Filter and export

Publications

188 Publications visible to you, out of a total of 188
Genetically programmed changes in transcription of the novel progranulin regulator
Genetical Statistics and Systems Biology

Abstract (Expand)

Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants … associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall \textgreater 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P \textless 1 \times 10-7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 \times 10-3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P \textless 1 \times 10-7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. KEY MESSAGES: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding. PSRC1 is also epigenetically regulated in subjects with high progranulin levels.

Authors: Maria Keller, Claudia Gebhardt, Sandra Huth, Dorit Schleinitz, Henrike Heyne, Markus Scholz, Michael Stumvoll, Yvonne Böttcher, Anke Tönjes, Peter Kovacs

Date Published: 1st Aug 2020

Publication Type: Journal article

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

Genetic association of objective sleep phenotypes with a functional polymorphism in the neuropeptide S receptor gene
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND The neuropeptide S receptor (NPSR1) and its ligand neuropeptide S (NPS) have received increased attention in the last few years, as both establish a previously unknown system of neuromodulation. …. Animal research studies have suggested that NPS may be involved in arousal/wakefulness and may also have a crucial role in sleep regulation. The single nucleotide polymorphism (SNP) rs324981 in NPSR1 has begun to shed light on a function of the NPS-system in human sleep regulation. Due to an amino acid exchange, the T-allele leads to an increased sensitivity of the NPSR1. In the only genome-wide association study to date on circadian sleep parameters in humans, an association was found between rs324981 and regular bedtime. However, the sleep parameters in this study were only measured by self-rating. Therefore, our study aimed to replicate these findings using an objective measure of sleep. METHODS The study included n = 393 white subjects (62-79 years) who participated in an actigraphic assessment for determining sleep duration, rest duration, sleep onset, rest onset and sleep onset latency. Genotyping of the SNP rs324981 was performed using the TaqMan OpenArray System. RESULTS The genotype at rs324981 was not significantly associated with rest onset (bedtime) or sleep onset (p = .146 and p = .199, respectively). However, the SNP showed a significant effect on sleep- and rest duration (p = .007 and p = .003, respectively). Subjects that were homozygous for the minor T-allele had a significantly decreased sleep- and rest duration compared to A-allele carriers. CONCLUSION The results of this study indicate that the sleep pattern in humans is influenced by the NPS-system. However, the previously reported association between bedtime and rs324981 could not be confirmed. The current finding of decreased sleep duration in T/T allele carriers is in accordance with studies in rodents reporting similar results after NPS application.

Authors: Janek Spada, Christian Sander, Ralph Burkhardt, Madlen Häntzsch, Roland Mergl, Markus Scholz, Ulrich Hegerl, Tilman Hensch

Date Published: 4th Jun 2014

Publication Type: Journal article

Genetic association study of eight steroid hormones and implications for sexual dimorphism of coronary artery disease
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

CONTEXT: Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed. OBJECTIVE: Our main objective …e was to identify genetic loci influencing steroid hormone levels. As secondary aim, we searched for causal effects of steroid hormones on CAD. DESIGN: We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, DHEA-S, estradiol and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, max. n=7667), and progesterone, 17-hydroxyprogesterone, androstenedione and aldosterone in LIFE-Heart only (max. n=2070). All genome-wide significant loci were tested for sex interactions. Further, we tested if previously reported CAD SNPs were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian Randomization (MR) approaches. RESULTS: We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEA-S, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism: CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, e.g., to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits. CONCLUSION: Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sex-dimorphisms in other complex diseases.

Authors: J. Pott, YJ. Bae, K. Horn, A. Teren, Andreas Kühnapfel, H. Kirsten, U. Ceglarek, Markus Löffler, J. Thiery, J. Kratzsch, Markus Scholz

Date Published: 6th Jun 2019

Publication Type: Not specified

Human Diseases: coronary artery disease

Genetic Contribution of Variants near SORT1 and APOE on LDL Cholesterol Independent of Obesity in Children
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity …y in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 101 to \textgreater104 fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.   OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants. //  OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.   OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants. //  OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.

Authors: Clara Breitling, Arnd Gross, Petra Büttner, Sebastian Weise, Dorit Schleinitz, Wieland Kiess, Markus Scholz, Peter Kovacs, Antje Körner

Date Published: 16th Sep 2015

Publication Type: Journal article

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.
Genetical Statistics and Systems Biology

Abstract (Expand)

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide … associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/beta-catenin, TGF-beta and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Authors: E. Hofer, G. V. Roshchupkin, H. H. H. Adams, M. J. Knol, H. Lin, S. Li, H. Zare, S. Ahmad, N. J. Armstrong, C. L. Satizabal, M. Bernard, J. C. Bis, N. A. Gillespie, M. Luciano, A. Mishra, M. Scholz, A. Teumer, R. Xia, X. Jian, T. H. Mosley, Y. Saba, L. Pirpamer, S. Seiler, J. T. Becker, O. Carmichael, J. I. Rotter, B. M. Psaty, O. L. Lopez, N. Amin, S. J. van der Lee, Q. Yang, J. J. Himali, P. Maillard, A. S. Beiser, C. DeCarli, S. Karama, L. Lewis, M. Harris, M. E. Bastin, I. J. Deary, A. Veronica Witte, F. Beyer, M. Loeffler, K. A. Mather, P. R. Schofield, A. Thalamuthu, J. B. Kwok, M. J. Wright, D. Ames, J. Trollor, J. Jiang, H. Brodaty, W. Wen, M. W. Vernooij, A. Hofman, A. G. Uitterlinden, W. J. Niessen, K. Wittfeld, R. Bulow, U. Volker, Z. Pausova, G. Bruce Pike, S. Maingault, F. Crivello, C. Tzourio, P. Amouyel, B. Mazoyer, M. C. Neale, C. E. Franz, M. J. Lyons, M. S. Panizzon, O. A. Andreassen, A. M. Dale, M. Logue, K. L. Grasby, N. Jahanshad, J. N. Painter, L. Colodro-Conde, J. Bralten, D. P. Hibar, P. A. Lind, F. Pizzagalli, J. L. Stein, P. M. Thompson, S. E. Medland, P. S. Sachdev, W. S. Kremen, J. M. Wardlaw, A. Villringer, C. M. van Duijn, H. J. Grabe, W. T. Jr Longstreth, M. Fornage, T. Paus, S. Debette, M. Arfan Ikram, H. Schmidt, R. Schmidt, S. Seshadri

Date Published: 22nd Sep 2020

Publication Type: Journal article

Genetic correlations reveal the shared genetic architecture of transcription in human peripheral blood
Genetical Statistics and Systems Biology

Abstract (Expand)

Transcript co-expression is regulated by a combination of shared genetic and environmental factors. Here, we estimate the proportion of co-expression that is due to shared genetic variance. To do so, … we estimated the genetic correlations between each pairwise combination of 2469 transcripts that are highly heritable and expressed in whole blood in 1748 unrelated individuals of European ancestry. We identify 556 pairs with a significant genetic correlation of which 77% are located on different chromosomes, and report 934 expression quantitative trait loci, identified in an independent cohort, with significant effects on both transcripts in a genetically correlated pair. We show significant enrichment for transcription factor control and physical proximity through chromatin interactions as possible mechanisms of shared genetic control. Finally, we construct networks of interconnected transcripts and identify their underlying biological functions. Using genetic correlations to investigate transcriptional co-regulation provides valuable insight into the nature of the underlying genetic architecture of gene regulation.Covariance of gene expression pairs is due to a combination of shared genetic and environmental factors. Here the authors estimate the genetic correlation between highly heritable pairs and identify transcription factor control and chromatin interactions as possible mechanisms of correlation.

Authors: Samuel W. Lukowski, Luke R. Lloyd-Jones, Alexander Holloway, Holger Kirsten, Gibran Hemani, Jian Yang, Kerrin Small, Jing Zhao, Andres Metspalu, Emmanouil T. Dermitzakis, Greg Gibson, Timothy D. Spector, Joachim Thiery, Markus Scholz, Grant W. Montgomery, Tonu Esko, Peter M. Visscher, Joseph E. Powell

Date Published: 1st Dec 2017

Publication Type: Journal article

Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality
Genetical Statistics and Systems Biology

Abstract (Expand)

Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in … 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p\textless/=10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p\textless/=10-5). The best association signal (rs117983287; p=8.16x10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99x10-6) and a region on chromosome 13q21.33 (p=3.34x10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities.   Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p\textless/=10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p\textless/=10-5). The best association signal (rs117983287; p=8.16x10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99x10-6) and a region on chromosome 13q21.33 (p=3.34x10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities. //  Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p\textless/=10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p\textless/=10-5). The best association signal (rs117983287; p=8.16x10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99x10-6) and a region on chromosome 13q21.33 (p=3.34x10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities.

Authors: Andre Scherag, Franziska Schoneweck, Miriam Kesselmeier, Stefan Taudien, Matthias Platzer, Marius Felder, Christoph Sponholz, Anna Rautanen, Adrian V. S. Hill, Charles J. Hinds, Hamid Hossain, Norbert Suttorp, Oliver Kurzai, Hortense Slevogt, Evangelos J. Giamarellos-Bourboulis, Apostolos Armaganidis, Evelyn Trips, Markus Scholz, Frank M. Brunkhorst

Date Published: 1st Oct 2016

Publication Type: Journal article

Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating …g plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes. METHODS We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290). RESULTS Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P=1.94\times10-17). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P=7.01\times10-9) and 7 suggestive hits (P\textless1\times10-6). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness. CONCLUSIONS Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00497887.

Authors: Janne Pott, Valentin Schlegel, Andrej Teren, Katrin Horn, Holger Kirsten, Christina Bluecher, Juergen Kratzsch, Markus Loeffler, Joachim Thiery, Ralph Burkhardt, Markus Scholz

Date Published: 1st May 2018

Publication Type: Journal article

Genetic regulation of serum phytosterol levels and risk of coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnPhytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We … used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnA genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)).\backslashr\backslashnCONCLUSION\backslashr\backslashnCommon variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

Authors: Daniel Teupser, Ronny Baber, Uta Ceglarek, Markus Scholz, Thomas Illig, Christian Gieger, Lesca Miriam Holdt, Alexander Leichtle, Karin H. Greiser, Dominik Huster, Patrick Linsel-Nitschke, Arne Schäfer, Peter S. Braund, Laurence Tiret, Klaus Stark, Dorette Raaz-Schrauder, Georg M. Fiedler, Wolfgang Wilfert, Frank Beutner, Stephan Gielen, Anika Grosshennig, Inke R. König, Peter Lichtner, Iris M. Heid, Alexander Kluttig, Nour E El Mokhtari, Diana Rubin, Arif B. Ekici, André Reis, Christoph D. Garlichs, Alistair S. Hall, Gert Matthes, Christian Wittekind, Christian Hengstenberg, Francois Cambien, Stefan Schreiber, Karl Werdan, Thomas Meitinger, Markus Loeffler, Nilesh J. Samani, Jeanette Erdmann, Heinz-Erich Wichmann, Heribert Schunkert, Joachim Thiery

Date Published: 1st Aug 2010

Publication Type: Journal article

Genetic variants of lipase activity in chronic pancreatitis
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Holger Kirsten, Markus Scholz, Peter Kovacs, Harald Grallert, Annette Peters, Konstantin Strauch, Josef Frank, Marcella Rietschel, Markus M. Nöthen, Heiko Witt, Jonas Rosendahl

Date Published: 8th Dec 2015

Publication Type: Journal article

Genetic variation and recent positive selection in worldwide human populations: evidence from nearly 1 million SNPs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnGenome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases … and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.\backslashr\backslashnMETHODOLOGY\backslashr\backslashnWe genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

Authors: David López Herráez, Marc Bauchet, Kun Tang, Christoph Theunert, Irina Pugach, Jing Li, Madhusudan R. Nandineni, Arnd Gross, Markus Scholz, Mark Stoneking

Date Published: 18th Nov 2009

Publication Type: Journal article

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity
Genetical Statistics and Systems Biology

Abstract (Expand)

Population isolates have long been of interest to genetic epidemiologists because of their potential to increase power to detect disease-causing genetic variants. The Sorbs of Germany are considered … as cultural and linguistic isolates and have recently been the focus of disease association mapping efforts. They are thought to have settled in their present location in eastern Germany after a westward migration from a largely Slavic-speaking territory during the Middle Ages. To examine Sorbian genetic diversity within the context of other European populations, we analyzed genotype data for over 30 000 autosomal single-nucleotide polymorphisms from over 200 Sorbs individuals. We compare the Sorbs with other European individuals, including samples from population isolates. Despite their geographical proximity to German speakers, the Sorbs showed greatest genetic similarity to Polish and Czech individuals, consistent with the linguistic proximity of Sorbian to other West Slavic languages. The Sorbs also showed evidence of subtle levels of genetic isolation in comparison with samples from non-isolated European populations. The level of genetic isolation was less than that observed for the Sardinians and French Basque, who were clear outliers on multiple measures of isolation. The finding of the Sorbs as only a minor genetic isolate demonstrates the need to genetically characterize putative population isolates, as they possess a wide range of levels of isolation because of their different demographic histories.

Authors: Krishna R. Veeramah, Anke Tönjes, Peter Kovacs, Arnd Gross, Daniel Wegmann, Patrick Geary, Daniela Gasperikova, Iwar Klimes, Markus Scholz, John Novembre, Michael Stumvoll

Date Published: 1st Sep 2011

Publication Type: Journal article

Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque … burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes. METHODS AND RESULTS: We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, beta = -0.401, p = 5.22x10-9), which was not associated in women (beta = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB. CONCLUSIONS: We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect.

Authors: J. Pott, F. Beutner, K. Horn, H. Kirsten, K. Olischer, K. Wirkner, M. Loeffler, M. Scholz

Date Published: 30th May 2020

Publication Type: Journal article

Human Diseases: cardiovascular system disease, atherosclerosis

Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System
Genetical Statistics and Systems Biology

Abstract (Expand)

Coronary artery disease (CAD) has a complex etiology involving numerous environmental and genetic factors of disease risk. To date, the genetic 9p21 locus represents the most robust genetic finding for … prevalent and incident CAD. However, limited information is available on the genetic background of the severity and distribution of CAD. CAD manifests itself as stable CAD or acute coronary syndrome. The Gensini score quantifies the extent CAD but requires coronary angiography. Here, we aimed to identify novel genetic variants associated with Gensini score severity and distribution of CAD. A two-stage approach including a discovery and a replication stage was used to assess genetic variants. In the discovery phase, a meta-analysis of genome-wide association data of 4,930 CAD-subjects assessed by the Gensini score was performed. Selected single nucleotide polymorphisms (SNPs) were replicated in 2,283 CAD-subjects by de novo genotyping. We identified genetic loci located on chromosome 2 and 9 to be associated with Gensini score severity and distribution of CAD in the discovery stage. Although the loci on chromosome 2 could not be replicated in the second stage, the known CAD-locus on chromosome 9p21, represented by rs133349, was identified and, thus, was confirmed as risk locus for CAD severity.

Authors: Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E. Kleber, Winfried März, Christoph Sinning, Fabian J. Brunner, Christoph Waldeyer, Till Keller, Christoph H. Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel

Date Published: 20th Sep 2017

Publication Type: Journal article

Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study.
LIFE Adult, Genetical Statistics and Systems Biology

Abstract (Expand)

The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical … variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P </= 5x 10(-8) (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 x 10(-8) ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 x 10(-8) ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies.

Authors: J. Spada, M. Scholz, H. Kirsten, T. Hensch, K. Horn, P. Jawinski, C. Ulke, R. Burkhardt, K. Wirkner, M. Loeffler, U. Hegerl, C. Sander

Date Published: 30th Apr 2016

Publication Type: Journal article

Genome-wide association analysis of pulse wave velocity traits provide new insights into the causal relationship between arterial stiffness and blood pressure
LIFE Adult

Abstract (Expand)

Background The pathophysiology of arterial stiffness is not completely understood. Pulse wave velocity (PWV) is an established marker for arterial stiffness. We compare genetics of three PWV modes, … namely carotid-femoral PWV (cfPWV), brachial-ankle (baPWV) and brachial-femoral (bfPWV), reflecting different vascular segments to analyse association with genetic variants, heritability and genetic correlation with other biological traits. Furthermore we searched for shared genetic architecture concerning PWV, blood pressure (BP) and coronary artery disease (CAD) and examined the causal relationship between PWV and BP. Methods and results We performed a genome-wide association study (GWAS) for cfPWV, baPWV and bfPWV in LIFE-Adult (N = 3,643–6,734). We analysed the overlap of detected genetic loci with those of BP and CAD and performed genetic correlation analyses. By bidirectional Mendelian Randomization, we assessed the causal relationships between PWV and BP. For cfPWV we identified a new locus with genome-wide significance near SLC4A7 on cytoband 3p24.1 (lead SNP rs939834: p = 2.05x10-8). We replicated a known PWV locus on cytoband 14q32.2 near RP11-61O1.1 (lead SNPs: rs17773233, p = 1.38x10-4; rs1381289, p = 1.91x10-4) For baPWV we estimated a heritability of 28% and significant genetic correlation with hypertension (rg = 0.27, p = 6.65x10-8). We showed a positive causal effect of systolic blood pressure on PWV modes (cfPWV: p = 1.51x10-4; bfPWV: p = 1.45x10-3; baPWV: p = 6.82x10-15). Conclusions We identified a new locus for arterial stiffness and successfully replicated an earlier proposed locus. PWV shares common genetic architecture with BP and CAD. BP causally affects PWV. Larger studies are required to further unravel the genetic determinants and effects of PWV.

Authors: Michael Rode, Andrej Teren, Kerstin Wirkner, Katrin Horn, Holger Kirsten, Markus Loeffler, Markus Scholz, Janne Pott

Date Published: 13th Aug 2020

Publication Type: Journal article

Human Diseases: arteriosclerosis, arteriosclerotic cardiovascular disease

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Genetical Statistics and Systems Biology

Abstract (Expand)

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely … understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

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

Date Published: 1st Dec 2019

Publication Type: Journal article

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the … genetic architecture of early AMD. METHODS To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. RESULTS Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10- 8), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). CONCLUSIONS Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

Authors: Thomas W. Winkler, Felix Grassmann, Caroline Brandl, Christina Kiel, Felix Günther, Tobias Strunz, Lorraine Weidner, Martina E. Zimmermann, Christina A. Korb, Alicia Poplawski, Alexander K. Schuster, Martina Müller-Nurasyid, Annette Peters, Franziska G. Rauscher, Tobias Elze, Katrin Horn, Markus Scholz, Marisa Cañadas-Garre, Amy Jayne McKnight, Nicola Quinn, Ruth E. Hogg, Helmut Küchenhoff, Iris M. Heid, Klaus J. Stark, Bernhard H. F. Weber

Date Published: 1st Dec 2020

Publication Type: Journal article

Genome-wide association study identifies an acute myeloid leukemia susceptibility locus near BICRA
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Christopher J. Walker, Christopher C. Oakes, Luke K. Genutis, Brian Giacopelli, Sandya Liyanarachchi, Deedra Nicolet, Ann-Kathrin Eisfeld, Markus Scholz, Pamela Brock, Jessica Kohlschmidt, Krzysztof Mrózek, Marius Bill, Andrew J. Carroll, Jonathan E. Kolitz, Bayard L. Powell, Eunice S. Wang, Dietger W. Niederwieser, Richard M. Stone, John C. Byrd, Sebastian Schwind, Albert de La Chapelle, Clara D. Bloomfield

Date Published: 1st Mar 2019

Publication Type: Journal article

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
Genetical Statistics and Systems Biology

Abstract (Expand)

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is … heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (\textgreekrgenetic = -0.59, p-value = 3.14 \times 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Authors: Dina Vojinovic, Hieab H. Adams, Xueqiu Jian, Qiong Yang, Albert Vernon Smith, Joshua C. Bis, Alexander Teumer, Markus Scholz, Nicola J. Armstrong, Edith Hofer, Yasaman Saba, Michelle Luciano, Manon Bernard, Stella Trompet, Jingyun Yang, Nathan A. Gillespie, Sven J. van der Lee, Alexander Neumann, Shahzad Ahmad, Ole A. Andreassen, David Ames, Najaf Amin, Konstantinos Arfanakis, Mark E. Bastin, Diane M. Becker, Alexa S. Beiser, Frauke Beyer, Henry Brodaty, R. Nick Bryan, Robin Bülow, Anders M. Dale, Philip L. de Jager, Ian J. Deary, Charles DeCarli, Debra A. Fleischman, Rebecca F. Gottesman, Jeroen van der Grond, Vilmundur Gudnason, Tamara B. Harris, Georg Homuth, David S. Knopman, John B. Kwok, Cora E. Lewis, Shuo Li, Markus Loeffler, Oscar L. Lopez, Pauline Maillard, Hanan El Marroun, Karen A. Mather, Thomas H. Mosley, Ryan L. Muetzel, Matthias Nauck, Paul A. Nyquist, Matthew S. Panizzon, Zdenka Pausova, Bruce M. Psaty, Ken Rice, Jerome I. Rotter, Natalie Royle, Claudia L. Satizabal, Reinhold Schmidt, Peter R. Schofield, Pamela J. Schreiner, Stephen Sidney, David J. Stott, Anbupalam Thalamuthu, Andre G. Uitterlinden, Maria C. Valdés Hernández, Meike W. Vernooij, Wei Wen, Tonya White, A. Veronica Witte, Katharina Wittfeld, Margaret J. Wright, Lisa R. Yanek, Henning Tiemeier, William S. Kremen, David A. Bennett, J. Wouter Jukema, Tomas Paus, Joanna M. Wardlaw, Helena Schmidt, Perminder S. Sachdev, Arno Villringer, Hans Jörgen Grabe, W. T. Longstreth, Cornelia M. van Duijn, Lenore J. Launer, Sudha Seshadri, M. Arfan Ikram, Myriam Fornage

Date Published: 1st Dec 2018

Publication Type: Journal article

Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin
Genetical Statistics and Systems Biology

Abstract (Expand)

Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis … of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p\textless5.0\times10-8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8\times10-14, beta = -0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p\textless0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.

Authors: Anke Tönjes, Markus Scholz, Jana Breitfeld, Carola Marzi, Harald Grallert, Arnd Gross, Claes Ladenvall, Dorit Schleinitz, Kerstin Krause, Holger Kirsten, Esa Laurila, Jennifer Kriebel, Barbara Thorand, Wolfgang Rathmann, Leif Groop, Inga Prokopenko, Bo Isomaa, Frank Beutner, Jürgen Kratzsch, Joachim Thiery, Mathias Fasshauer, Nora Klöting, Christian Gieger, Matthias Blüher, Michael Stumvoll, Peter Kovacs

Date Published: 18th Dec 2014

Publication Type: Journal article

Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.
Genetical Statistics and Systems Biology

Abstract (Expand)

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of … genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 x 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 x 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

Authors: A. Tonjes, M. Scholz, J. Kruger, K. Krause, D. Schleinitz, H. Kirsten, C. Gebhardt, C. Marzi, H. Grallert, C. Ladenvall, H. Heyne, E. Laurila, J. Kriebel, C. Meisinger, W. Rathmann, C. Gieger, L. Groop, I. Prokopenko, B. Isomaa, F. Beutner, J. Kratzsch, A. Fischer-Rosinsky, A. Pfeiffer, K. Krohn, J. Spranger, J. Thiery, M. Bluher, M. Stumvoll, P. Kovacs

Date Published: 1st Feb 2018

Publication Type: Journal article

Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND AIMS: Carotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify … genetic variants associated with carotid plaque and to examine the potential shared genetic basis with CAD. METHODS: After investigating the reliability of plaque detection, we performed a genome-wide meta-association study in two independent cohorts (LIFE-Adult, n = 4037 and LIFE-Heart, n = 3152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS. RESULTS: We identified two loci with genome-wide significance for PS. One locus is the known CAD-locus at chromosome 9p21 (lead SNP rs9644862, p = 8.73 x 10(-12)). We also describe a novel locus on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p = 1.97 x 10(-8)). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance. CONCLUSIONS: We showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations.

Authors: J. Pott, R. Burkhardt, F. Beutner, K. Horn, A. Teren, H. Kirsten, L. M. Holdt, G. Schuler, D. Teupser, M. Loeffler, J. Thiery, M. Scholz

Date Published: 11th Mar 2017

Publication Type: Journal article

Human Diseases: atherosclerosis

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.
Genetical Statistics and Systems Biology

Abstract (Expand)

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their … surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one’s occupation.

Authors: Jean Shin, Shaojie Ma, Edith Hofer, Yash Patel, Daniel E. Vosberg, Steven Tilley, Gennady V. Roshchupkin, André M. M. Sousa, Xueqiu Jian, Rebecca Gottesman, Thomas H. Mosley, Myriam Fornage, Yasaman Saba, Lukas Pirpamer, Reinhold Schmidt, Helena Schmidt, Amaia Carrion-Castillo, Fabrice Crivello, Bernard Mazoyer, Joshua C. Bis, Shuo Li, Qiong Yang, Michelle Luciano, Sherif Karama, Lindsay Lewis, Mark E. Bastin, Mathew A. Harris, Joanna M. Wardlaw, Ian E. Deary, Markus Scholz, Markus Loeffler, A. Veronica Witte, Frauke Beyer, Arno Villringer, Nicola J. Armstrong, Karen A. Mather, David Ames, Jiyang Jiang, John B. Kwok, Peter R. Schofield, Anbupalam Thalamuthu, Julian N. Trollor, Margaret J. Wright, Henry Brodaty, Wei Wen, Perminder S. Sachdev, Natalie Terzikhan, Tavia E. Evans, Hieab H. H. H. Adams, M. Arfan Ikram, Stefan Frenzel, Sandra van der Auwera-Palitschka, Katharina Wittfeld, Robin Bülow, Hans Jörgen Grabe, Christophe Tzourio, Aniket Mishra, Sophie Maingault, Stephanie Debette, Nathan A. Gillespie, Carol E. Franz, William S. Kremen, Linda Ding, Neda Jahanshad, Nenad Sestan, Zdenka Pausova, Sudha Seshadri, Tomas Paus

Date Published: 1st Jun 2020

Publication Type: Journal article

Growth and Final Height Among Children With Phenylketonuria
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND OBJECTIVES Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the …e most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with PKU. METHODS Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild hyperphenylalaninemia determined by newborn screening and early treatment initiation. RESULTS From birth to adulthood, patients with PKU were significantly shorter than healthy German children (height SDS at 18 years: -0.882 \pm 0.108, P \textless .001). They missed their target height by 3 cm by adulthood (women: P = .02) and 5 cm (men: P = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with patients receiving amino acid mixtures (P \textless .001). Growth rate was significantly reduced during their first 2 years of life and in puberty (growth rate SDS: -1.1 to -0.5 m/year, P \textless .001 and -0.5; P \textless .02). CONCLUSIONS Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods.

Authors: Alena G. Thiele, Ruth Gausche, Cornelia Lindenberg, Christoph Beger, Maria Arelin, Carmen Rohde, Ulrike Mütze, Johannes F. Weigel, Klaus Mohnike, Christoph Baerwald, Markus Scholz, Wieland Kiess, Roland Pfäffle, Skadi Beblo

Date Published: 1st Nov 2017

Publication Type: Journal article

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Genetical Statistics and Systems Biology

Abstract (Expand)

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses … of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Authors: Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan Sargurupremraj, Niina Pitkänen, Oscar Franzén, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih-Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, André G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Pasaniuc, Brenda W. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’Leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, Eric Boerwinkle, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline de Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. L. M. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimaki, Mike A. Nalls, Olle Melander, Olli Raitakari, Oscar H. Franco, Oscar L. Rueda-Ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, Reinhold Schmidt, Renée de Mutsert, Richard W. Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela McLachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf de Faire, Vincent Plagnol, Wayne D. Rosamond, Wendy Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. van Duijn, Deborah A. Lawlor, Dennis O. Mook-Kanamori, Donald W. Bowden, Helena Schmidt, James F. Wilson, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo-Pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Gudnason, Aroon D. Hingorani, Johan L. M. Björkegren, Juan P. Casas, Christopher J. O’Donnell

Date Published: 1st Dec 2018

Publication Type: Journal article

Navigate

Health Atlas - Local Data Hub/Leipzig

The Health Atlas - Local Data Hub/Leipzig is an alliance of medical ontologists, medical systems biologists and clinical trials groups to design and implement a multi-functional and quality-assured atlas. It provides models, data and metadata on specific use cases from medical research fields.

Registered Repository

re3data.org Badge
Powered by
 (v.1.13.0-master)
Health Atlas | Funding and Programmes | Credits | Terms & Conditions | Privacy Policy | Imprint
Copyright © 2008 - 2021 The University of Manchester and HITS gGmbH
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig

By continuing to use this site you agree to the use of cookies