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Genetic architecture of subcortical brain structures in 38,851 individuals
Genetical Statistics and Systems Biology

Abstract (Expand)

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, … caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Authors: Claudia L. Satizabal, Hieab H. H. Adams, Derrek P. Hibar, Charles C. White, Maria J. Knol, Jason L. Stein, Markus Scholz, Muralidharan Sargurupremraj, Neda Jahanshad, Gennady V. Roshchupkin, Albert V. Smith, Joshua C. Bis, Xueqiu Jian, Michelle Luciano, Edith Hofer, Alexander Teumer, Sven J. van der Lee, Jingyun Yang, Lisa R. Yanek, Tom V. Lee, Shuo Li, Yanhui Hu, Jia Yu Koh, John D. Eicher, Sylvane Desrivières, Alejandro Arias-Vasquez, Ganesh Chauhan, Lavinia Athanasiu, Miguel E. Rentería, Sungeun Kim, David Hoehn, Nicola J. Armstrong, Qiang Chen, Avram J. Holmes, Anouk den Braber, Iwona Kloszewska, Micael Andersson, Thomas Espeseth, Oliver Grimm, Lucija Abramovic, Saud Alhusaini, Yuri Milaneschi, Martina Papmeyer, Tomas Axelsson, Stefan Ehrlich, Roberto Roiz-Santiañez, Bernd Kraemer, Asta K. Håberg, Hannah J. Jones, G. Bruce Pike, Dan J. Stein, Allison Stevens, Janita Bralten, Meike W. Vernooij, Tamara B. Harris, Irina Filippi, A. Veronica Witte, Tulio Guadalupe, Katharina Wittfeld, Thomas H. Mosley, James T. Becker, Nhat Trung Doan, Saskia P. Hagenaars, Yasaman Saba, Gabriel Cuellar-Partida, Najaf Amin, Saima Hilal, Kwangsik Nho, Nazanin Mirza-Schreiber, Konstantinos Arfanakis, Diane M. Becker, David Ames, Aaron L. Goldman, Phil H. Lee, Dorret I. Boomsma, Simon Lovestone, Sudheer Giddaluru, Stephanie Le Hellard, Manuel Mattheisen, Marc M. Bohlken, Dalia Kasperaviciute, Lianne Schmaal, Stephen M. Lawrie, Ingrid Agartz, Esther Walton, Diana Tordesillas-Gutierrez, Gareth E. Davies, Jean Shin, Jonathan C. Ipser, Louis N. Vinke, Martine Hoogman, Tianye Jia, Ralph Burkhardt, Marieke Klein, Fabrice Crivello, Deborah Janowitz, Owen Carmichael, Unn K. Haukvik, Benjamin S. Aribisala, Helena Schmidt, Lachlan T. Strike, Ching-Yu Cheng, Shannon L. Risacher, Benno Pütz, Debra A. Fleischman, Amelia A. Assareh, Venkata S. Mattay, Randy L. Buckner, Patrizia Mecocci, Anders M. Dale, Sven Cichon, Marco P. Boks, Mar Matarin, Brenda W. J. H. Penninx, Vince D. Calhoun, M. Mallar Chakravarty, Andre F. Marquand, Christine Macare, Shahrzad Kharabian Masouleh, Jaap Oosterlaan, Philippe Amouyel, Katrin Hegenscheid, Jerome I. Rotter, Andrew J. Schork, David C. M. Liewald, Greig I. de Zubicaray, Tien Yin Wong, Li Shen, Philipp G. Sämann, Henry Brodaty, Joshua L. Roffman, Eco J. C. de Geus, Magda Tsolaki, Susanne Erk, Kristel R. van Eijk, Gianpiero L. Cavalleri, Nic J. A. van der Wee, Andrew M. McIntosh, Randy L. Gollub, Kazima B. Bulayeva, Manon Bernard, Jennifer S. Richards, Jayandra J. Himali, Markus Loeffler, Nanda Rommelse, Wolfgang Hoffmann, Lars T. Westlye, Maria C. Valdés Hernández, Narelle K. Hansell, Theo G. M. van Erp, Christiane Wolf, John B. J. Kwok, Bruno Vellas, Andreas Heinz, Loes M. Olde Loohuis, Norman Delanty, Beng-Choon Ho, Christopher R. K. Ching, Elena Shumskaya, Baljeet Singh, Albert Hofman, Dennis van der Meer, Georg Homuth, Bruce M. Psaty, Mark E. Bastin, Grant W. Montgomery, Tatiana M. Foroud, Simone Reppermund, Jouke-Jan Hottenga, Andrew Simmons, Andreas Meyer-Lindenberg, Wiepke Cahn, Christopher D. Whelan, Marjolein M. J. van Donkelaar, Qiong Yang, Norbert Hosten, Robert C. Green, Anbupalam Thalamuthu, Sebastian Mohnke, Hilleke E. Hulshoff Pol, Honghuang Lin, Clifford R. Jack, Peter R. Schofield, Thomas W. Mühleisen, Pauline Maillard, Steven G. Potkin, Wei Wen, Evan Fletcher, Arthur W. Toga, Oliver Gruber, Matthew Huentelman, George Davey Smith, Lenore J. Launer, Lars Nyberg, Erik G. Jönsson, Benedicto Crespo-Facorro, Nastassja Koen, Douglas N. Greve, André G. Uitterlinden, Daniel R. Weinberger, Vidar M. Steen, Iryna O. Fedko, Nynke A. Groenewold, Wiro J. Niessen, Roberto Toro, Christophe Tzourio, William T. Longstreth, M. Kamran Ikram, Jordan W. Smoller, Marie-Jose van Tol, Jessika E. Sussmann, Tomas Paus, Hervé Lemaître, Matthias L. Schroeter, Bernard Mazoyer, Ole A. Andreassen, Florian Holsboer, Chantal Depondt, Dick J. Veltman, Jessica A. Turner, Zdenka Pausova, Gunter Schumann, Daan van Rooij, Srdjan Djurovic, Ian J. Deary, Katie L. McMahon, Bertram Müller-Myhsok, Rachel M. Brouwer, Hilkka Soininen, Massimo Pandolfo, Thomas H. Wassink, Joshua W. Cheung, Thomas Wolfers, Jean-Luc Martinot, Marcel P. Zwiers, Matthias Nauck, Ingrid Melle, Nicholas G. Martin, Ryota Kanai, Eric Westman, René S. Kahn, Sanjay M. Sisodiya, Tonya White, Arvin Saremi, Hans van Bokhoven, Han G. Brunner, Henry Völzke, Margaret J. Wright, Dennis van ’t Ent, Markus M. Nöthen, Roel A. Ophoff, Jan K. Buitelaar, Guillén Fernández, Perminder S. Sachdev, Marcella Rietschel, Neeltje E. M. van Haren, Simon E. Fisher, Alexa S. Beiser, Clyde Francks, Andrew J. Saykin, Karen A. Mather, Nina Romanczuk-Seiferth, Catharina A. Hartman, Anita L. DeStefano, Dirk J. Heslenfeld, Michael W. Weiner, Henrik Walter, Pieter J. Hoekstra, Paul A. Nyquist, Barbara Franke, David A. Bennett, Hans J. Grabe, Andrew D. Johnson, Christopher Chen, Cornelia M. van Duijn, Oscar L. Lopez, Myriam Fornage, Joanna M. Wardlaw, Reinhold Schmidt, Charles DeCarli, Philip L. de Jager, Arno Villringer, Stéphanie Debette, Vilmundur Gudnason, Sarah E. Medland, Joshua M. Shulman, Paul M. Thompson, Sudha Seshadri, M. Arfan Ikram

Date Published: 1st Nov 2019

Publication Type: Journal article

Human brain arousal in the resting state: a genome-wide association study
Genetical Statistics and Systems Biology

Abstract (Expand)

Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, … stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.   Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders. // Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.

Authors: Philippe Jawinski, Holger Kirsten, Christian Sander, Janek Spada, Christine Ulke, Jue Huang, Ralph Burkhardt, Markus Scholz, Tilman Hensch, Ulrich Hegerl

Date Published: 1st Nov 2019

Publication Type: Journal article

Circulating oxytocin is genetically determined and associated with obesity and impaired glucose tolerance
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Despite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well powered studies addressing the relationship of circulating OXT with obesity and diabetes. …. OBJECTIVES AND DESIGN Here, we measured OXT in a study cohort (n=721; 396 women, 325 men; mean age\pmSD - 47.7\pm15.2 years) with sub-phenotypes related to obesity including anthropometric traits such as body mass index (BMI; mean\pmSD - 47.7\pm15.2 kg/m2), waist-to-hip-ratio (WHR; 0.88\pm0.09), blood parameters (glucose - 5.32\pm0.50 mmol/l, insulin - 5.3\pm3.3 µU/ml, lipids) and oral glucose tolerance test (OGTT) to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the inter-individual variation in OXT serum levels might be explained by genetic variation. RESULTS The OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference and triglyceride levels. The OXT concentration in subjects with BMI\textless25 kg/m2 was significantly lower (n=256; 78.6 pg/ml) than in subjects with a BMI between 25-30 kg/m2 (n=314; 98.5 pg/ml, p=6x10-6) and with BMI\textgreater30 kg/m2 (n=137; 106.4 pg/ml, p=8x10-6). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (p=4.6x10-3). Heritability of OXT was estimated to 12.8%. In a GWAS, two hits in linkage disequilibrium close (19kb) to the OXT reached genome-wide significant association (top-hit rs12625893, p=3.1x10-8, explained variance 3%). CONCLUSIONS Our data show that OXT is genetically affected by a variant in OXT and is associated with obesity and impaired glucose tolerance.

Authors: Mark Florian Joachim Weingarten, Markus Scholz, Tobias Wohland, Katrin Horn, Michael Stumvoll, Peter Kovacs, Anke Tönjes

Date Published: 1st Nov 2019

Publication Type: Journal article

Common variants in glyoxalase I do not increase chronic pancreatitis risk
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts …s (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP). METHODS Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples. RESULTS In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087). CONCLUSIONS Common GLO1 variants do not increase chronic pancreatitis risk.

Authors: Tom Kaune, Marcus Hollenbach, Bettina Keil, Jian-Min Chen, Emmanuelle Masson, Carla Becker, Marko Damm, Claudia Ruffert, Robert Grützmann, Albrecht Hoffmeister, Rene H. M. Te Morsche, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Adrian Saftoiu, Ewa Malecka-Panas, Stanislaw Głuszek, Peter Bugert, Markus M. Lerch, Frank Ulrich Weiss, Wen-Bin Zou, Zhuan Liao, Peter Hegyi, Joost Ph Drenth, Jan Riedel, Claude Férec, Markus Scholz, Holger Kirsten, Andrea Tóth, Maren Ewers, Heiko Witt, Heidi Griesmann, Patrick Michl, Jonas Rosendahl

Date Published: 29th Oct 2019

Publication Type: Journal article

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Genetical Statistics and Systems Biology

Abstract (Expand)

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 … individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Authors: Adrienne Tin, Jonathan Marten, Victoria L. Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B. Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, Ayush Giri, Gardar Sveinbjornsson, Man Li, Audrey Y. Chu, Anselm Hoppmann, Luke J. O’Connor, Bram Prins, Teresa Nutile, Damia Noce, Masato Akiyama, Massimiliano Cocca, Sahar Ghasemi, Peter J. van der Most, Katrin Horn, Yizhe Xu, Christian Fuchsberger, Sanaz Sedaghat, Saima Afaq, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Eric Boerwinkle, Erwin P. Bottinger, Thibaud S. Boutin, Marco Brumat, Ralph Burkhardt, Eric Campana, Archie Campbell, Harry Campbell, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Marina Ciullo, Maria Pina Concas, Josef Coresh, Tanguy Corre, Daniele Cusi, Sala Cinzia Felicita, Martin H. de Borst, Alessandro de Grandi, Renée de Mutsert, Aiko P. J. de Vries, Graciela Delgado, Ayşe Demirkan, Olivier Devuyst, Katalin Dittrich, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Michele K. Evans, Ron T. Gansevoort, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Martin Gögele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B. Harris, Caroline Hayward, Andrew A. Hicks, Edith Hofer, Hilma Holm, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M. Arfan Ikram, Raychel M. Lewis, Erik Ingelsson, Johanna Jakobsdottir, Ingileif Jonsdottir, Helgi Jonsson, Peter K. Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Shona M. Kerr, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Körner, Peter Kovacs, Bernhard K. Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Martina La Bianca, Leslie A. Lange, Benjamin Lehne, Terho Lehtimäki, Jun Liu, Markus Loeffler, Ruth J. F. Loos, Leo-Pekka Lyytikäinen, Reedik Magi, Anubha Mahajan, Nicholas G. Martin, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Christopher J. O’Donnell, Otis D. Wilson, J. Michael Gaziano, Pashupati P. Mishra, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Jeffrey R. O’Connell, Isleifur Olafsson, Sandosh Padmanabhan, Brenda W. J. H. Penninx, Thomas Perls, Annette Peters, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Ozren Polasek, Belen Ponte, David J. Porteous, Tanja Poulain, Michael H. Preuss, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Federica Rizzi, Antonietta Robino, Igor Rudan, Alena Krajcoviechova, Renata Cifkova, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Christian M. Shaffer, Albert V. Smith, Blair H. Smith, Cassandra N. Spracklen, Konstantin Strauch, Michael Stumvoll, Patrick Sulem, Salman M. Tajuddin, Andrej Teren, Joachim Thiery, Chris H. L. Thio, Unnur Thorsteinsdottir, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Simona Vaccargiu, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, John B. Whitfield, Sarah H. Wild, James F. Wilson, Qiong Yang, Weihua Zhang, Alan B. Zonderman, Murielle Bochud, James G. Wilson, Sarah A. Pendergrass, Kevin Ho, Afshin Parsa, Peter P. Pramstaller, Bruce M. Psaty, Carsten A. Böger, Harold Snieder, Adam S. Butterworth, Yukinori Okada, Todd L. Edwards, Kari Stefansson, Katalin Susztak, Markus Scholz, Iris M. Heid, Adriana M. Hung, Alexander Teumer, Cristian Pattaro, Owen M. Woodward, Veronique Vitart, Anna Köttgen

Date Published: 1st Oct 2019

Publication Type: Journal article

Effectiveness of different central venous catheter fixation suture techniques: An in vitro crossover study
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE Proper fixation of central venous catheters (CVCs) is an integral part of safety to avoid dislodgement and malfunction. However, the effectiveness of different CVC securement sutures is unknown. …. METHODS Analysis of maximum dislodgement forces for CVCs from three different manufacturers using four different suture techniques in an in vitro tensile loading experiment: 1. \textquotedblclamp only\textquotedbl, 2. \textquotedblclamp and compression suture\textquotedbl, 3. \textquotedblfinger trap\textquotedbl and 4. \textquotedblcomplete\textquotedbl, i.e., \textquotedblclamp + compression suture + finger trap\textquotedbl. Twenty-five tests were performed for each of the three CVC models and four securement suture techniques (n = 300 test runs). RESULTS The primary cause of catheter dislodgement was sliding through the clamp in techniques 1 and 2. In contrast, rupture of the suture was the predominant cause for dislodgement in techniques 2 and 3. Median (IQR 25-75%) dislodgement forces were 26.0 (16.6) N in technique 1, 26.5 (18.8) N in technique 2, 76.7 (18.7) N in technique 3, and 84.8 (11.8) N in technique 4. Post-hoc analysis demonstrated significant differences (P < .001) between all pairwise combinations of techniques except technique 1 vs. 2 (P = .98). CONCLUSIONS \textquotedblFinger trap\textquotedbl fixation at the segmentation site considerably increases forces required for dislodgement compared to clamp-based approaches.

Authors: Manuel Florian Struck, Lars Friedrich, Stefan Schleifenbaum, Holger Kirsten, Wolfram Schummer, Bernd E. Winkler

Date Published: 12th Sep 2019

Publication Type: Journal article

Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study
Genetical Statistics and Systems Biology

Abstract (Expand)

Importance Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. …. Objective To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures Type 2 diabetes and glycemic traits. Results This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 \times 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (\textgreekb = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

Authors: Tao Huang, Tiange Wang, Yan Zheng, Christina Ellervik, Xiang Li, Meng Gao, Zhe Fang, Jin-Fang Chai, Tarun Veer S. Ahluwalia, Yujie Wang, Trudy Voortman, Raymond Noordam, Alexis Frazier-Wood, Markus Scholz, Emily Sonestedt, Masato Akiyama, Rajkumar Dorajoo, Ang Zhou, Tuomas O. Kilpeläinen, Marcus E. Kleber, Sarah R. Crozier, Keith M. Godfrey, Rozenn Lemaitre, Janine F. Felix, Yuan Shi, Preeti Gupta, Chiea-Chuen Khor, Terho Lehtimäki, Carol A. Wang, Carla M. T. Tiesler, Elisabeth Thiering, Marie Standl, Peter Rzehak, Eirini Marouli, Meian He, Cécile Lecoeur, Dolores Corella, Chao-Qiang Lai, Luis A. Moreno, Niina Pitkänen, Colin A. Boreham, Tao Zhang, Seang Mei Saw, Paul M. Ridker, Mariaelisa Graff, Frank J. A. van Rooij, Andre G. Uitterlinden, Albert Hofman, Diana van Heemst, Frits R. Rosendaal, Renée de Mutsert, Ralph Burkhardt, Christina-Alexandra Schulz, Ulrika Ericson, Yoichiro Kamatani, Jian-Min Yuan, Chris Power, Torben Hansen, Thorkild I. A. Sørensen, Anne Tjønneland, Kim Overvad, Graciela Delgado, Cyrus Cooper, Luc Djousse, Fernando Rivadeneira, Karen Jameson, Wanting Zhao, Jianjun Liu, Nanette R. Lee, Olli Raitakari, Mika Kähönen, Jorma Viikari, Veit Grote, Jean-Paul Langhendries, Berthold Koletzko, Joaquin Escribano, Elvira Verduci, George Dedoussis, Caizheng Yu, Yih Chung Tham, Blanche Lim, Sing Hui Lim, Philippe Froguel, Beverley Balkau, Nadia R. Fink, Rebecca K. Vinding, Astrid Sevelsted, Hans Bisgaard, Oscar Coltell, Jean Dallongeville, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Oluf Pedersen, Winfried März, Hazel Inskip, Vincent W. V. Jaddoe, Elaine Dennison, Tien Yin Wong, Charumathi Sabanayagam, E-Shyong Tai, Karen L. Mohlke, David A. Mackey, Dariusz Gruszfeld, Panagiotis Deloukas, Katherine L. Tucker, Frédéric Fumeron, Klaus Bønnelykke, Peter Rossing, Ramon Estruch, Jose M. Ordovas, Donna K. Arnett, Aline Meirhaeghe, Philippe Amouyel, Ching-Yu Cheng, Xueling Sim, Yik Ying Teo, Rob M. van Dam, Woon-Puay Koh, Marju Orho-Melander, Markus Loeffler, Michiaki Kubo, Joachim Thiery, Dennis O. Mook-Kanamori, Dariush Mozaffarian, Bruce M. Psaty, Oscar H. Franco, Tangchun Wu, Kari E. North, George Davey Smith, Jorge E. Chavarro, Daniel I. Chasman, Lu Qi

Date Published: 4th Sep 2019

Publication Type: Journal article

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