, Kim, Sk, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, Paolo, Pirastu, M, Jukema, Jw, Probst Hensch, Nm, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, D, van Duijn, Cm, Borecki, Ib, Kardia, Sl, Liu, Y, Curhan, Gc, Rudan, I, Gyllensten, U, Wilson, Jf, Franke, A, Pramstaller, Pp, Rettig, R, Prokopenko, I, Witteman, J, Hayward, C, Ridker, Pm, Parsa, A, Bochud, M, Heid, Im, Kao, Wl, Fox, C, and Köttgen, A.
Subjects: Candidate gene, Amino Acid Transport Systems, Basic/genetics, Genome-wide association study, Gene, Genome, Inhibin-beta Subunits/genetics, GWAS, kidney, eGFR, Genetics (clinical), Inhibin-beta Subunits, Glomerular Filtration Rate/genetics, Genetics, 0303 health sciences, Genetic Predisposition to Disease/genetics, Association Studies Articles, 030305 genetics & heredity, Intracellular Signaling Peptides and Proteins, General Medicine, Low Density Lipoprotein Receptor-Related Protein-2/genetics, Polymorphism, Single Nucleotide/genetics, LRP2, 3. Good health, Low Density Lipoprotein Receptor-Related Protein-2, Genome-Wide Association Study/methods, Single Nucleotide/genetics, Glomerular Filtration Rate, Fusion Regulatory Protein 1, Heavy Chain, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome-Wide Association Studies, Humans, SNP, Genetic Predisposition to Disease, ddc:610, Membrane Proteins/genetics, Polymorphism, Molecular Biology, 030304 developmental biology, Genetic association, Fusion Regulatory Protein 1, Heavy Chain/genetics, Fusion Regulatory Protein 1, Genes, Kidney Function, Membrane Proteins, ta3121, Amino Acid Transport Systems, Basic, Amino Acid Transport Systems, Basic/genetics, Heavy Chain/genetics, Intracellular Signaling Peptides and Proteins/genetics, Candidate Disease Gene, Genome-Wide Association Study
Abstract: In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Published: 2012

40. Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population

Author: Teresa Nutile, Paolo Gasparini, Silvia Bione, Pio D'Adamo, Daniela Toniolo, Rossella Sorice, Cinzia Sala, Serena Sansanelli, Emmanouil Athanasakis, Clara Camaschella, Carmela Lanzara, Marina Ciullo, Sheila Ulivi, R., Sorice, S., Bione, S., Sansanelli, S., Ulivi, Athanasakis, Emmanouil, C., Lanzara, T., Nutile, C., Sala, C., Camaschella, D'Adamo, ADAMO PIO, Gasparini, Paolo, M., Ciullo, D., Toniolo, Sorice, R, Bione, S, Sansanelli, S, Ulivi, S, Athanasakis, E, Lanzara, C, Nutile, T, Sala, C, Camaschella, Clara, D'Adamo, P, Gasparini, P, Ciullo, M, and Toniolo, D.
Subjects: Population, Short Report, Nerve Tissue Proteins, Single-nucleotide polymorphism, Genome-wide association study, Receptors, Nicotinic, Biology, Nicotinic, Polymorphism, Single Nucleotide, Polymorphism (computer science), Receptors, Genetics, Humans, SNP, Genetic Predisposition to Disease, Polymorphism, education, Genetics (clinical), Genetic association, genetic [Nicotinic], education.field_of_study, Genome-Wide Association Study, Italy, Multigene Family, Nerve Tissue Proteins: genetics, Nicotinic: genetics, Single Nucleotide, Smoking, Smoking: genetics, Tobacco Use Disorder, Tobacco Use Disorder: genetics, genetic [Smoking], genetic [Nerve Tissue Proteins], Nerve Tissue Protein, Genetic structure, genetics [Tobacco Use Disorder], Genetic isolate, Human, Receptor
Abstract: Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region.European Journal of Human Genetics advance online publication, 19 January 2011; doi:10.1038/ejhg.2010.240.
Published: 2011
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41. Metabonomics and population studies: age-related amino acids excretion and inferring networks through the study of urine samples in two Italian isolated populations

Author: Uros Hladnik, Sheila Ulivi, Manuel Palacín, Giovambattista Capasso, Gilberto Andrighetto, Virginia Nunes, Paolo Gasparini, Amerigo Beneduci, G. Pontoni, Carmela Lanzara, Pio D'Adamo, D'Adamo, P., Ulivi, S., Beneduci, A., Pontoni, G., Capasso, Giovambattista, Lanzara, C., Andrighetto, G., Hladnik, U., Nunes, V., Palacin, M., Gasperini, P., D'Adamo, ADAMO PIO, S., Ulivi, A., Beneduci, G., Pontoni, G., Capasso, C., Lanzara, G., Andrighetto, U., Hladnik, V., Nune, M., Palacin, and Gasparini, Paolo
Subjects: Male, Rural Population, Adolescent, Adult, Age Factors, Aged, Amino Acids, Amino Acids: chemistry, Amino Acids: urine, Child, Female, Humans, Italy, Metabolomics, Middle Aged, Population Groups, Preschool, Young Adult, Clinical Biochemistry, Urine, Biochemistry, chemistry.chemical_compound, Age Factor, chemistry.chemical_classification, education.field_of_study, Amino acid, Amino Acid, Child, Preschool, Population studie, urine [Amino Acids], Tubular handling, Human, Population Group, medicine.medical_specialty, Population, Metabolomic, Biology, Excretion, Internal medicine, Mole, Metabonomic, medicine, education, Creatinine, chemistry [Amino Acids], Organic Chemistry, Endocrinology, chemistry, Nucleic acid
Abstract: The study of two different Italian isolated populations was combined with a metabonomic approach to better understand tubular handling of amino acids. Levels of amino acids and metabolites have been analyzed by Nucleic Magnetic Resonance and expressed as ratio vs urinary creatinine concentration (mmol/mol). For most of the amino acids there is an age-related U shape pattern of excretion, with the peaks during childhood and old age, and a significant reduction in the adult age. Hierarchical cluster analysis has clearly identified three groups clustering the same amino acids: His, Thr and Ala (group one); Gly and Phe (group two) and a third larger one. Results have been further confirmed by factor and regression analysis, and used to confirm and, in some cases, infer new amino acids networks. As a matter of facts, the identification of strong evidences for clustering of urine excretion of several neutral amino acids suggests the predominant impact of relevant and common transporters.
Published: 2008
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42. Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism

Author: Gabriele Baj, Sheila Ulivi, Stefania Cappellani, Pio D'Adamo, Ruggiero Francavilla, Davide Carlino, Enrico Tongiorgi, Paolo Gasparini, Karolina Kulak, Carlino, Davide, Francavilla, Ruggiero, Baj, Gabriele, Kulak, Karolina, D'Adamo, ADAMO PIO, Ulivi, Sheila, Cappellani, Stefania, Gasparini, Paolo, and Tongiorgi, Enrico
Subjects: Genetics and Molecular Biology (all), Genome wide analysi, lcsh:Medicine, Psychiatry and Psychology, Anxiety, Serum biomarker, Global Health, Biochemistry, Specific phobia, Generalized anxiety disorder, Neurotrophic factors, education.field_of_study, General Neuroscience, Medicine (all), Genomics, General Medicine, Val66Met polymorphism, Neurotrophin, Sex factors, medicine.symptom, General Agricultural and Biological Sciences, Medical Genetics, Anxiety disorder, medicine.medical_specialty, Sex factor, Population, Genome wide analysis, Neurotrophins, General Biochemistry, Genetics and Molecular Biology, Brain-derived neurotrophic factor, Serum biomarkers, Social phobia, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Neuroscience (all), Internal medicine, medicine, Psychiatry, education, business.industry, Panic disorder, lcsh:R, medicine.disease, Endocrinology, business, Neuroscience
Abstract: Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.
Published: 2015

43. Purging of deleterious variants due to drift and founder effect in Italian populations with extended autozygosity

Author: Massimiliano Cocca, Marc Pybus, Pier Francesco Palamara, Erik Garrison, Michela Traglia, Cinzia F Sala, Sheila Ulivi, Yasin Memari, Anja Kolb-Kokocinski, Shane McCarthy, Richard Durbin, Paolo Gasparini, Daniela Toniolo, Nicole Soranzo, and Vincenza Colonna
Subjects: Genetics, 0303 health sciences, 03 medical and health sciences, Natural selection, 030305 genetics & heredity, Genotype, Consanguinity, 1000 Genomes Project, Biology, Inbreeding, Consanguineous Marriage, 030304 developmental biology, Deleterious alleles
Abstract: Purging through inbreeding occurs when consanguineous marriages increases the rate at which deleterious alleles are present in a homozygous state. In this study we carried out low-read depth (4-10x) whole-genome sequencing in 568 individuals from three Italian founder populations, and compared it to data from other Italian and European populations from the 1000 Genomes Project. We show extended consanguinity and depletion of homozygous genotypes at potentially detrimental sites in the founder populations compared to outbred populations. However these patterns are not compatible with the hypothesis of consanguinity driving the purging of highly deleterious mutations according to simulations. Therefore we conclude that genetic drift and the founder effect should be responsible for the observed purging of deleterious variants.
Published: 2015
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44. Age- And Sex-Related Variations in Platelet Count in Italy: A Proposal of Reference Ranges Based on 40987 Subjects' Data

Author: Kathleen, Freson, Ginevra, Biino, Iolanda, Santimone, Cosetta, Minelli, Rossella, Sorice, Bruno, Frongia, Traglia, Michela, Sheila, Ulivi, Augusto Di Castelnuovo, Martin, Gögele, Teresa, Nutile, Marcella, Francavilla, Cinzia, Sala, Pirastu, Nicola, Chiara, Cerletti, Licia, Iacoviello, Gasparini, Paolo, Daniela, Toniolo, Marina, Ciullo, Peter, Pramstaller, Mario, Pirastu, Giovanni de Gaetano, Balduini, Carlo L., Kathleen, Freson, Ginevra, Biino, Iolanda, Santimone, Cosetta, Minelli, Rossella, Sorice, Bruno, Frongia, Traglia, Michela, Sheila, Ulivi, Augusto Di, Castelnuovo, Martin, Gögele, Teresa, Nutile, Marcella, Francavilla, Cinzia, Sala, Pirastu, Nicola, Chiara, Cerletti, Licia, Iacoviello, Gasparini, Paolo, Daniela, Toniolo, Marina, Ciullo, Peter, Pramstaller, Mario, Pirastu, Giovanni de, Gaetano, and Carlo L., Balduini
Subjects: Male, Blood Platelets, epidemiology, reference ranges, Health Screening, Percentile, Pediatrics, Hematologic Cancers and Related Disorders, Adult women, Reference Values, Epidemiology, Medicine, Platelet, Child, Aged, 80 and over, Thrombocytosis, education.field_of_study, Multidisciplinary, Age Factors, Hematology, Middle Aged, Italy, Child, Preschool, Observational Studies, Female, Public Health, Research Article, Platelets, Adult, medicine.medical_specialty, Adolescent, Clinical Research Design, General Science & Technology, Science, European Continental Ancestry Group, Population, Age and sex, White People, Sex Factors, Diagnostic Medicine, MD Multidisciplinary, Humans, education, Aged, Myeloproliferative Disorders, Platelet Count, business.industry, Infant, Newborn, Infant, medicine.disease, Thrombocytopenia, Reference intervals, Blood Platelet, business
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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45. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author: Lynne J. Hocking, Caterina Barbieri, Jenny Chang-Claude, David Karasik, Dieter Flesch-Janys, James F. Wilson, Mark S. Goldberg, Henry Voelzke, Archie Campbell, Stig E. Bojesen, David R. Weir, Ailith Pirie, Megan L. Grove, Melissa Wellons, Georg Homuth, Corrado Masciullo, Jennifer A. Brody, Hermann Brenner, Paolo Gasparini, Andrew D. Johnson, Patrick Neven, Graham G. Giles, Peter Kraft, André G. Uitterlinden, Wei Zheng, Alkes L. Price, Anja Rudolph, Arto Mannermaa, Nicholas G. Martin, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Daniela Ruggiero, Toshiko Tanaka, Kathryn L. Lunetta, Julie E. Buring, John R. B. Perry, Robert Winqvist, Laufey Tryggvadottir, Angela Cox, Serena Sanna, Nicola Pirastu, Anna Jakubowska, Paul D.P. Pharoah, David J. Porteous, Dragana Vuckovic, Andrea D. Coviello, Giorgia Girotto, Sara Lindstroem, Patrick Sulem, Astrid Petersmann, Xin Li, Maartje J. Hooning, Lili Milani, Sven Bergmann, Marek Zygmunt, Javier Benitez, Vilmundur Gudnason, Fernando Rivadeneira, Volker Arndt, Marina Ciullo, Caroline Hayward, Sheila Ulivi, Janet E. Olson, Hoda Anton-Culver, Maria Kabisch, Sara Margolin, Vessela N. Kristensen, Patrick F. McArdle, Tanguy Corre, Nora Franceschini, Veli-Matti Kosma, Hiltrud Brauch, Roger L. Milne, Eric Boerwinkle, Matthias W. Beckmann, Charles Kooperberg, Qin Wang, Jessica D. Faul, Stephen J. Chanock, Alexander Teumer, Mark O. Goodarzi, Unnur Thorsteinsdottir, R Maegi, Paul M. Ridker, Antonis C. Antoniou, Ozren Polasek, Daniel F. Gudbjartsson, Barbara McKnight, Melissa E. Garcia, Manjeet K. Bolla, Alanna C. Morrison, Paolo Radice, Xiuqing Guo, Lude L. Franke, Michela Traglia, Marjanka K. Schmidt, Heli Nevanlinna, Teresa Nutile, Cinzia Sala, Pascal Guénel, Jennifer E. Huffman, Stephen T. Turner, Anna Murray, Carl Blomqvist, Margaux F. Keller, Samuel E. Jones, Montserrat Garcia-Closas, Ivana Kolcic, Anne B. Newman, Jan Lubinski, Albert Hofman, Isabel dos-Santos-Silva, Hilary K. Finucane, Anne Lise Børresen-Dale, Alexander P. Reiner, Tim D. Spector, Gonneke Willemsen, John D. Eicher, Douglas F. Easton, Claudia Langenberg, Anthony J. Swerdlow, Natalia Bogdanova, Alison M. Dunning, Giorgio Pistis, Tõnu Esko, Behrooz Z. Alizadeh, Martina Mueller-Nurasyid, Eleonora Porcu, Laura M. Yerges-Armstrong, Leslie J. Raffel, Laura Crisponi, Gonçalo R. Abecasis, Jerome I. Rotter, Yii-Der Ida Chen, Antonietta Robino, Katri Pylkaes, Ken K. Ong, Thibaud Boutin, Elinor J. Sawyer, Daniel I. Chasman, Brian E. Henderson, Frank B. Hu, Leslie Bernstein, Drakoulis Yannoukakos, Tamara B. Harris, Dorret I. Boomsma, Katherine S. Ruth, Jie Yao, Keith Humphreys, Jennifer A. Smith, Elisabeth Altmaier, Ulrike Peters, Doris Stoeckl, Eva Albrecht, Tatijana Zemunik, Jenny A. Visser, Minouk J. Schoemaker, Diego Vozzi, Thilo Doerk, J. Ross Chapman, Irene L. Andrulis, Joanne M. Murabito, Alan F. Wright, Lisette Stolk, Jonathan Marten, Alice M. Arnold, Paolo Peterlongo, Harry Campbell, Natalia Pervjakova, Jingmei Li, Jennifer Kriebel, Alicia Beeghly-Fadiel, Immaculata De Vivo, Jouke-Jan Hottenga, Kari Stefansson, Cornelia M. van Duijn, Brendan Bulik-Sullivan, Evelin Mihailov, Chunyan He, Joe Dennis, Nicholas J. Wareham, Yongmei Liu, Sharon L.R. Kardia, Lynda M. Rose, Felix R. Day, Georgia Chenevix-Trench, Albert V. Smith, David J. Hunter, Sandosh Padmanabhan, Christian Gieger, Konstantin Strauch, Igor Rudan, Jacques Simard, Jian'an Luan, Robert A. Scott, Kyriaki Michailidou, Bruce M. Psaty, Per Hall, Suzette J. Bielinski, Rita K. Schmutzler, Julian Peto, Ellen W. Demerath, Ursula M. Schick, Rossella Sorice, Wei Zhao, Børge G. Nordestgaard, Andres Metspalu, Jonine D. Figueroa, Julia A. Knight, Barbara Burwinkel, Thomas Bruening, Judith Manz, Anna González-Neira, Ilaria Gandin, Ian Tomlinson, Thérèse Truong, Kent D. Taylor, Amanda E. Toland, Deborah J. Thompson, Alfons Meindl, Caroline M. Seynaeve, Benjamin M. Neale, Fergus J. Couch, Mike A. Nalls, Ute Hamann, Kamila Czene, John L. Hopper, Bruce H. R. Wolffenbuttel, Grant W. Montgomery, Hatef Darabi, Daniela Toniolo, Jinyan Huang, Peter Devilee, Cathy E. Elks, David Schlessinger, Luigi Ferrucci, Frank Schmidt, Peter A. Fasching, Diether Lambrechts, Najaf Amin, Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, Mcardle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Gonçalo R, Andrulis, Irene L, Anton Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, CATERINA MARIA, Beckmann, Matthias W, Beeghly Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen Dale, Anne Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thoma, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J. Ro, Chen, Yii Der Ida, Chenevix Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos Santos Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García Closas, Montserrat, Giles, Graham G, Girotto, Giorgia, Goldberg, Mark S, González Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, Hamann, Ute, Henderson, Brian E, Hocking, Lynne J, Hofman, Albert, Homuth, Georg, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Huang, Jinyan, Humphreys, Keith, Hunter, David J, Jakubowska, Anna, Jones, Samuel E, Kabisch, Maria, Karasik, David, Knight, Julia A, Kolcic, Ivana, Kooperberg, Charle, Kosma, Veli Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindström, Sara, Liu, Yongmei, Luan, Jian'An, Lubinski, Jan, Mägi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G, Masciullo, Corrado, Meindl, Alfon, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Müller Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M, Nevanlinna, Heli, Neven, Patrick, Newman, Anne B, Nordestgaard, Børge G, Olson, Janet E, Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P, Pirastu, Nicola, Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M, Pylkäs, Katri, Radice, Paolo, Raffel, Leslie J, Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F, Sanna, Serena, Sawyer, Elinor J, Schlessinger, David, Schmidt, Marjanka K, Schmidt, Frank, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Robert A, Seynaeve, Caroline M, Simard, Jacque, Sorice, Rossella, Southey, Melissa C, Stöckl, Dori, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D, Thorsteinsdottir, Unnur, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Tryggvadottir, Laufey, Turner, Stephen T, Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F, Winqvist, Robert, Wolffenbuttel, Bruce B. H. R, Wright, Alan F, Yannoukakos, Drakouli, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I, Buring, Julie E, Ferrucci, Luigi, Montgomery, Grant W, Gudnason, Vilmundur, Spector, Tim D, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Ciullo, Marina, Crisponi, Laura, Easton, Douglas F, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Hayward, Caroline, Kardia, Sharon L. R, Kraft, Peter, Mcknight, Barbara, Metspalu, Andre, Morrison, Alanna C, Reiner, Alex P, Ridker, Paul M, Rotter, Jerome I, Toniolo, Daniela, Uitterlinden, André G, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Weir, David R, Yerges Armstrong, Laura M, Price, Alkes L, Stefansson, Kari, Visser, Jenny A, Ong, Ken K, Chang Claude, Jenny, Murabito, Joanne M, Perry, John R. B, Murray, Anna, Internal Medicine, Epidemiology, Medical Oncology, Clinical Genetics, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, PRACTICAL Consortium, kConFab Investigators, AOCS Investigators, EPIC-InterAct Consortium, LifeLines Cohort Study, Generation, Scotland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: Netherlands Twin Register (NTR), Aging, DNA Repair, LOCI, Genome-wide association study, BLOOD-PRESSURE, Disease, CHROMOSOMAL INSTABILITY, Bioinformatics, HOMOLOGOUS RECOMBINATION, PREMATURE OVARIAN FAILURE, Genotype, BRCA2 MUTATION CARRIERS, WIDE ASSOCIATION, Gene Regulatory Networks, NATURAL MENOPAUSE, Genetics, education.field_of_study, menopause, DDR, BODY-MASS INDEX, CELL-TYPES, BRCA1 Protein, Reproduction, BRCA1-mediated DNA repair, Age Factors, Obstetrics and Gynecology, General Medicine, Genomics, Middle Aged, 3. Good health, Menopause, Phenotype, Female, medicine.symptom, Signal Transduction, Delayed puberty, Adult, DNA repair, Population, Hypothalamus, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Lower risk, DDR, Article, Breast cancer, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Genetic association, Models, Genetic, business.industry, Genetic Variation, medicine.disease, Aging/genetics, BRCA1 Protein/genetics, Breast Neoplasms/genetics, Gene Regulatory Networks/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genomics/methods, Hypothalamus/metabolism, Menopause/genetics, Reproduction/genetics, Signal Transduction/genetics, business, Genome-Wide Association Study
Abstract: Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10-14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.
Published: 2015
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46. Analysis of functional variants reveals new candidate genes associated with alexithymia

Author: Massimo Mezzavilla, Sheila Ulivi, Antonietta Robino, Martina La Bianca, Paolo Gasparini, Davide Carlino, Mezzavilla, Massimo, Ulivi, Sheila, La Bianca, Martina, Carlino, Davide, Gasparini, Paolo, and Robino, Antonietta
Subjects: Alexithymia, Male, Candidate gene, Personality Inventory, Emotions, ABCB4, Functional variants, Adolescent, Adult, Affective Symptoms, Aged, Case-Control Studies, DNA-Binding Proteins, Female, Humans, Membrane Proteins, Middle Aged, P-Glycoproteins, Phenotype, Tumor Suppressor Proteins, Young Adult, Psychiatry and Mental Health, Biological Psychiatry, Medicine (all), Developmental psychology, Membrane Protein, media_common, Genetics, Affective Symptom, Trait, Biological psychiatry, Personality Assessment Inventory, Case-Control Studie, Psychology, Human, ATP Binding Cassette Transporter, Subfamily B, DNA-Binding Protein, media_common.quotation_subject, Functional variant, medicine, Personality, Gene, Emotion, Tumor Suppressor Protein, P-Glycoprotein, medicine.disease
Abstract: In this study we explored the possible association between 36,915 functional variants and alexithymia, a personality trait characterized by the inability to identify and describe emotions and feelings. From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype.
Published: 2015

47. Rare coding variants and X-linked loci associated with age at menarche

Author: Kathryn L. Lunetta, Felix R. Day, Patrick Sulem, Katherine S. Ruth, Joyce Y. Tung, David A. Hinds, Tõnu Esko, Cathy E. Elks, Elisabeth Altmaier, Chunyan He, Jennifer E. Huffman, Evelin Mihailov, Eleonora Porcu, Antonietta Robino, Lynda M. Rose, Ursula M. Schick, Lisette Stolk, Alexander Teumer, Deborah J. Thompson, Michela Traglia, Carol A. Wang, Laura M. Yerges-Armstrong, Antonis C. Antoniou, Caterina Barbieri, Andrea D. Coviello, Francesco Cucca, Ellen W. Demerath, Alison M. Dunning, Ilaria Gandin, Megan L. Grove, Daniel F. Gudbjartsson, Lynne J. Hocking, Albert Hofman, Jinyan Huang, Rebecca D. Jackson, David Karasik, Jennifer Kriebel, Ethan M. Lange, Leslie A. Lange, Claudia Langenberg, Xin Li, Jian'an Luan, Reedik Mägi, Alanna C. Morrison, Sandosh Padmanabhan, Ailith Pirie, Ozren Polasek, David Porteous, Alex P. Reiner, Fernando Rivadeneira, Igor Rudan, Cinzia F. Sala, David Schlessinger, Robert A. Scott, Doris Stöckl, Jenny A. Visser, Uwe Völker, Diego Vozzi, James G. Wilson, Marek Zygmunt, Nita G. Forouhi, Nicola D. Kerrison, Stephen J. Sharp, Matt Sims, Inês Barroso, Panos Deloukas, Mark I. McCarthy, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Heiner Boeing, Paul W. Franks, Carlos Gonzalez, Sara Grioni, Rudolf Kaaks, Timothy J. Key, Carmen Navarro, Peter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, María‐José Sánchez, Nadia Slimani, Anne Tjonneland, Rosario Tumino, Daphne L. van der A, Yvonne T. van der Schouw, Elio Riboli, Blair H. Smith, Archie Campbell, Ian J. Deary, Andrew M. McIntosh, Eric Boerwinkle, Julie E. Buring, Laura Crisponi, Douglas F. Easton, Caroline Hayward, Frank B. Hu, Simin Liu, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Konstantin Strauch, Elizabeth A. Streeten, Daniela Toniolo, André G. Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J. Wareham, Melissa Wellons, Nora Franceschini, Daniel I. Chasman, Unnur Thorsteinsdottir, Anna Murray, Kari Stefansson, Joanne M. Murabito, Ken K. Ong, John R. B. Perry
Published: 2015
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48. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Author: Ozren Polasek, Bo Jacobsson, Eleonora Porcu, Vinicius Tragante, Joel Eriksson, Jie Yao, Mika Kähönen, Mark Alan Fontana, Stefania Cappellani, J. Viikari, Rick Jansen, Crysovalanto Mamasoula, Linda Broer, Tamara B. Harris, Ellen A. Nohr, Genevieve Lachance, Johan G. Eriksson, Nicholas Eriksson, Rico Rueedi, Francesco Cucca, Jaakko Kaprio, Nicholas J. Timpson, George Dedoussis, Matt McGue, Per Magnus, Klaus Berger, Olli T. Raitakari, Cornelia M. van Duijn, Brenda W.J.H. Penninx, Jing Hua Zhao, Peter Eibich, Sheila Ulivi, Hugoline G. de Haan, Ronny Myhre, Ruth McQuillan, Florian Kronenberg, Markus Perola, Klaus Bønnelykke, Robert Karlsson, Martina La Bianca, Paul Mitchell, Ian J. Deary, Melinda Mills, Teresa Nutile, Patrick J. F. Groenen, Stacey A. Missmer, Nicholas G. Martin, Panos Deloukas, Mario Pirastu, Lindsay K. Matteson, Robert Luben, Veikko Salomaa, Renée de Mutsert, Chris Power, Nir Barzilai, Annette Kifley, Hamdi Mbarek, Denis A. Evans, Erica P. Gunderson, Tim D. Spector, Anke Tönjes, Michela Traglia, Claire Monnereau, Karin Halina Greiser, Sharon L.R. Kardia, John M. Starr, Peter K. Joshi, Sandra Lai, Doris Stöckl, James J. Lee, Heather J. Cordell, Andrew Bakshi, Nicholas J. Wareham, David C. Liewald, P Koponen, Paul M. Ridker, Joyce Y. Tung, Ilaria Gandin, Kauko Heikkilä, Johannes Haerting, Gonneke Willemsen, Janet W. Rich-Edwards, Andrew C. Heath, Astanand Jugessur, John L. Hopper, Stefan Kiechl, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Dan Mellström, Simon R. Cox, Yasaman Saba, Magnus Johannesson, Ginevra Biino, David Schlessinger, Kirsi Auro, Dennis O. Mook-Kanamori, Christa Meisinger, Igor Rudan, Audrey J. Gaskins, Lars Bertram, Roy Thurik, Laura M. Yerges-Armstrong, Caterina Barbieri, Katri Räikkönen, Lawrence F. Bielak, Aviv Bergman, Philipp Koellinger, Ronald de Vlaming, Tian Liu, Johannes W. A. Smit, Peter Kovacs, Vincent W. V. Jaddoe, Jennifer A. Smith, Sven Bergmann, Inga Prokopenko, Xiuqing Guo, Marina Ciullo, Krina T. Zondervan, Marcel den Hoed, Daniel J. Benjamin, Kathryn Roll, Alan F. Wright, Helena Schmidt, William G. Iacono, Jie Jin Wang, Harold Snieder, Juho Wedenoja, Tarunveer S. Ahluwalia, David R. Weir, Ken K. Ong, Daniela Toniolo, Ruifang Li-Gao, Evelin Mihailov, Edith Hofer, Leslie J. Raffel, Daniel I. Chasman, Alexander Kluttig, Bernard Keavney, Eco J. C. de Geus, Kathleen A. Ryan, Kristin L. Ayers, Lude Franke, S. Fleur W. Meddens, Alison Pattie, Jornt J. Mandemakers, Eva Albrecht, David Cesarini, Beverley Balkau, Grant W. Montgomery, Michael Stumvoll, Ahmad Vaez, Michael B. Miller, Najaf Amin, Gyda Bjornsdottir, Cecile Lecoeur, Enes Makalic, Marc Jan Bonder, Terho Lehtimäki, Albert Hofman, Loic Yengo, Lynda M. Rose, Lisette Stolk, Juergen Wellmann, Gail Davies, Eero Kajantie, Nicole Schupf, Hans Bisgaard, Unnur Thorsteinsdottir, Konstantin Strauch, Ivana Kolcic, Lili Milani, Chunyan He, Claes Ohlsson, Yongmei Liu, Gil Atzmon, Janine F. Felix, Christian Gieger, Mike A. Nalls, Riitta Luoto, Nicola Barban, Philippe Froguel, Daniel F. Schmidt, Dorret I. Boomsma, Harry Campbell, Xia Shen, Vasiliki Lagou, Danny Ben-Avraham, Veronique Vitart, Ioanna P. Kalafati, Kari Stefansson, Daria V. Zhernakova, Constance Turman, Julie E. Buring, Johannes Waage, James F. Wilson, Maria Pina Concas, Zoltán Kutalik, Peter Willeit, Jørn Olsen, Dan Rujescu, Caroline Hayward, Penelope A. Lind, George McMahon, Elizabeth G. Holliday, Ilja M. Nolte, Fahimeh Falahi, Minh Bui, Gudmar Thorleifsson, Patrick F. McArdle, Cinzia Sala, Alana Cavadino, Rossella Sorice, Wei Zhao, Andres Metspalu, Sander W. van der Laan, Stavroula Kanoni, Elina Hyppönen, Morris A. Swertz, Simona Vaccargiu, Felix C. Tropf, Michael Lucht, Susan M. Ring, Elizabeth A. Streeten, Reinhold Schmidt, Augustine Kong, Johann Willeit, Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Tõnu Esko, Antonietta Robino, Lavinia Paternoster, Peter J. van der Most, Kumar B. Rajan, George Davey-Smith, Dragana Vuckovic, Hans J. Grabe, Jari Lahti, Giorgia Girotto, Jorge E. Chavarro, Robert F. Krueger, Hongyan Huang, Georg Homuth, Paolo Gasparini, Sarah E. Medland, Gert G. Wagner, Peter Kraft, André G. Uitterlinden, Cornelius A. Rietveld, Howard Andrews, Cecilia M. Lindgren, Peter Vollenweider, Perry, John [0000-0001-6483-3771], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, BARBAN N, Rick Jansen, Ronald de Vlaming, Ahmad Vaez, Jornt J Mandemaker, Felix C Tropf, Xia Shen, James F Wilson, Daniel I Chasman, Ilja M Nolte, Vinicius Tragante, Sander W van der Laan, John R B Perry, Augustine Kong, BIOS Consortium, Tarunveer S Ahluwalia, Eva Albrecht, Laura Yerges-Armstrong, Gil Atzmon, Kirsi Auro, Kristin Ayer, Andrew Bakshi, Danny Ben-Avraham, Klaus Berger, Aviv Bergman, Lars Bertram, Lawrence F Bielak, Gyda Bjornsdottir, Marc Jan Bonder, Linda Broer, Minh Bui, Caterina Barbieri, Alana Cavadino, Jorge E Chavarro, Constance Turman, Maria Pina Conca, Heather J Cordell, Gail Davie, Peter Eibich, Nicholas Eriksson, Tõnu Esko, Joel Eriksson, Fahimeh Falahi, Janine F Felix, Mark Alan Fontana, Lude Franke, Ilaria Gandin, Audrey J Gaskin, Christian Gieger, Erica P Gunderson, Xiuqing Guo, Caroline Hayward, Chunyan He, Edith Hofer, Hongyan Huang, Peter K Joshi, Stavroula Kanoni, Robert Karlsson, Stefan Kiechl, Annette Kifley, Alexander Kluttig, Peter Kraft, Vasiliki Lagou, Cecile Lecoeur, Jari Lahti, Ruifang Li-Gao, Penelope A Lind, Tian Liu, Enes Makalic, Crysovalanto Mamasoula, Lindsay Matteson, Hamdi Mbarek, Patrick F McArdle, George McMahon, S Fleur W Medden, Evelin Mihailov, Mike Miller, Stacey A Missmer, Claire Monnereau, Peter J van der Most, Ronny Myhre, Mike A Nall, Teresa Nutile, Ioanna Panagiota Kalafati, Eleonora Porcu, Inga Prokopenko, Kumar B Rajan, Janet Rich-Edward, Cornelius A Rietveld, Antonietta Robino, Lynda M Rose, Rico Rueedi, Kathleen A Ryan, Yasaman Saba, Daniel Schmidt, Jennifer A Smith, Lisette Stolk, Elizabeth Streeten, Anke Tönje, Gudmar Thorleifsson, Sheila Ulivi, Juho Wedenoja, Juergen Wellmann, Peter Willeit, Jie Yao, Loic Yengo, Jing Hua Zhao, Wei Zhao, Daria V Zhernakova, Najaf Amin, Howard Andrew, Beverley Balkau, Nir Barzilai, Sven Bergmann, Ginevra Biino, Hans Bisgaard, Klaus Bønnelykke, Dorret I Boomsma, Julie E Buring, Harry Campbell, Stefania Cappellani, Marina Ciullo, Simon R Cox, Francesco Cucca, Daniela Toniolo, George Davey-Smith, Ian J Deary, George Dedoussi, Panos Delouka, Cornelia M van Duijn, Eco J C de Geu, Johan G Eriksson, Denis A Evan, Jessica D Faul, Cinzia Felicita Sala, Philippe Froguel, Paolo Gasparini, Giorgia Girotto, Hans-Jörgen Grabe, Karin Halina Greiser, Patrick J F Groenen, Hugoline G de Haan, Johannes Haerting, Tamara B Harri, Andrew C Heath, Kauko Heikkilä, Albert Hofman, Georg Homuth, Elizabeth G Holliday, John Hopper, Elina Hyppönen, Bo Jacobsson, Vincent W V Jaddoe, Magnus Johannesson, Astanand Jugessur, Mika Kähönen, Eero Kajantie, Sharon L R Kardia, Bernard Keavney, Ivana Kolcic, Päivikki Koponen, Peter Kovac, Florian Kronenberg, Zoltan Kutalik, Martina La Bianca, Genevieve Lachance, William G Iacono, Sandra Lai, Terho Lehtimäki, David C Liewald, LifeLines Cohort Study, Cecilia M Lindgren, Yongmei Liu, Robert Luben, Michael Lucht, Riitta Luoto, Per Magnu, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Ruth McQuillan, Sarah E Medland, Christa Meisinger, Dan Mellström, Andres Metspalu, Michela Traglia, Lili Milani, Paul Mitchell, Grant W Montgomery, Dennis Mook-Kanamori, Renée de Mutsert, Ellen A Nohr, Claes Ohlsson, Jørn Olsen, Ken K Ong, Lavinia Paternoster, Alison Pattie, Brenda W J H Penninx, Markus Perola, Patricia A Peyser, Mario Pirastu, Ozren Polasek, Chris Power, Jaakko Kaprio, Leslie J Raffel, Katri Räikkönen, Olli Raitakari, Paul M Ridker, Susan M Ring, Kathryn Roll, Igor Rudan, Daniela Ruggiero, Dan Rujescu, Veikko Salomaa, David Schlessinger, Helena Schmidt, Reinhold Schmidt, Nicole Schupf, Johannes Smit, Rossella Sorice, Tim D Spector, John M Starr, Doris Stöckl, Konstantin Strauch, Michael Stumvoll, Morris A Swertz, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Joyce Y Tung, André G Uitterlinden, Simona Vaccargiu, Jorma Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Dragana Vuckovic, Johannes Waage, Gert G Wagner, Jie Jin Wang, Nicholas J Wareham, David R Weir, Gonneke Willemsen, Johann Willeit, Alan F Wright, Krina T Zondervan, Kari Stefansson, Robert F Krueger, James J Lee, Daniel J Benjamin, David Cesarini, Philipp D Koellinger, Marcel den Hoed, Harold Snieder & Melinda C Mills, Barban, N, Jansen, R, de Vlaming, R, Vaez, A, Mandemakers, Jj, Tropf, Fc, Shen, X, Wilson, Jf, Chasman, Di, Nolte, Im, Tragante, V, van der Laan, Sw, Perry, Jr, Kong, A, Ahluwalia, T, Albrecht, E, Yerges Armstrong, L, Atzmon, G, Auro, K, Ayers, K, Bakshi, A, Ben Avraham, D, Berger, K, Bergman, A, Bertram, L, Bielak, Lf, Bjornsdottir, G, Bonder, Mj, Broer, L, Bui, M, Barbieri, CATERINA MARIA, Cavadino, A, Chavarro, Je, Turman, C, Concas, MARIA PINA, Cordell, Hj, Davies, G, Eibich, P, Eriksson, N, Esko, T, Eriksson, J, Falahi, F, Felix, Jf, Fontana, Ma, Franke, L, Gandin, Ilaria, Gaskins, Aj, Gieger, C, Gunderson, Ep, Guo, X, Hayward, C, He, C, Hofer, E, Huang, H, Joshi, Pk, Kanoni, S, Karlsson, R, Kiechl, S, Kifley, A, Kluttig, A, Kraft, P, Lagou, V, Lecoeur, C, Lahti, J, Li Gao, R, Lind, Pa, Liu, T, Makalic, E, Mamasoula, C, Matteson, L, Mbarek, H, Mcardle, Pf, Mcmahon, G, Meddens, Sf, Mihailov, E, Miller, M, Missmer, Sa, Monnereau, C, van der Most, Pj, Myhre, R, Nalls, Ma, Nutile, T, Kalafati, Ip, Porcu, E, Prokopenko, I, Rajan, Kb, Rich Edwards, J, Rietveld, Ca, Robino, Antonietta, Rose, Lm, Rueedi, R, Ryan, Ka, Saba, Y, Schmidt, D, Smith, Ja, Stolk, L, Streeten, E, Tönjes, A, Thorleifsson, G, Ulivi, Sheila, Wedenoja, J, Wellmann, J, Willeit, P, Yao, J, Yengo, L, Zhao, Jh, Zhao, W, Zhernakova, Dv, Amin, N, Andrews, H, Balkau, B, Barzilai, N, Bergmann, S, Biino, G, Bisgaard, H, Bønnelykke, K, Boomsma, Di, Buring, Je, Campbell, H, Cappellani, Stefania, Ciullo, M, Cox, Sr, Cucca, F, Toniolo, D, Davey Smith, G, Deary, Ij, Dedoussis, G, Deloukas, P, van Duijn, Cm, de Geus, Ej, Eriksson, Jg, Evans, Da, Faul, Jd, Sala, Cf, Froguel, P, Gasparini, Paolo, Girotto, Giorgia, Grabe, Hj, Greiser, Kh, Groenen, Pj, de Haan, Hg, Haerting, J, Harris, Tb, Heath, Ac, Heikkilä, K, Hofman, A, Homuth, G, Holliday, Eg, Hopper, J, Hyppönen, E, Jacobsson, B, Jaddoe, Vw, Johannesson, M, Jugessur, A, Kähönen, M, Kajantie, E, Kardia, Sl, Keavney, B, Kolcic, I, Koponen, P, Kovacs, P, Kronenberg, F, Kutalik, Z, LA BIANCA, Martina, Lachance, G, Iacono, Wg, Lai, S, Lehtimäki, T, Liewald, Dc, Lindgren, Cm, Liu, Y, Luben, R, Lucht, M, Luoto, R, Magnus, P, Magnusson, Pk, Martin, Ng, Mcgue, M, Mcquillan, R, Medland, Se, Meisinger, C, Mellström, D, Metspalu, A, Traglia, Michela, Milani, L, Mitchell, P, Montgomery, Gw, Mook Kanamori, D, de Mutsert, R, Nohr, Ea, Ohlsson, C, Olsen, J, Ong, Kk, Paternoster, L, Pattie, A, Penninx, Bw, Perola, M, Peyser, Pa, Pirastu, M, Polasek, O, Power, C, Kaprio, J, Raffel, Lj, Räikkönen, K, Raitakari, O, Ridker, Pm, Ring, Sm, Roll, K, Rudan, I, Ruggiero, D, Rujescu, D, Salomaa, V, Schlessinger, D, Schmidt, H, Schmidt, R, Schupf, N, Smit, J, Sorice, R, Spector, Td, Starr, Jm, Stöckl, D, Strauch, K, Stumvoll, M, Swertz, Ma, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tung, Jy, Uitterlinden, Ag, Vaccargiu, S, Viikari, J, Vitart, V, Völzke, H, Vollenweider, P, Vuckovic, Dragana, Waage, J, Wagner, Gg, Wang, Jj, Wareham, Nj, Weir, Dr, Willemsen, G, Willeit, J, Wright, Af, Zondervan, Kt, Stefansson, K, Krueger, Rf, Lee, Jj, Benjamin, Dj, Cesarini, D, Koellinger, Pd, den Hoed, M, Snieder, H, Mills, Mc, Sociology/ICS, Life Course Epidemiology (LCE), Isotope Research, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Barban, Nicola, Jansen, Rick, De Vlaming, Ronald, Vaez, Ahmad, Hyppönen, Elina, Mills, Melinda C, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, EMGO - Mental health, Applied Economics, Public Health, Internal Medicine, Erasmus MC other, Epidemiology, Econometrics, Pediatrics, EMGO+ - Lifestyle, Overweight and Diabetes, Complex Trait Genetics, and Biological Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), PROTEIN, WASS, Genome-wide association study, Reproductive Behavior, MOUSE, Genome-wide association studies, GWAS, reproductive behavior, fertility, 0302 clinical medicine, G1 PHASE, Pregnancy, Genetics & Heredity, Genetics, HUMAN-DISEASES, Reproduction, Human Reproduction, 11 Medical And Health Sciences, ASSOCIATION, Genome-Wide, POLYCYSTIC-OVARY-SYNDROME, Sociologie van Consumptie en Huishoudens, Parity, Phenotype, Behavioural genetics, Medical genetics, Female, BIOS Consortium, FOS: Medical biotechnology, Life Sciences & Biomedicine, Maternal Age, Infertility, medicine.medical_specialty, GENE PRIORITIZATION, Quantitative Trait Loci, Sociology of Consumption and Households, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, AGE, QUALITY-CONTROL, medicine, Journal Article, Life Science, SNP, Humans, gene, reproductive, behaviour, Science & Technology, ta1184, 06 Biological Sciences, medicine.disease, Genetic architecture, human reproductive behavior, 030104 developmental biology, Fertility, Human genome, Birth Order, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis, Genome-Wide Association Study
Abstract: Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A; BIOS Consortium, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC; LifeLines Cohort Study, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, Mills MC.
Published: 2016
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49. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

Author: Sophie H. Van Wingerden, Wei V. Zhuang, Mladen Boban, John R. B. Perry, Joop S.E. Laven, Shah Ebrahim, Andrea D. Coviello, Barbara McKnight, Laura Crisponi, Sharon L.R. Kardia, Daniel I. Chasman, Lorna M. Lopez, George Dedoussis, Stefania Bandinelli, Nora Franceschini, Florian Ernst, A. Cecile J.W. Janssens, Yvonne T. van der Schouw, Henri Wallaschofski, Jari Lahti, Triin Laisk, Elizabeth A. Streeten, Joanne M. Murabito, Liana Ferreli, Harold Snieder, Dale R. Nyholt, Lenore J. Launer, Panagiotis Deloukas, Melissa E. Garcia, Eco J. C. de Geus, H.-Erich Wichmann, John M. Starr, Eva Albrecht, Paul M. Ridker, N. Charlotte Onland-Moret, Petra H.M. Peeters, Massimo Mangino, Jacques S. Beckmann, Stephen J. Chanock, Grant W. Montgomery, Julie E. Buring, Barbara Thorand, Diederick E. Grobbee, Irena Martinović Klarić, Constance Chen, So-Youn Shin, Ozren Polasek, Daniel F. Gudbjartsson, Patrick Sulem, Carla H. van Gils, Eleonora Porcu, Cinzia Sala, Tim D. Spector, Alexander N. Parker, Ellen W. Demerath, Guillaume Paré, Krista Fischer, Simon N. Stacey, Mara Marongiu, Lina Zgaga, Jouke-Jan Hottenga, Unnur Styrkarsdottir, Debbie A Lawlor, Douglas P. Kiel, Guangju Zhai, Kari Stefansson, Lisette Stolk, Igor Rudan, David Schlessinger, Katri R Currency Signikkönen, Z. Kutalik, Ian J. Deary, Frank J.M. Broekmans, Ulf de Faire, Vincent Mooser, Luigi Ferrucci, Maria G. Stathopoulou, Pio D'Adamo, Marek Zygmunt, Linda Broer, James F. Wilson, Lovorka Barać Lauc, Angelo Scuteri, Patrik K. E. Magnusson, Frank B. Hu, Jennifer A. Smith, Toomas Haller, Giorgio Pistis, Colette J M Wijnands-van Gent, Emil Rehnberg, Marlies Voorhuis, Anna Murray, David Melzer, Chunyan He, Tamara B. Harris, Merli Hass, Patrick F. McArdle, Valur Emilsson, Gérard Waeber, Manuela Uda, Nancy L. Pedersen, Jenny A. Visser, Behrooz Z. Alizadeh, Andres Salumets, Andrew D. Johnson, Gonneke Willemsen, Sheila Ulivi, Tmu Esko, Vilmundur Gudnason, Bart C.J.M. Fauser, Maja Barbalić, Henry Völzke, Ronald P. Stolk, Aarno Palotie, Peter Van Nierop, Thor Aspelund, Elisabeth Widen, Caroline Hayward, Johan G. Eriksson, Alan F. Wright, Marilyn C. Cornelis, Tanguy Corre, Eric Boerwinkle, Ben A. Oostra, Alice M. Arnold, Kathleen Stirrups, Yvonne V. Louwers, M. Carola Zillikens, Anne B. Newman, Jerome I. Rotter, Jianjun Liu, Per Hall, Aaron R. Folsom, David Karasik, Yan V. Sun, Albert Hofman, Gudny Eiriksdottir, Andrew B. Singleton, Victor J M Pop, Pau Navarro, Tatijana Zemunik, Andres Metspalu, Andrew S. Plump, Cornelia M. van Duijn, Dorret I. Boomsma, Harry Campbell, Nicole Soranzo, Bruce M. Psaty, Enda M. Byrne, Christian Gieger, Albert Tenesa, Nicholas G. Martin, Unnur Thorsteinsdottir, Kathryn L. Lunetta, Laufey Tryggvadottir, Serena Sanna, Kim Tsui, Ivana Kolcic, Laura M. Yerges-Armstrong, Jacqueline M. Vink, Bruce H. R. Wolffenbuttel, Daniela Toniolo, Peter M. Visscher, Rob M. van Dam, Erik Ingelsson, Sandra Lai, Corrado Masciullo, Albert V. Smith, Paolo Gasparini, Sarah E. Medland, Nicole L. Glazer, Peter Kraft, André G. Uitterlinden, David J. Hunter, Andrea Burri, Jules J. Keyzer, Susan E. Hankinson, Gail Davies, Andrew C. Heath, Biological Psychology, EMGO+ - Mental Health, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Surgery, Hematology, Clinical Genetics, Study T.L., Lisette, Stolk, John R. B., Perry, Daniel I., Chasman, Chunyan, He, Massimo, Mangino, Patrick, Sulem, Maja, Barbalic, Linda, Broer, Enda M., Byrne, Florian, Ernst, Tõnu, Esko, Nora, Franceschini, Daniel F., Gudbjartsson, Jouke Jan, Hottenga, Peter, Kraft, Patrick F., Mcardle, Eleonora, Porcu, So Youn, Shin, Albert V., Smith, Sophie van, Wingerden, Guangju, Zhai, Wei V., Zhuang, Eva, Albrecht, Behrooz Z., Alizadeh, Thor, Aspelund, Stefania, Bandinelli, Lovorka Barac, Lauc, Jacques S., Beckmann, Mladen, Boban, Eric, Boerwinkle, Frank J., Broekman, Andrea, Burri, Harry, Campbell, Stephen J., Chanock, Constance, Chen, Marilyn C., Corneli, Tanguy, Corre, Andrea D., Coviello, D'Adamo, ADAMO PIO, Gail, Davie, Ulf de, Faire, Eco J. C., de Geu, Ian J., Deary, George V. Z., Dedoussi, Panagiotis, Delouka, Shah, Ebrahim, Gudny, Eiriksdottir, Valur, Emilsson, Johan G., Eriksson, Bart C. J. M., Fauser, Liana, Ferreli, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Melissa E., Garcia, Gasparini, Paolo, Christian, Gieger, Nicole, Glazer, Diederick E., Grobbee, Per, Hall, Toomas, Haller, Susan E., Hankinson, Merli, Ha, Caroline, Hayward, Andrew C., Heath, Albert, Hofman, Erik, Ingelsson, A. Cecile J. W., Janssen, Andrew D., Johnson, David, Karasik, Sharon L. R., Kardia, Jules, Keyzer, Douglas P., Kiel, Ivana, Kolcic, Zoltán, Kutalik, Jari, Lahti, Sandra, Lai, Triin, Laisk, Joop S. E., Laven, Debbie A., Lawlor, Jianjun, Liu, Lorna M., Lopez, Yvonne V., Louwer, Patrik K. E., Magnusson, Mara, Marongiu, Nicholas G., Martin, Irena Martinovic, Klaric, Corrado, Masciullo, Barbara, Mcknight, Sarah E., Medland, David, Melzer, Vincent, Mooser, Pau, Navarro, Anne B., Newman, Dale R., Nyholt, N., Charlotte Onland Moret, Aarno, Palotie, Guillaume, Paré, Alex N., Parker, Nancy L., Pedersen, Petra H. M., Peeter, Giorgio, Pisti, Andrew S., Plump, Ozren, Polasek, Victor J. M., Pop, Bruce M., Psaty, Katri, Räikkönen, Emil, Rehnberg, Jerome I., Rotter, Igor, Rudan, Cinzia, Sala, Andres, Salumet, Angelo, Scuteri, Andrew, Singleton, Jennifer A., Smith, Harold, Snieder, Nicole, Soranzo, Simon N., Stacey, John M., Starr, Maria G., Stathopoulou, Kathleen, Stirrup, Ronald P., Stolk, Unnur, Styrkarsdottir, Yan V., Sun, Albert, Tenesa, Barbara, Thorand, Daniela, Toniolo, Laufey, Tryggvadottir, Kim, Tsui, Sheila, Ulivi, Rob M., van Dam, Yvonne T., van der Schouw, Carla H., van Gil, Peter van, Nierop, Jacqueline M., Vink, Peter M., Visscher, Marlies, Voorhui, Gérard, Waeber, Henri, Wallaschofski, H., Erich Wichmann, Elisabeth, Widen, Colette J. M., Wijnands van Gent, Gonneke, Willemsen, James F., Wilson, Bruce H. R., Wolffenbuttel, Alan F., Wright, Laura M., Yerges Armstrong, Tatijana, Zemunik, Lina, Zgaga, M., Carola Zilliken, Marek, Zygmunt, The LifeLines Cohort, Study, Alice M., Arnold, Dorret I., Boomsma, Julie E., Buring, Laura, Crisponi, Ellen W., Demerath, Vilmundur, Gudnason, Tamara B., Harri, Frank B., Hu, David J., Hunter, Lenore J., Launer, Andres, Metspalu, Grant W., Montgomery, Ben A., Oostra, Paul M., Ridker, Serena, Sanna, David, Schlessinger, Tim D., Spector, Kari, Stefansson, Elizabeth A., Streeten, Unnur, Thorsteinsdottir, Manuela, Uda, André G., Uitterlinden, Cornelia M., van Duijn, Henry, Völzke, Anna, Murray, Joanne M., Murabito, Jenny A., Visser, Kathryn L., Lunetta, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Netherlands Twin Register (NTR), Candidate gene, Menopause, dna repair, DNA Repair, PROTEIN, Genome-wide association study, DNA-Directed DNA Polymerase, medicine.disease_cause, Bioinformatics, DISEASE, PREMATURE OVARIAN FAILURE, 0302 clinical medicine, NATURAL MENOPAUSE, MUTATION, GENE-EXPRESSION, Genetics, 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, Age Factors, 3. Good health, Premature ovarian failure, DNA Polymerase gamma, menopause, loci, genetics, Female, DNA repair, DNA Primase, Biology, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, FOLLICLE-STIMULATING-HORMONEPREMATURE OVARIAN FAILUREGENOME-WIDE ASSOCIATIONGENE-EXPRESSIONONSETPOLYMORPHISMSMUTATIONHERITABILITYCHROMOSOMEMENARCHE, medicine, Humans, GENOME-WIDE ASSOCIATION, Gene, POLYMORPHISMS, 030304 developmental biology, Genetic association, DNA Helicases, Immunity, Proteins, medicine.disease, FOLLICLE-STIMULATING-HORMONE, DNA Repair Enzymes, Exodeoxyribonucleases, Genetic Loci, ONSET, Genome-Wide Association Study
Abstract: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 - 10 g8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-I °B signaling and mitochondrial dysfunction as biological processes related to timing of menopause. © 2012 Nature America, Inc. All rights reserved.
Published: 2012
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50. HLA genotypes and disease severity assessed by magnetic resonance imaging findings in patients with multiple sclerosis

Author: Marino Zorzon, Robert Zivadinov, Laura Locatelli, Christina Furlan, Laura Uxa, A. Bosco, Alessio Bratina, Giuseppe Cazzato, Roberto Pozzi-Mucelli, Sheila Ulivi, D. Nasuelli, Tullio Zacchi, Attillio Grop, Maria Antonietta Tommasi, Maja Ukmar, Zivadinov, R., Uxa, L., Zacchi, T., Nasuelli, D., Ukmar, M., Furlan, C., POZZI MUCELLI, R., Tommasi, M. A., Locatelli, L., Ulivi, S., Bratina, Alessio, Bosco, A., Grop, A., Cazzato, G., and Zorzon, Marino
Subjects: Adult, Male, medicine.medical_specialty, Pathology, Multiple Sclerosis, Genotype, Human leukocyte antigen, Severity of Illness Index, Gastroenterology, Central nervous system disease, multiple sclerosis, HLA, MRI, HLA Antigens, Internal medicine, Severity of illness, Confidence Intervals, Odds Ratio, medicine, Humans, Chi-Square Distribution, Expanded Disability Status Scale, medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, Odds ratio, Middle Aged, medicine.disease, Magnetic Resonance Imaging, HLA, Neurology, Regression Analysis, Female, Neurology (clinical), business, MRI
Abstract: The objective of the study was to examine the relationship between HLA genotypes and disease severity as measured by brain MRI quantitative markers of demyelinating and destructive pathology in patients with multiple sclerosis (MS). We studied 100 patients with MS and 122 age, sex-, ethnic- and residence-matched controls. The DNA extraction and the genomic typing (A, B, DRB1 and DQB1 loci) were obtained with sequence-specific oligonucleotide method, using a commercially available reversible line blot assay (INNO-LIPA). All patients underwent a 1.5 tesla MRI examination of the brain. Disease severity was assessed by clinical (Expanded Disability Status Scale (EDSS)) and MRI (T2- and T1-lesion load (LL) and brain parenchymal fraction (BPF)) outcome measures. HLA-DQB1* 02 (OR 19.9, 95% C. I. 16.2-24.3, uncorrected (uncorr)- p
Published: 2003
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