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1. The exact dimension of Liouville numbers: The Fourier side

Author

Polasek, Iván and Rela, Ezequiel

Subjects
Mathematics - Classical Analysis and ODEs, 42A38, 26A12
Abstract

In this article we study the generalized Fourier dimension of the set of Liouville numbers $\mathbb{L}$. Being a set of zero Hausdorff dimension, the analysis has to be done at the level of functions with a slow decay at infinity acting as control for the Fourier transform of (Rajchman) measures supported on $\mathbb{L}$. We give an almost complete characterization of admissible decays for this set in terms of comparison to power-like functions. This work can be seen as the ``Fourier side'' of the analysis made by Olsen and Renfro regarding the generalized Hausdorff dimension using gauge functions. We also provide an approach to deal with the problem of classifying oscillating candidates for a Fourier decay for $\mathbb{L}$ relying on its translation invariance property.

Published
2024

2. 'I HATE Poetry!' Understanding through Unlearning: A Poetic Inquiry

Author

Polasek, Tanya

Abstract

Engaging the methodology of poetic inquiry, this paper explores both the teaching and learning of poetry. Through a combination of interpretation and reflection, the reader embarks on a journey from the author's childhood experiences with poetry to the experiences of her students in an ELA class. Pinar's method of currere provides a lens to explore the ideas of understanding through unlearning. Weaving original, found, and fusion poetry into a conversation with relevant literature, the author hopes to inspire other teachers to approach poetry in their lives and their classrooms with a sense of wonder and curiosity.

Published
2023

4. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

Author

Scholz, Markus, Horn, Katrin, Pott, Janne, Wuttke, Matthias, Kühnapfel, Andreas, Nasr, M, Kirsten, Holger, Li, Yong, Hoppmann, Anselm, Gorski, Mathias, Ghasemi, Sahar, Li, Man, Tin, Adrienne, Chai, Jin-Fang, Cocca, Massimiliano, Wang, Judy, Nutile, Teresa, Akiyama, Masato, Åsvold, Bjørn, Bansal, Nisha, Biggs, Mary, Boutin, Thibaud, Brenner, Hermann, Brumpton, Ben, Burkhardt, Ralph, Cai, Jianwen, Campbell, Archie, Campbell, Harry, Chalmers, John, Chasman, Daniel, Chee, Miao, Chen, Xu, Cheng, Ching-Yu, Cifkova, Renata, Daviglus, Martha, Delgado, Graciela, Dittrich, Katalin, Edwards, Todd, Endlich, Karlhans, Michael Gaziano, J, Giri, Ayush, Giulianini, Franco, Gordon, Scott, Gudbjartsson, Daniel, Hallan, Stein, Hamet, Pavel, Hartman, Catharina, Hayward, Caroline, Heid, Iris, Hellwege, Jacklyn, Holleczek, Bernd, Holm, Hilma, Hutri-Kähönen, Nina, Hveem, Kristian, Isermann, Berend, Jonas, Jost, Joshi, Peter, Kamatani, Yoichiro, Kanai, Masahiro, Kastarinen, Mika, Khor, Chiea, Kiess, Wieland, Kleber, Marcus, Körner, Antje, Kovacs, Peter, Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard, Kuokkanen, Mikko, Kähönen, Mika, Lange, Leslie, Lash, James, Lehtimäki, Terho, Li, Hengtong, Lin, Bridget, Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Magnusson, Patrik, Martin, Nicholas, Matsuda, Koichi, Milaneschi, Yuri, Mishra, Pashupati, Mononen, Nina, Montgomery, Grant, Mook-Kanamori, Dennis, Mychaleckyj, Josyf, März, Winfried, Nauck, Matthias, Nikus, Kjell, Nolte, Ilja, Noordam, Raymond, Okada, Yukinori, Olafsson, Isleifur, Oldehinkel, Albertine, Penninx, Brenda, Perola, Markus, Pirastu, Nicola, and Polasek, Ozren

Subjects
Humans, Male, Female, Androgens, Genome-Wide Association Study, Kidney, Chromosomes, Human, X, Response Elements, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Tetraspanins
Abstract

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Published
2024

5. Ultra-inert lanthanide chelates as mass tags for multiplexed bioanalysis

Author

Tomáš David, Miroslava Šedinová, Aneta Myšková, Jaroslav Kuneš, Lenka Maletínská, Radek Pohl, Martin Dračínský, Helena Mertlíková-Kaiserová, Karel Čížek, Blanka Klepetářová, Miroslava Litecká, Antonín Kaňa, David Sýkora, Adam Jaroš, Michal Straka, and Miloslav Polasek

Subjects
Science
Abstract

Abstract Coordination compounds of lanthanides are indispensable in biomedical applications as MRI contrast agents and radiotherapeutics. However, since the introduction of the chelator DOTA four decades ago, there has been only limited progress on improving their thermodynamic stability and kinetic inertness, which are essential for safe in vivo use. Here, we present ClickZip, an innovative synthetic strategy employing a coordination-templated formation of a 1 ,5-triazole bridge that improves kinetic inertness up to a million-fold relative to DOTA, expanding utility of lanthanide chelates beyond traditional uses. Acting as unique mass tags, the ClickZip chelates can be released from (biological) samples by acidic hydrolysis, chromatographically distinguished from interfering lanthanide species, and sensitively detected by mass spectrometry. Lanthanides enclosed in ClickZip chelates are chemically almost indistinguishable, providing a more versatile alternative to chemically identical isotopic labels for multiplexed analysis. The bioanalytical potential is demonstrated on tagged cell-penetrating peptides in vitro, and anti-obesity prolactin-releasing peptides in vivo.

Published
2024
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7. Time series of freshwater macroinvertebrate abundances and site characteristics of European streams and rivers

Author

Welti, Ellen A. R., Bowler, Diana E., Sinclair, James S., Altermatt, Florian, Álvarez-Cabria, Mario, Amatulli, Giuseppe, Angeler, David G., Archambaud, Gaït, Arrate Jorrín, Iñaki, Aspin, Thomas, Azpiroz, Iker, Baker, Nathan Jay, Bañares, Iñaki, Barquín Ortiz, José, Bodin, Christian L., Bonacina, Luca, Bonada, Núria, Bottarin, Roberta, Cañedo-Argüelles, Miguel, Csabai, Zoltán, Datry, Thibault, de Eyto, Elvira, Dohet, Alain, Domisch, Sami, Dörflinger, Gerald, Drohan, Emma, Eikland, Knut A., England, Judy, Eriksen, Tor E., Evtimova, Vesela, Feio, Maria J., Ferréol, Martial, Floury, Mathieu, Forcellini, Maxence, Forio, Marie Anne Eurie, Fornaroli, Riccardo, Friberg, Nikolai, Fruget, Jean-François, Garcia Marquez, Jaime R., Georgieva, Galia, Goethals, Peter, Graça, Manuel A. S., House, Andy, Huttunen, Kaisa-Leena, Jensen, Thomas Correll, Johnson, Richard K., Jones, J. Iwan, Kiesel, Jens, Larrañaga, Aitor, Leitner, Patrick, L’Hoste, Lionel, Lizée, Marie-Hélène, Lorenz, Armin W., Maire, Anthony, Manzanos Arnaiz, Jesús Alberto, Mckie, Brendan, Millán, Andrés, Muotka, Timo, Murphy, John F., Ozolins, Davis, Paavola, Riku, Paril, Petr, Peñas Silva, Francisco Jesús, Polasek, Marek, Rasmussen, Jes, Rubio, Manu, Sánchez Fernández, David, Sandin, Leonard, Schäfer, Ralf B., Schmidt-Kloiber, Astrid, Scotti, Alberto, Shen, Longzhu Q., Skuja, Agnija, Stoll, Stefan, Straka, Michal, Stubbington, Rachel, Timm, Henn, Tyufekchieva, Violeta G., Tziortzis, Iakovos, Uzunov, Yordan, van der Lee, Gea H., Vannevel, Rudy, Varadinova, Emilia, Várbíró, Gábor, Velle, Gaute, Verdonschot, Piet F. M., Verdonschot, Ralf C. M., Vidinova, Yanka, Wiberg-Larsen, Peter, and Haase, Peter

Published
2024
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8. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author

Mei, Hao, Simino, Jeannette, Li, Lianna, Jiang, Fan, Bis, Joshua C., Davies, Gail, Hill, W David, Xia, Charley, Gudnason, Vilmundur, Yang, Qiong, Lahti, Jari, Smith, Jennifer A., Kirin, Mirna, De Jager, Philip, Armstrong, Nicola J., Ghanbari, Mohsen, Kolcic, Ivana, Moran, Christopher, Teumer, Alexander, Sargurupremraj, Murali, Mahmud, Shamsed, Fornage, Myriam, Zhao, Wei, Satizabal, Claudia L., Polasek, Ozren, Räikkönen, Katri, Liewald, David C., Homuth, Georg, Callisaya, Michele, Mather, Karen A., Windham, B. Gwen, Zemunik, Tatijana, Palotie, Aarno, Pattie, Alison, van der Auwera, Sandra, Thalamuthu, Anbupalam, Knopman, David S., Rudan, Igor, Starr, John M., Wittfeld, Katharina, Kochan, Nicole A., Griswold, Michael E., Vitart, Veronique, Brodaty, Henry, Gottesman, Rebecca, Cox, Simon R., Psaty, Bruce M., Boerwinkle, Eric, Chasman, Daniel I., Grodstein, Francine, Sachdev, Perminder S., Srikanth, Velandai, Hayward, Caroline, Wilson, James F., Eriksson, Johan G., Kardia, Sharon L. R., Grabe, Hans J., Bennett, David A., Ikram, M. Arfan, Deary, Ian J., van Duijn, Cornelia M., Launer, Lenore, Fitzpatrick, Annette L., Seshadri, Sudha, Bressler, Jan, Debette, Stephanie, and Mosley, Jr, Thomas H.

Published
2024
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9. Genome-wide characterization of circulating metabolic biomarkers

Author

Karjalainen, Minna K., Karthikeyan, Savita, Oliver-Williams, Clare, Sliz, Eeva, Allara, Elias, Fung, Wing Tung, Surendran, Praveen, Zhang, Weihua, Jousilahti, Pekka, Kristiansson, Kati, Salomaa, Veikko, Goodwin, Matt, Hughes, David A., Boehnke, Michael, Fernandes Silva, Lilian, Yin, Xianyong, Mahajan, Anubha, Neville, Matt J., van Zuydam, Natalie R., de Mutsert, Renée, Li-Gao, Ruifang, Mook-Kanamori, Dennis O., Demirkan, Ayse, Liu, Jun, Noordam, Raymond, Trompet, Stella, Chen, Zhengming, Kartsonaki, Christiana, Li, Liming, Lin, Kuang, Hagenbeek, Fiona A., Hottenga, Jouke Jan, Pool, René, Ikram, M. Arfan, van Meurs, Joyce, Haller, Toomas, Milaneschi, Yuri, Kähönen, Mika, Mishra, Pashupati P., Joshi, Peter K., Macdonald-Dunlop, Erin, Mangino, Massimo, Zierer, Jonas, Acar, Ilhan E., Hoyng, Carel B., Lechanteur, Yara T. E., Franke, Lude, Kurilshikov, Alexander, Zhernakova, Alexandra, Beekman, Marian, van den Akker, Erik B., Kolcic, Ivana, Polasek, Ozren, Rudan, Igor, Gieger, Christian, Waldenberger, Melanie, Asselbergs, Folkert W., Hayward, Caroline, Fu, Jingyuan, den Hollander, Anneke I., Menni, Cristina, Spector, Tim D., Wilson, James F., Lehtimäki, Terho, Raitakari, Olli T., Penninx, Brenda W. J. H., Esko, Tonu, Walters, Robin G., Jukema, J. Wouter, Sattar, Naveed, Ghanbari, Mohsen, Willems van Dijk, Ko, Karpe, Fredrik, McCarthy, Mark I., Laakso, Markku, Järvelin, Marjo-Riitta, Timpson, Nicholas J., Perola, Markus, Kooner, Jaspal S., Chambers, John C., van Duijn, Cornelia, Slagboom, P. Eline, Boomsma, Dorret I., Danesh, John, Ala-Korpela, Mika, Butterworth, Adam S., and Kettunen, Johannes

Published
2024
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10. Personality vulnerabilities and adverse event reporting in phase 1 clinical studies

Author

Joanna Skommer, Krish Gunesh, and Thomas M. Polasek

Subjects
Phase 1 clinical trials, Healthy volunteers, Personality, Medicine (General), R5-920
Abstract

Abstract Background Phase 1 clinical trials involve rigorous safety monitoring to identify any adverse effects of investigational treatments. There is growing evidence that healthy volunteers recruited in these studies may differ with respect to personality traits from the general population. This, in turn, may have a significant impact on the reporting of adverse events, particularly in trials investigating psychoactive treatments, including the psychedelic substances. Main body This analysis stems from our combined experience as investigators in phase 1 clinical trials and conveys an experiential understanding of the impact of psychological heterogeneity on study participation, reporting of adverse events and study outcomes. Conclusion Participant variability due to psychological characteristics is regularly overlooked in phase 1 clinical trials and may significantly impact on reporting of the adverse events. In our opinion, healthy volunteers who present for these studies should not only be defined by the absence of past or current medical and psychiatric illness but also characterised by their psychological attributes.

Published
2024
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11. Time series of freshwater macroinvertebrate abundances and site characteristics of European streams and rivers

Author

Ellen A. R. Welti, Diana E. Bowler, James S. Sinclair, Florian Altermatt, Mario Álvarez-Cabria, Giuseppe Amatulli, David G. Angeler, Gaït Archambaud, Iñaki Arrate Jorrín, Thomas Aspin, Iker Azpiroz, Nathan Jay Baker, Iñaki Bañares, José Barquín Ortiz, Christian L. Bodin, Luca Bonacina, Núria Bonada, Roberta Bottarin, Miguel Cañedo-Argüelles, Zoltán Csabai, Thibault Datry, Elvira de Eyto, Alain Dohet, Sami Domisch, Gerald Dörflinger, Emma Drohan, Knut A. Eikland, Judy England, Tor E. Eriksen, Vesela Evtimova, Maria J. Feio, Martial Ferréol, Mathieu Floury, Maxence Forcellini, Marie Anne Eurie Forio, Riccardo Fornaroli, Nikolai Friberg, Jean-François Fruget, Jaime R. Garcia Marquez, Galia Georgieva, Peter Goethals, Manuel A. S. Graça, Andy House, Kaisa-Leena Huttunen, Thomas Correll Jensen, Richard K. Johnson, J. Iwan Jones, Jens Kiesel, Aitor Larrañaga, Patrick Leitner, Lionel L’Hoste, Marie-Hélène Lizée, Armin W. Lorenz, Anthony Maire, Jesús Alberto Manzanos Arnaiz, Brendan Mckie, Andrés Millán, Timo Muotka, John F. Murphy, Davis Ozolins, Riku Paavola, Petr Paril, Francisco Jesús Peñas Silva, Marek Polasek, Jes Rasmussen, Manu Rubio, David Sánchez Fernández, Leonard Sandin, Ralf B. Schäfer, Astrid Schmidt-Kloiber, Alberto Scotti, Longzhu Q. Shen, Agnija Skuja, Stefan Stoll, Michal Straka, Rachel Stubbington, Henn Timm, Violeta G. Tyufekchieva, Iakovos Tziortzis, Yordan Uzunov, Gea H. van der Lee, Rudy Vannevel, Emilia Varadinova, Gábor Várbíró, Gaute Velle, Piet F. M. Verdonschot, Ralf C. M. Verdonschot, Yanka Vidinova, Peter Wiberg-Larsen, and Peter Haase

Subjects
Science
Abstract

Abstract Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Published
2024
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12. Genetic insights into resting heart rate and its role in cardiovascular disease.

Author

van de Vegte, Yordi, Eppinga, Ruben, van der Ende, M, Hagemeijer, Yanick, Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert, Tan, Vanessa, Arking, Dan, Ntalla, Ioanna, Appel, Emil, Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing, Isaacs, Aaron, Wang, Lihua, Luan, Jianan, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus, Guo, Xiuqing, Lin, Henry, Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling, Li, Hengtong, van der Most, Peter, Nolte, Ilja, Lyytikäinen, Leo-Pekka, Said, M, Witte, Daniel, Iribarren, Carlos, Launer, Lenore, Ring, Susan, de Vries, Paul, Sever, Peter, Linneberg, Allan, Bottinger, Erwin, Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Arnar, David, Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley, Silva, Claudia, Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu, Mohlke, Karen, Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru, Cornelis, Marilyn, Faul, Jessica, Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, and Sinner, Moritz

Subjects
Humans, Cardiovascular Diseases, Risk Factors, Heart Rate, Genetic Predisposition to Disease, Atrial Fibrillation, Mendelian Randomization Analysis, Genome-Wide Association Study, Polymorphism, Single Nucleotide
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

13. Professional Learning Communities as a Model for Effective English Language Arts Curriculum Implementation

Author

Polasek, Tanya

Abstract

Successful implementation of the current English Language Arts (ELA) curriculum invites a new approach to teacher professional learning (PL). A focus on establishing and renewing relationships must play a role in developing the collaboration necessary for curriculum implementation. This article presents a research-based argument that effective and sustainable teacher professional development, structured to build teachers' capacity and improve student learning outcomes, would support the implementation of the Manitoba ELA curriculum.

Published
2022

14. GDF15 linked to maternal risk of nausea and vomiting during pregnancy

Author

Fejzo, M., Rocha, N., Cimino, I., Lockhart, S. M., Petry, C. J., Kay, R. G., Burling, K., Barker, P., George, A. L., Yasara, N., Premawardhena, A., Gong, S., Cook, E., Rimmington, D., Rainbow, K., Withers, D. J., Cortessis, V., Mullin, P. M., MacGibbon, K. W., Jin, E., Kam, A., Campbell, A., Polasek, O., Tzoneva, G., Gribble, F. M., Yeo, G. S. H., Lam, B. Y. H., Saudek, V., Hughes, I. A., Ong, K. K., Perry, J. R. B., Sutton Cole, A., Baumgarten, M., Welsh, P., Sattar, N., Smith, G. C. S., Charnock-Jones, D. S., Coll, A. P., Meek, C. L., Mettananda, S., Hayward, C., Mancuso, N., and O’Rahilly, S.

Published
2024
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15. Virtual twins for model‐informed precision dosing of clozapine in patients with treatment‐resistant schizophrenia

Author

Sam Mostafa, Reza Rafizadeh, Thomas M. Polasek, Chad A. Bousman, Amin Rostami‐Hodjegan, Robert Stowe, Prescilla Carrion, Leslie J. Sheffield, and Carl M. J. Kirkpatrick

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Model‐informed precision dosing using virtual twins (MIPD‐VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD‐VT approach (Simcyp version 21), we predicted the steady‐state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment‐resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD‐VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady‐state clozapine concentrations were overpredicted two to four‐fold. This work supports the application of a high virtualization MIPD‐VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug–drug interactions, particularly with fluvoxamine augmentation.

Published
2024
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16. Efficacy and safety of pharmacogenomic-guided antidepressant prescribing in patients with depression: an umbrella review and updated meta-analysis

Author

Kiflu G. Tesfamicael, Lijun Zhao, Rubén Fernández-Rodríguez, David L. Adelson, Michael Musker, Thomas M. Polasek, and Martin David Lewis

Subjects
depression, antidepressant, pharmacogenomics (PGx), pharmacogenomics-guided prescribing, genotyping panels, Psychiatry, RC435-571
Abstract

AimTo determine the efficacy and safety of pharmacogenomics (PGx)-guided antidepressant prescribing in patients with depression through an umbrella review and updated meta-analysis.MethodsA comprehensive systematic search was conducted on PsycINFO, PubMed, Embase and the Cochrane databases. The pooled effect sizes of randomized controlled trials (RCTs) were expressed as mean differences for continuous data and risk ratios for noncontinuous data.ResultsPatients who received PGx-guided medications were 41% to 78% more likely to achieve remission and 20% to 49% more likely to respond to antidepressants than patients receiving treatment-as-usual (TAU).ConclusionPGx-guided antidepressant prescribing improves the treatment of depression. However, the significance and magnitude of the benefit varies widely between studies and different PGx testing panels.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022321324.

Published
2024
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17. Helicopter Parenting in High School

Author

Polasek, Tanya

Abstract

While parental involvement is often seen as a cornerstone in high school students' success, too much involvement can be problematic. Often teachers feel caught between supporting students' personal growth and parental expectations of students' academic achievement. Certain practices can be developed and implemented at a classroom and school level that can help parents and students. Developing student skills in areas of personal autonomy and self-control is helpful. Creating parent-teacher and student-teacher partnerships can support student growth and may mitigate the negative effects of helicopter parenting.

Published
2021

18. Quantity and quality of minichromosome maintenance protein complexes couple replication licensing to genome integrity

Author

Anoop Kumar Yadav and Hana Polasek-Sedlackova

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Accurate and complete replication of genetic information is a fundamental process of every cell division. The replication licensing is the first essential step that lays the foundation for error-free genome duplication. During licensing, minichromosome maintenance protein complexes, the molecular motors of DNA replication, are loaded to genomic sites called replication origins. The correct quantity and functioning of licensed origins are necessary to prevent genome instability associated with severe diseases, including cancer. Here, we delve into recent discoveries that shed light on the novel functions of licensed origins, the pathways necessary for their proper maintenance, and their implications for cancer therapies.

Published
2024
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19. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author

Hao Mei, Jeannette Simino, Lianna Li, Fan Jiang, Joshua C. Bis, Gail Davies, W David Hill, Charley Xia, Vilmundur Gudnason, Qiong Yang, Jari Lahti, Jennifer A. Smith, Mirna Kirin, Philip De Jager, Nicola J. Armstrong, Mohsen Ghanbari, Ivana Kolcic, Christopher Moran, Alexander Teumer, Murali Sargurupremraj, Shamsed Mahmud, Myriam Fornage, Wei Zhao, Claudia L. Satizabal, Ozren Polasek, Katri Räikkönen, David C. Liewald, Georg Homuth, Michele Callisaya, Karen A. Mather, B. Gwen Windham, Tatijana Zemunik, Aarno Palotie, Alison Pattie, Sandra van der Auwera, Anbupalam Thalamuthu, David S. Knopman, Igor Rudan, John M. Starr, Katharina Wittfeld, Nicole A. Kochan, Michael E. Griswold, Veronique Vitart, Henry Brodaty, Rebecca Gottesman, Simon R. Cox, Bruce M. Psaty, Eric Boerwinkle, Daniel I. Chasman, Francine Grodstein, Perminder S. Sachdev, Velandai Srikanth, Caroline Hayward, James F. Wilson, Johan G. Eriksson, Sharon L. R. Kardia, Hans J. Grabe, David A. Bennett, M. Arfan Ikram, Ian J. Deary, Cornelia M. van Duijn, Lenore Launer, Annette L. Fitzpatrick, Sudha Seshadri, Jan Bressler, Stephanie Debette, and Thomas H. Mosley

Subjects
Genome-wide association study, Memory, Expression, Immunity, Multi-omics, Delayed recall, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Published
2024
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20. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Author

Markus Scholz, Katrin Horn, Janne Pott, Matthias Wuttke, Andreas Kühnapfel, M. Kamal Nasr, Holger Kirsten, Yong Li, Anselm Hoppmann, Mathias Gorski, Sahar Ghasemi, Man Li, Adrienne Tin, Jin-Fang Chai, Massimiliano Cocca, Judy Wang, Teresa Nutile, Masato Akiyama, Bjørn Olav Åsvold, Nisha Bansal, Mary L. Biggs, Thibaud Boutin, Hermann Brenner, Ben Brumpton, Ralph Burkhardt, Jianwen Cai, Archie Campbell, Harry Campbell, John Chalmers, Daniel I. Chasman, Miao Ling Chee, Miao Li Chee, Xu Chen, Ching-Yu Cheng, Renata Cifkova, Martha Daviglus, Graciela Delgado, Katalin Dittrich, Todd L. Edwards, Karlhans Endlich, J. Michael Gaziano, Ayush Giri, Franco Giulianini, Scott D. Gordon, Daniel F. Gudbjartsson, Stein Hallan, Pavel Hamet, Catharina A. Hartman, Caroline Hayward, Iris M. Heid, Jacklyn N. Hellwege, Bernd Holleczek, Hilma Holm, Nina Hutri-Kähönen, Kristian Hveem, Berend Isermann, Jost B. Jonas, Peter K. Joshi, Yoichiro Kamatani, Masahiro Kanai, Mika Kastarinen, Chiea Chuen Khor, Wieland Kiess, Marcus E. Kleber, Antje Körner, Peter Kovacs, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Mikko Kuokkanen, Mika Kähönen, Leslie A. Lange, James P. Lash, Terho Lehtimäki, Hengtong Li, Bridget M. Lin, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Patrik K. E. Magnusson, Nicholas G. Martin, Koichi Matsuda, Yuri Milaneschi, Pashupati P. Mishra, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Winfried März, Matthias Nauck, Kjell Nikus, Ilja M. Nolte, Raymond Noordam, Yukinori Okada, Isleifur Olafsson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Markus Perola, Nicola Pirastu, Ozren Polasek, David J. Porteous, Tanja Poulain, Bruce M. Psaty, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Humaira Rasheed, Dermot F. Reilly, Kenneth M. Rice, Anne Richmond, Paul M. Ridker, Jerome I. Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J. Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O. Svensson, E-Shyong Tai, Kent D. Taylor, Bamidele O. Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Laurent F. Thomas, Johanne Tremblay, Anke Tönjes, Peter J. van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B. Whitfield, Sarah H. Wild, James F. Wilson, Thomas W. Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y. Chu, Mary F. Feitosa, Unnur Thorsteinsdottir, Adriana M. Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, and Cristian Pattaro

Subjects
Science
Abstract

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Published
2024
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21. The craft and coordination of data curation: complicating 'workflow' views of data science

Author

Thomer, Andrea K., Akmon, Dharma, York, Jeremy, Tyler, Allison R. B., Polasek, Faye, Lafia, Sara, Hemphill, Libby, and Yakel, Elizabeth

Subjects
Computer Science - Digital Libraries, Computer Science - Databases, Computer Science - Human-Computer Interaction
Abstract

Data curation is the process of making a dataset fit-for-use and archiveable. It is critical to data-intensive science because it makes complex data pipelines possible, makes studies reproducible, and makes data (re)usable. Yet the complexities of the hands-on, technical and intellectual work of data curation is frequently overlooked or downplayed. Obscuring the work of data curation not only renders the labor and contributions of the data curators invisible; it also makes it harder to tease out the impact curators' work has on the later usability, reliability, and reproducibility of data. To better understand the specific work of data curation -- and thereby, explore ways of showing curators' impact -- we conducted a close examination of data curation at a large social science data repository, the Inter-university Consortium of Political and Social Research (ICPSR). We asked, What does curatorial work entail at ICPSR, and what work is more or less visible to different stakeholders and in different contexts? And, how is that curatorial work coordinated across the organization? We triangulate accounts of data curation from interviews and records of curation in Jira tickets to develop a rich and detailed account of curatorial work. We find that curators describe a number of craft practices needed to perform their work, which defies the rote sequence of events implied by many lifecycle or workflow models. Further, we show how best practices and craft practices are deeply intertwined., Comment: submitted to CSCW 2022 (Feb revision cycle)

Published
2022
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22. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Author

Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Åsa K., Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E., Gieger, Christian, Needham, Elise J., Surendran, Praveen, Paul, Dirk S., Polasek, Ozren, Thorand, Barbara, Grallert, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Åsa, Gyllensten, Ulf, Powell, Nick, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K., Danesh, John, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F., Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam S., and Peters, James E.

Published
2023
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23. Experimental and computational studies on the reactivity of methanimine radical cation (H$_2$CNH$^{+\cdot}$) and its isomer aminomethylene (HCNH$_2^{+\cdot}$) with C$_2$H$_2$

Author

Richardson, Vincent, Ascenzi, Daniela, Sundelin, David, Alcaraz, Christian, Romanzin, Claire, Thissen, Roland, Guillemin, Jean-Claude, Polášek, Miroslav, Tosi, Paolo, Žabka, Jan, and Geppert, Wolf D.

Subjects
Physics - Chemical Physics, Astrophysics - Earth and Planetary Astrophysics, Astrophysics - Astrophysics of Galaxies, Astrophysics - Solar and Stellar Astrophysics
Abstract

Experimental and theoretical studies are presented on the reactivity of the radical cation isomers methanimine and aminomethylene with ethyne. Selective isomer generation is performed via dissociative photoionization of suitable neutral precursors and via direct photoionization of methanimine. Reactive cross sections and product branching ratios are measured as a function of photon and collision energies. Results are discussed in light of ab initio calculations of reaction mechanisms. The major channels, for both isomers, are due to H atom elimination from covalently bound adducts to give [C3NH4]+. Theoretical calculations show that while for the reaction of aminomethylene with acetylene any of the three lowest energy [C3NH4]+ isomers can form via barrierless and exothermic pathways, for the methanimine reagent the only barrierless pathway is the one leading to the production of protonated vinyl cyanide (CH2CHCNH+), a prototypical branched nitrile species that has been proposed as a likely intermediate in star forming regions and in the atmosphere of Titan. The astrochemical implications of the results are briefly addressed., Comment: 16 pages, 8 figures, 2 Tables. Supplementary material available at Publisher's site

Published
2021
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24. The reactivity of methanimine radical cation (H$_2$CNH$^{+\cdot}$) and its isomer aminomethylene (HCNH$_2^{+\cdot}$) with C$_2$H$_4$

Author

Sundelin, David, Ascenzi, Daniela, Richardson, Vincent, Alcaraz, Christian, Polášek, Miroslav, Romanzin, Claire, Thissen, Roland, Tosi, Paolo, Žabka, Jan, and Geppert, Wolf D.

Subjects
Physics - Chemical Physics, Astrophysics - Astrophysics of Galaxies, Astrophysics - Solar and Stellar Astrophysics
Abstract

Experimental and theoretical studies are presented on the reactivity of methanimine and aminomethylene cations with ethene. Selective isomer generation is performed via dissociative photoionization of suitable neutral precursors and reactive cross sections and branching ratios are measured as a function of photon and collision energies., Comment: 15 pages, 6 figures, 2 Tables

Published
2021
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25. The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care

Author

Saya, Sibel, Chondros, Patty, Abela, Anastasia, Mihalopolous, Cathrine, Chatterton, Mary Lou, Gunn, Jane, Chen, Timothy F., Polasek, Thomas M., Dettmann, Elise, Brooks, Rachel, King, Michelle, Spencer, Luke, Alphonse, Pavithran, Milton, Shakira, Ramsay, Georgia, Siviour, Zoe, Liew, Jamie, Ly, Philip, Thoenig, Matthew, Seychell, Raushaan, La Rocca, Floriana, Hesson, Luke B., Mejias, Nydia, Sivertsen, Terri, Galea, Melanie Anne, Bousman, Chad, and Emery, Jon

Published
2023
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26. Exceptionally bright optical emission from a rare and distant $\gamma-$ray burst

Author

Oganesyan, Gor, Karpov, Sergey, Jelínek, Martin, Beskin, Gregory, Ronchini, Samuele, Banerjee, Biswajit, Branchesi, Marica, Štrobl, Jan, Polášek, Cyril, Hudec, René, Ivanov, Eugeny, Katkova, Elena, Perkov, Alexey, Biryukov, Anton, Lyapshina, Nadezhda, Sasyuk, Vyacheslav, Mašek, Martin, Janeček, Petr, Ebr, Jan, Juryšek, Jakub, Cunniffe, Ronan, and Prouza, Michael

Subjects
Astrophysics - High Energy Astrophysical Phenomena
Abstract

Long $\rm \gamma$-ray bursts (GRBs) are produced by the dissipation of ultra-relativistic jets launched by newly-born black holes after the collapse of massive stars. Right after the luminous and highly variable $\gamma$-ray emission, the multi-wavelength afterglow is released by the external dissipation of the jet in circumburst medium. We report the discovery of a very bright ($\rm \sim 10$ mag) optical emission $\rm \sim 28$ s after the explosion of the extremely luminous and energetic GRB 210619B located at redshift 1.937. Early multi-filter observations allowed us to witness the end of the shock wave propagation into the GRB ejecta. We observed the spectral transition from a bright reverse to the forward shock emission, demonstrating that the early and late GRB multi-wavelength emission is originated from a very narrow jet propagating into an unusually rarefied interstellar medium. We also find evidence of an additional component of radiation, coming from the jet wings which is able explain the uncorrelated optical/X-ray emission.

Published
2021
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27. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin D.

Published
2023
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28. 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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29. A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers

Author

Richard T. Kenney, John K. Cini, Susan Dexter, Manuel DaFonseca, Justus Bingham, Isabelle Kuan, Sant P. Chawla, Thomas M. Polasek, Jason Lickliter, and Philip J. Ryan

Subjects
SON-1010, recombinant IL-12, albumin, fully human albumin binding (FHAB) domain, healthy volunteers, immunotherapy, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundThe benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T½), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (FHAB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted.MethodsSB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101.ResultsParticipants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines.ConclusionSON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.

Published
2024
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30. Environmental Impact of Bundling Transport Deliveries Using SUMO: Analysis of a cooperative approach in Austria

Author

Validi, Aso, Polasek, Nicole, Alabi, Leonie, Leitner, Michael, and Olaverri-Monreal, Cristina

Subjects
Computer Science - Other Computer Science
Abstract

Urban Traffic is recognized as one of the major CO2 contributors that puts a high burden on the environment. Different attempts have been made for reducing the impacts ranging from traffic management actions to shared-vehicle concepts to simply reducing the number of vehicles on the streets. By relying on cooperative approaches between different logistics companies, such as sharing and pooling resources for bundling deliveries in the same zone, an increased environmental benefit can be attained. To quantify this benefit we compare the CO2 emissions, fuel consumption and total delivery time resulting from deliveries performed by one cargo truck with two trailers versus by two single-trailer cargo trucks under real conditions in a simulation scenario in the city of Linz in Austria. Results showed a fuel consumption and CO2 emissions reduction of 28% and 34% respectively in the scenario in which resources were bundled in one single truck., Comment: 5 pages, 7 figures, 2 tables, paper accepted for the proceedings of the CISTI'2020 - 15th Iberian Conference on Information Systems and Technologies

Published
2020
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31. The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care

Author

Sibel Saya, Patty Chondros, Anastasia Abela, Cathrine Mihalopolous, Mary Lou Chatterton, Jane Gunn, Timothy F. Chen, Thomas M. Polasek, Elise Dettmann, Rachel Brooks, Michelle King, Luke Spencer, Pavithran Alphonse, Shakira Milton, Georgia Ramsay, Zoe Siviour, Jamie Liew, Philip Ly, Matthew Thoenig, Raushaan Seychell, Floriana La Rocca, Luke B. Hesson, Nydia Mejias, Terri Sivertsen, Melanie Anne Galea, Chad Bousman, and Jon Emery

Subjects
Major depressive disorder, Mental health, Pharmacogenomics, Primary care, General practice, Antidepressants, Medicine (General), R5-920
Abstract

Abstract Background The evidence for the clinical utility of pharmacogenomic (PGx) testing is growing, and guidelines exist for the use of PGx testing to inform prescribing of 13 antidepressants. Although previous randomised controlled trials of PGx testing for antidepressant prescribing have shown an association with remission of depression in clinical psychiatric settings, few trials have focused on the primary care setting, where most antidepressant prescribing occurs. Methods The PRESIDE Trial is a stratified double-blinded randomised controlled superiority trial that aims to evaluate the impact of a PGx-informed antidepressant prescribing report (compared with standard prescribing using the Australian Therapeutic Guidelines) on depressive symptoms after 12 weeks, when delivered in primary care. Six hundred seventy-two patients aged 18–65 years of general practitioners (GPs) in Victoria with moderate to severe depressive symptoms, measured using the Patient Health Questionnaire-9 (PHQ-9), will be randomly allocated 1:1 to each arm using a computer-generated sequence. Participants and GPs will be blinded to the study arm. The primary outcome is a difference between arms in the change of depressive symptoms, measured using the PHQ-9 after 12 weeks. Secondary outcomes include a difference between the arms in change in PHQ-9 score at 4, 8 and 26 weeks, proportion in remission at 12 weeks, a change in side effect profile of antidepressant medications, adherence to antidepressant medications, change in quality of life and cost-effectiveness of the intervention. Discussion This trial will provide evidence as to whether PGx-informed antidepressant prescribing is clinically efficacious and cost-effective. It will inform national and international policy and guidelines about the use of PGx to select antidepressants for people with moderate to severe depressive symptoms presenting in primary care. Trial registration Australian and New Zealand Clinical Trial Registry ACTRN12621000181808. Registered on 22 February 2021.

Published
2023
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32. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Cuellar-Partida, Gabriel, Tung, Joyce Y, Eriksson, Nicholas, Albrecht, Eva, Aliev, Fazil, Andreassen, Ole A, Barroso, Inês, Beckmann, Jacques S, Boks, Marco P, Boomsma, Dorret I, Boyd, Heather A, Breteler, Monique MB, Campbell, Harry, Chasman, Daniel I, Cherkas, Lynn F, Davies, Gail, de Geus, Eco JC, Deary, Ian J, Deloukas, Panos, Dick, Danielle M, Duffy, David L, Eriksson, Johan G, Esko, Tõnu, Feenstra, Bjarke, Geller, Frank, Gieger, Christian, Giegling, Ina, Gordon, Scott D, Han, Jiali, Hansen, Thomas F, Hartmann, Annette M, Hayward, Caroline, Heikkilä, Kauko, Hicks, Andrew A, Hirschhorn, Joel N, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Liang-Dar, Ikram, M Arfan, Kaprio, Jaakko, Kemp, John P, Khaw, Kay-Tee, Klopp, Norman, Konte, Bettina, Kutalik, Zoltan, Lahti, Jari, Li, Xin, Loos, Ruth JF, Luciano, Michelle, Magnusson, Sigurdur H, Mangino, Massimo, Marques-Vidal, Pedro, Martin, Nicholas G, McArdle, Wendy L, McCarthy, Mark I, Medina-Gomez, Carolina, Melbye, Mads, Melville, Scott A, Metspalu, Andres, Milani, Lili, Mooser, Vincent, Nelis, Mari, Nyholt, Dale R, O’Connell, Kevin S, Ophoff, Roel A, Palmer, Cameron, Palotie, Aarno, Palviainen, Teemu, Pare, Guillaume, Paternoster, Lavinia, Peltonen, Leena, Penninx, Brenda WJH, Polasek, Ozren, Pramstaller, Peter P, Prokopenko, Inga, Raikkonen, Katri, Ripatti, Samuli, Rivadeneira, Fernando, Rudan, Igor, Rujescu, Dan, Smit, Johannes H, Smith, George Davey, Smoller, Jordan W, Soranzo, Nicole, Spector, Tim D, Pourcain, Beate St, Starr, John M, Stefánsson, Hreinn, Steinberg, Stacy, Teder-Laving, Maris, Thorleifsson, Gudmar, Stefánsson, Kári, Timpson, Nicholas J, Uitterlinden, André G, van Duijn, Cornelia M, van Rooij, Frank JA, Vink, Jaqueline M, Vollenweider, Peter, Vuoksimaa, Eero, and Waeber, Gérard

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Human Genome, Mental Health, Brain Disorders, Neurosciences, Schizophrenia, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adult, Aged, Female, Functional Laterality, Gene Frequency, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Sex Factors, Biomedical and clinical sciences, Health sciences
Abstract

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P

Published
2021

33. Association of low-frequency and rare coding variants with information processing speed

Author

Bressler, Jan, Davies, Gail, Smith, Albert V, Saba, Yasaman, Bis, Joshua C, Jian, Xueqiu, Hayward, Caroline, Yanek, Lisa, Smith, Jennifer A, Mirza, Saira S, Wang, Ruiqi, Adams, Hieab HH, Becker, Diane, Boerwinkle, Eric, Campbell, Archie, Cox, Simon R, Eiriksdottir, Gudny, Fawns-Ritchie, Chloe, Gottesman, Rebecca F, Grove, Megan L, Guo, Xiuqing, Hofer, Edith, Kardia, Sharon LR, Knol, Maria J, Koini, Marisa, Lopez, Oscar L, Marioni, Riccardo E, Nyquist, Paul, Pattie, Alison, Polasek, Ozren, Porteous, David J, Rudan, Igor, Satizabal, Claudia L, Schmidt, Helena, Schmidt, Reinhold, Sidney, Stephen, Simino, Jeannette, Smith, Blair H, Turner, Stephen T, van der Lee, Sven J, Ware, Erin B, Whitmer, Rachel A, Yaffe, Kristine, Yang, Qiong, Zhao, Wei, Gudnason, Vilmundur, Launer, Lenore J, Fitzpatrick, Annette L, Psaty, Bruce M, Fornage, Myriam, Arfan Ikram, M, van Duijn, Cornelia M, Seshadri, Sudha, Mosley, Thomas H, and Deary, Ian J

Subjects
Genetics, Brain Disorders, Aging, Human Genome, Adult, Cognition, Genome-Wide Association Study, Geroscience, Humans, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10-6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

Published
2021

34. Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin D.

Published
2023
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35. 730 A phase I safety and tolerability study of VAXinia (CF33-hNIS), a novel chimeric oncolytic poxvirus, administered intratumorally or intravenously in adults with metastatic or advanced solid tumors

Author

Yuman Fong, Amanda Seiz, Hirva Mamdani, Melissa Polasek, Daneng Li, Leslie Chong, Alexander I Spira, Jennifer Leddon, Seymour Fein, Nick Ede, Ursula McCurry, Sharon Yavrom, and Giovanni Selvaggi

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2023
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36. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization [version 1; peer review: 2 approved]

Author

Natasha H. J. Ng, Sara M. Willems, Jian'an Luan, Rebecca S. Fine, Juan Fernandez, Jennifer Wessel, Eleanor Wheeler, Gaelle Marenne, Hidetoshi Kitajima, Hanieh Yaghootkar, Xueling Sim, Ian J. Deary, Sai Chen, Shuai Wang, Yii-Der Ida Chen, Caroline Hayward, Yuning Chen, Jennifer L. Asimit, Claudia Langenberg, Tibor V. Varga, Archie Campbell, Rona J. Strawbridge, Shuang Feng, Tarunveer S. Ahluwalia, Erica L. Kleinbrink, Emil V. Appel, Ping An, Lawrence F. Bielak, Dan E. Arking, Jennifer A. Brody, Nathan A. Bihlmeyer, David Porteous, Ayse Demirkan, Audrey Y. Chu, Franco Giulianini, James S. Floyd, Stefan Gustafsson, Xiuqing Guo, Johanna Jakobsdottir, Anne U. Jackson, Stavroula Kanoni, Richard A. Jensen, Igor Rudan, Man Li, Sirkka Keinanen-Kiukaanniemi, Alisa K. Manning, Yingchang Lu, Karina Meidtner, Jonathan Marten, Giorgio Pistis, Taulant Muka, Kenneth M. Rice, Bram Prins, Albert Vernon Smith, Serena Sanna, Lorraine Southam, Jennifer A. Smith, Vinicius Tragante, Heather M. Stringham, Helen R. Warren, Sander W. van der Laan, Andrianos M. Yiorkas, Jie Yao, Wei Zhao, Weihua Zhang, Heather M. Highland, Mariaelisa Graff, Eirini Marouli, Anne E. Justice, Wesam A. Alhejily, Saima Afaq, Folkert W. Asselbergs, Najaf Amin, Michiel L. Bots, Lori L. Bonnycastle, Ji Chen, Ivan Brandslund, Abbas Dehghan, John Danesh, Tapani Ebeling, Jessica D. Faul, Aliki-Eleni Farmaki, Steve Franks, Paul W. Franks, Anette P. Gjesing, Andreas Fritsche, Göran Hallmans, Mark O. Goodarzi, Karl-Heinz Herzig, Tamara B. Harris, Min A Jhun, Marie-France Hivert, Marit E. Jørgensen, Torben Jørgensen, Eero Kajantie, Pekka Jousilahti, Sharon L.R. Kardia, Maria Karaleftheri, Heikki A. Koistinen, Leena Kinnunen, Peter Kovacs, Pirjo Komulainen, Markku Laakso, Johanna Kuusisto, Aaron Leong, Lenore J. Launer, Jocelyn E. Manning Fox, Jaana Lindström, Nisa M. Maruthur, Satu Männistö, Antonella Mulas, Leena Moilanen, Matthew Neville, Mike A. Nalls, Alison Pattie, James S. Pankow, Hannu Puolijoki, Eva R.B. Petersen, Paul Redmond, Asif Rasheed, Michael Roden, Frida Renström, Juha Saltevo, Danish Saleheen, Sylvain Sebert, Kai Savonen, Alena Stančáková, Kerrin S. Small, Konstantin Strauch, Jakob Stokholm, Betina H. Thuesen, Juha Auvinen, E-Shyong Tai, Emmanouil Tsafantakis, Anke Tönjes, Jaakko Tuomilehto, Tiinamaija Tuomi, Marja Vääräsmäki, Matti Uusitupa, Magdalena Zoledziewska, Ilonca Vaartjes, Beverley Balkau, Goncalo Abecasis, Alexandra I. Blakemore, Hans Bisgaard, Heiner Boeing, Ruth J.F. Loos, Matthias Blüher, Klaus Bønnelykke, Eric Boerwinkle, Mark J. Caulfield, Erwin P. Bottinger, Daniel I. Chasman, John C. Chambers, Francis S. Collins, Ching-Yu Cheng, Francesco Cucca, Josef Coresh, George Dedoussis, Gert J. de Borst, Hester M. den Ruijter, Panos Deloukas, Ele Ferrannini, Michele K. Evans, Harald Grallert, Oscar H. Franco, Arfan Ikram, Joel N. Hirschhorn, Fredrik Karpe, Erik Ingelsson, Wieland Kiess, Carolina Medina-Gomez, Kay-Tee Kaw, Antje Körner, Jaspal S. Kooner, Cecilia M. Lindgren, Timo Lakka, Ching-Ti Liu, Leonard Lipovich, Patrick E. MacDonald, Jun Liu, Andrew D. Morris, Karen L. Mohlke, Alison Murray, Patricia B. Munroe, Gerard Pasterkamp, Colin N. A . Palmer, Patricia A. Peyser, Oluf Pedersen, Paul M. Ridker, Rainer Rauramaa, Patrik Rorsman, Olov Rolandsson, Veikko Salomaa, Frits R. Rosendaal, Robert Sladek, Matthias B. Schulze, Michael Stumvoll, Timothy D. Spector, Mark Walker, Cornelia M. van Duijn, David R. Weir, Nick J. Wareham, Tien Yin Wong, James G. Wilson, Alan B. Zonderman, Eleftheria Zeggini, Andrew P. Morris, Jerome I. Rotter, Jose C. Florez, Michael Boehnke, James B. Meigs, Mark I. McCarthy, Robert A. Scott, Anubha Mahajan, Inês Barroso, Anna L. Gloyn, Michael A. Province, Niels Grarup, Ruifang Li-Gao, Jette Bork-Jensen, Yongmei Liu, Allan Linneberg, Leslie A. Lange, Sandosh Padmanabhan, Gail Davies, Lars Lind, Bruce M. Psaty, Tea Skaaby, Torben Hansen, Ozren Polasek, John M. Starr, Dennis O. Mook-Kanamori, Vilmundur Gudnason, Kent D. Taylor, Marjo-Riitta Järvelin, Renée de Mutsert, Paul Elliott, Josée Dupuis, Blair H. Smith, and Andrew T. Hattersley

Subjects
exome chip, glycaemic traits, genetic discovery, effector genes, summary statistics resources, eng, Medicine, Science
Abstract

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Published
2023
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37. Virtual twin for healthcare management

Author

Thomas M. Polasek

Subjects
virtual twin, precision medicine, personalized medicine, precision dosing, pharmacogenomics (PGx), Medicine, Public aspects of medicine, RA1-1270, Electronic computers. Computer science, QA75.5-76.95
Abstract

Healthcare is increasingly fragmented, resulting in escalating costs, patient dissatisfaction, and sometimes adverse clinical outcomes. Strategies to decrease healthcare fragmentation are therefore attractive from payer and patient perspectives. In this commentary, a patient-centered smart phone application called Virtual Twin for Healthcare Management (VTHM) is proposed, including its organizational layout, basic functionality, and potential clinical applications. The platform features a virtual twin hub that displays the body and its health data. This is a physiologically based human model that is “virtualized” for the patient based on their unique genetic, molecular, physiological, and disease characteristics. The spokes of the system are a full service and interoperable electronic-health record, accessible to healthcare providers with permission on any device with internet access. Theoretical case studies based on real scenarios are presented to show how VTHM could potentially improve patient care and clinical efficiency. Challenges that must be overcome to turn VTHM into reality are also briefly outlined. Notably, the VTHM platform is designed to operationalize current and future precision medicine initiatives, such as access to molecular diagnostic results, pharmacogenomics-guided prescribing, and model-informed precision dosing.

Published
2023
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38. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Author

Ntalla, Ioanna, Weng, Lu-Chen, Cartwright, James H, Hall, Amelia Weber, Sveinbjornsson, Gardar, Tucker, Nathan R, Choi, Seung Hoan, Chaffin, Mark D, Roselli, Carolina, Barnes, Michael R, Mifsud, Borbala, Warren, Helen R, Hayward, Caroline, Marten, Jonathan, Cranley, James J, Concas, Maria Pina, Gasparini, Paolo, Boutin, Thibaud, Kolcic, Ivana, Polasek, Ozren, Rudan, Igor, Araujo, Nathalia M, Lima-Costa, Maria Fernanda, Ribeiro, Antonio Luiz P, Souza, Renan P, Tarazona-Santos, Eduardo, Giedraitis, Vilmantas, Ingelsson, Erik, Mahajan, Anubha, Morris, Andrew P, Del Greco M, Fabiola, Foco, Luisa, Gögele, Martin, Hicks, Andrew A, Cook, James P, Lind, Lars, Lindgren, Cecilia M, Sundström, Johan, Nelson, Christopher P, Riaz, Muhammad B, Samani, Nilesh J, Sinagra, Gianfranco, Ulivi, Sheila, Kähönen, Mika, Mishra, Pashupati P, Mononen, Nina, Nikus, Kjell, Caulfield, Mark J, Dominiczak, Anna, Padmanabhan, Sandosh, Montasser, May E, O'Connell, Jeff R, Ryan, Kathleen, Shuldiner, Alan R, Aeschbacher, Stefanie, Conen, David, Risch, Lorenz, Thériault, Sébastien, Hutri-Kähönen, Nina, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Raitakari, Olli T, Barnes, Catriona LK, Campbell, Harry, Joshi, Peter K, Wilson, James F, Isaacs, Aaron, Kors, Jan A, van Duijn, Cornelia M, Huang, Paul L, Gudnason, Vilmundur, Harris, Tamara B, Launer, Lenore J, Smith, Albert V, Bottinger, Erwin P, Loos, Ruth JF, Nadkarni, Girish N, Preuss, Michael H, Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Müller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D, Rienstra, Michiel, van de Vegte, Yordi J, van der Harst, Pim, Verweij, Niek, Kääb, Stefan, Schramm, Katharina, Sinner, Moritz F, Strauch, Konstantin, Cutler, Michael J, Fatkin, Diane, London, Barry, Olesen, Morten, and Roden, Dan M

Subjects
Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, Electrocardiography, Gene Expression, Multifactorial Inheritance, Quantitative Trait Loci, Female, Male, Arrhythmias, Cardiac, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Endophenotypes, Arrhythmias, Cardiac
Abstract

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.

Published
2020

39. Electron collisions with cyanoacetylene HCCCN: vibrational excitation and dissociative electron attachment

Author

Ranković, M., Nag, P., Zawadzki, M., Ballauf, L., Žabka, J., Polášek, M., Kočišek, J., and Fedor, J.

Subjects
Physics - Chemical Physics
Abstract

We experimentally probe electron collisions with HC$_3$N in the energy range from 0 to 10 eV with the focus on vibrational excitation and dissociative electron attachment. The vibrational excitation cross sections show a number of resonances which are mode specific: the two dominant $\pi^*$ resonances are visible in the excitation of all the vibrational modes, however, broad $\sigma^*$ resonances are visible only in certain bond-stretching vibrational modes. The lower $\pi^*$ resonance shows a pronounced boomerang structure. Since it overlaps with the threshold peak originating from a long-range electron-molecule interaction, the interference pattern is rather unusual. Somewhat surprisingly, the boomerang structure is visible also in the elastic scattering cross section. The dissociative electron attachment cross sections agree qualitatively with the data of Gilmore and Field [J. Phys. B 48 (2015) 035201], however, approximately a factor of two difference is found in the absolute values.

Published
2018
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40. Delineating gene–environment effects using virtual twins of patients treated with clozapine

Author

Sam Mostafa, Thomas M. Polasek, Chad Bousman, Amin Rostami‐Hodjegan, Leslie J. Sheffield, Ian Everall, Christos Pantelis, and Carl M. J. Kirkpatrick

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model‐informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine‐treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: “low” (demographic), “medium” (demographic and environmental interaction), and “high” (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R2) from 0.07 in the low model to 0.391 and 0.368 in the medium and high models, respectively. Whereas R2 was similar between the medium and high models, the high covariate virtualization model had improved accuracy, with systematic bias of predicted clozapine plasma concentration improving from −138.48 ng/ml to −74.65 ng/ml. A high level of covariate virtualization (demographic, environmental, and genotype) may be required for MIPD using VTs.

Published
2023
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41. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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42. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Soren, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Jr, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., and Hoed, Marcel den

Published
2022
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43. Solving the MCM paradox by visualizing the scaffold of CMG helicase at active replisomes

Author

Hana Polasek-Sedlackova, Thomas C. R. Miller, Jana Krejci, Maj-Britt Rask, and Jiri Lukas

Subjects
Science
Abstract

For several decades the MCM2-7 proteins, the core of the DNA replicative helicase, eluded detection at DNA replication sites. Here, the authors solve this conundrum by gene editing, which enables visualization of replication dynamics in living cells.

Published
2022
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44. Author Correction: Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Author

Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Åsa K., Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E., Gieger, Christian, Needham, Elise J., Surendran, Praveen, Paul, Dirk S., Polasek, Ozren, Thorand, Barbara, Grallert, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Åsa, Gyllensten, Ulf, Powell, Nick, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K., Danesh, John, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F., Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam S., and Peters, James E.

Published
2023
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45. New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Author

Evangelou, Evangelos, Gao, He, Chu, Congying, Ntritsos, Georgios, Blakeley, Paul, Butts, Andrew R, Pazoki, Raha, Suzuki, Hideaki, Koskeridis, Fotios, Yiorkas, Andrianos M, Karaman, Ibrahim, Elliott, Joshua, Luo, Qiang, Aeschbacher, Stefanie, Bartz, Traci M, Baumeister, Sebastian E, Braund, Peter S, Brown, Michael R, Brody, Jennifer A, Clarke, Toni-Kim, Dimou, Niki, Faul, Jessica D, Homuth, Georg, Jackson, Anne U, Kentistou, Katherine A, Joshi, Peter K, Lemaitre, Rozenn N, Lind, Penelope A, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Milaneschi, Yuri, Nelson, Christopher P, Nolte, Ilja M, Perälä, Mia-Maria, Polasek, Ozren, Porteous, David, Ratliff, Scott M, Smith, Jennifer A, Stančáková, Alena, Teumer, Alexander, Tuominen, Samuli, Thériault, Sébastien, Vangipurapu, Jagadish, Whitfield, John B, Wood, Alexis, Yao, Jie, Yu, Bing, Zhao, Wei, Arking, Dan E, Auvinen, Juha, Liu, Chunyu, Männikkö, Minna, Risch, Lorenz, Rotter, Jerome I, Snieder, Harold, Veijola, Juha, Blakemore, Alexandra I, Boehnke, Michael, Campbell, Harry, Conen, David, Eriksson, Johan G, Grabe, Hans J, Guo, Xiuqing, van der Harst, Pim, Hartman, Catharina A, Hayward, Caroline, Heath, Andrew C, Jarvelin, Marjo-Riitta, Kähönen, Mika, Kardia, Sharon LR, Kühne, Michael, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lehtimäki, Terho, McIntosh, Andrew M, Mohlke, Karen L, Morrison, Alanna C, Martin, Nicholas G, Oldehinkel, Albertine J, Penninx, Brenda WJH, Psaty, Bruce M, Raitakari, Olli T, Rudan, Igor, Samani, Nilesh J, Scott, Laura J, Spector, Tim D, Verweij, Niek, Weir, David R, Wilson, James F, Levy, Daniel, Tzoulaki, Ioanna, Bell, Jimmy D, Matthews, Paul M, Rothenfluh, Adrian, Desrivières, Sylvane, Schumann, Gunter, and Elliott, Paul

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Epidemiology, Health Sciences, Psychology, Pharmacology and Pharmaceutical Sciences, Biotechnology, Substance Misuse, Brain Disorders, Mental Health, Neurosciences, Serious Mental Illness, Alcoholism, Alcohol Use and Health, Schizophrenia, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Mental health, Stroke, Cancer, Oral and gastrointestinal, Good Health and Well Being, Adult, Aged, Alcohol Drinking, Alcoholism, Brain, Female, Genes, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Neuroimaging, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Biomedical and clinical sciences, Health sciences
Abstract

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

Published
2019

46. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Author

Sabater-Lleal, Maria, Huffman, Jennifer E, de Vries, Paul S, Marten, Jonathan, Mastrangelo, Michael A, Song, Ci, Pankratz, Nathan, Ward-Caviness, Cavin K, Yanek, Lisa R, Trompet, Stella, Delgado, Graciela E, Guo, Xiuqing, Bartz, Traci M, Martinez-Perez, Angel, Germain, Marine, de Haan, Hugoline G, Ozel, Ayse B, Polasek, Ozren, Smith, Albert V, Eicher, John D, Reiner, Alex P, Tang, Weihong, Davies, Neil M, Stott, David J, Rotter, Jerome I, Tofler, Geoffrey H, Boerwinkle, Eric, de Maat, Moniek PM, Kleber, Marcus E, Welsh, Paul, Brody, Jennifer A, Chen, Ming-Huei, Vaidya, Dhananjay, Soria, José Manuel, Suchon, Pierre, van Hylckama Vlieg, Astrid, Desch, Karl C, Kolcic, Ivana, Joshi, Peter K, Launer, Lenore J, Harris, Tamara B, Campbell, Harry, Rudan, Igor, Becker, Diane M, Li, Jun Z, Rivadeneira, Fernando, Uitterlinden, André G, Hofman, Albert, Franco, Oscar H, Cushman, Mary, Psaty, Bruce M, Morange, Pierre-Emmanuel, McKnight, Barbara, Chong, Michael R, Fernandez-Cadenas, Israel, Rosand, Jonathan, Lindgren, Arne, Consortium, INVENT Consortium MEGASTROKE Consortium of the International Stroke Genetics, Gudnason, Vilmundur, Wilson, James F, Hayward, Caroline, Ginsburg, David, Fornage, Myriam, Rosendaal, Frits R, Souto, Juan Carlos, Becker, Lewis C, Jenny, Nancy S, März, Winfried, Jukema, J Wouter, Dehghan, Abbas, Trégouët, David-Alexandre, Morrison, Alanna C, Johnson, Andrew D, O’Donnell, Christopher J, Strachan, David P, Lowenstein, Charles J, and Smith, Nicholas L

Subjects
Epidemiology, Health Sciences, Hematology, Biotechnology, Rare Diseases, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Blood, Cardiovascular, Arterial Occlusive Diseases, Biomarkers, Blood Coagulation, Blood Coagulation Disorders, Inherited, Factor VIII, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Ribosomal Protein L3, Risk Factors, Venous Thrombosis, von Willebrand Factor, cardiovascular diseases, factor VIII, genome-wide association studies, genetics, risk factors, von Willebrand factor, INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Sports science and exercise
Abstract

BackgroundFactor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.MethodsWe meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.ResultsWe identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.ConclusionsThe meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Published
2019

47. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author

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

Subjects
Biology (General), QH301-705.5
Abstract

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

Published
2022
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48. Paramagnetic encoding of molecules

Author

Jan Kretschmer, Tomáš David, Martin Dračínský, Ondřej Socha, Daniel Jirak, Martin Vít, Radek Jurok, Martin Kuchař, Ivana Císařová, and Miloslav Polasek

Subjects
Science
Abstract

Molecules offer enormous capacity for information storage. Here, the authors show that information can be encoded into molecules with sequences of paramagnetic lanthanide ions, and decoded using nuclear magnetic resonance spectroscopy.

Published
2022
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49. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author

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, Niels, 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, JW, 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, Marcus, van Duijn, Cornelia M, Gasparini, Paolo, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hansen, Torben, Kääb, Stefan, Kanters, Jørgen K, Kooperberg, Charles, Lehtimäki, Terho, Lin, Henry J, Lubitz, Steven A, Mook-Kanamori, Dennis O, Conti, Francesco J, Newton-Cheh, Christopher H, Rosand, Jonathan, Rudan, Igor, and Samani, Nilesh J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, ADAMTS Proteins, Animals, Black People, Connexin 43, Electrocardiography, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mice, Middle Aged, Myocardium, Open Reading Frames, Polymorphism, Single Nucleotide, White People, Exome Sequencing, Exome chip, Conduction, ADAMTS6, Meta-analysis, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundGenome-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.ResultsHere, 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.ConclusionsOur approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Published
2018

50. Coronary artery perforation successfully treated with a second drug-eluting stent

Author

Matej Strycek, Lukas Jaworski, Rostislav Polasek, and Pavol Tomasov

Subjects
Medicine (General), R5-920
Abstract

A coronary artery perforation is a rare, but potentially lethal, complication of percutaneous coronary intervention. We present a case of massive main vessel coronary perforation of the right coronary artery in a patient with acute ST segment elevation myocardial infarction, which was successfully treated with a second drug-eluting stent. This uncommon therapeutic approach was used to preserve flow to the large side branch. Early recognition, rapid balloon re-inflation at the perforation site and a “ping-pong” guiding technique allowed us to prepare the optimal strategy and to treat the perforation without developing cardiac tamponade.

Published
2023
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