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65 Publications matching the given criteria: (Clear all filters)
Programme: LIFE Management Cluster65
The Human Blood Transcriptome in a Large Population Cohort and Its Relation to Aging and Health.
LIFE Adult, oBIG - omics Bioinformatics for Health

Abstract (Expand)

Background: The blood transcriptome is expected to provide a detailed picture of an organism's physiological state with potential outcomes for applications in medical diagnostics and molecular and … epidemiological research. We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration. Methods: Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features. Results: The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes. Conclusions: Machine learning applications for large and heterogeneous omics data provide a holistic view on the diversity of the human blood transcriptome. It provides a tool for comparative analyses of transcriptional signatures and of associated phenotypes in population studies and medical applications.

Authors: M. Schmidt, L. Hopp, A. Arakelyan, H. Kirsten, C. Engel, K. Wirkner, K. Krohn, R. Burkhardt, J. Thiery, M. Loeffler, H. Loeffler-Wirth, H. Binder

Date Published: 11th Mar 2021

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

Norms of Interocular Circumpapillary Retinal Nerve Fiber Layer Thickness Differences at 768 Retinal Locations
LIFE Adult

Abstract (Expand)

Purpose: The onset and progression of optic neuropathies like glaucoma often occurs asymmetrically between the two eyes of a patient. Interocular circumpapillary retinal nerve fiber layer thickness … (cpRNFLT) differences could detect disease earlier. To apply such differences diagnostically, detailed location specific norms are necessary. Methods: Spectral-domain optical coherence tomography cpRNFLT circle scans from the population-based Leipzig Research Centre for Civilization Diseases–Adult study were selected. At each of the 768 radial scanning locations, normative interocular cpRNFLT difference distributions were calculated based on age and interocular radius difference. Results: A total of 8966 cpRNFLT scans of healthy eyes (4483 patients; 55% female; age range, 20–79 years) were selected. Global cpRNFLT average was 1.53 µm thicker in right eyes (P < 2.2 × 10–16). On 96% of the 768 locations, left minus right eye differences were significant (P < 0.05), varying between +11.6 µm (superonasal location) and −11.8 µm (nasal location). Increased age and difference in interocular scanning radii were associated with an increased mean and variance of interocular cpRNFLT difference at most retinal locations, apart from the area temporal to the inferior RNF bundle where cpRNFLT becomes more similar between eyes with age. Conclusions: We provide pointwise normative distributions of interocular cpRNFLT differences at an unprecedentedly high spatial resolution of 768 A-scans and reveal considerable location specific asymmetries as well as their associations with age and scanning radius differences between eyes. Translational Relevance: To facilitate clinical application, we implement these age- and radius-specific norms across all 768 locations in an open-source software to generate patient-specific normative color plots.

Authors: Neda Baniasadi, Franziska G. Rauscher, Dian Li, Mengyu Wang, Eun Young Choi, Hui Wang, Thomas Peschel, Kerstin Wirkner, Toralf Kirsten, Joachim Thiery, Christoph Engel, Markus Loeffler, Tobias Elze

Date Published: 3rd Aug 2020

Publication Type: Journal article

The aging human body shape.
LIFE Adult

Abstract (Expand)

Body shape and composition are heterogeneous among humans with possible impact for health. Anthropometric methods and data are needed to better describe the diversity of the human body in human … populations, its age dependence, and associations with health risk. We applied whole-body laser scanning to a cohort of 8499 women and men of age 40-80 years within the frame of the LIFE (Leipzig Research Center for Civilization Diseases) study aimed at discovering health risk in a middle European urban population. Body scanning delivers multidimensional anthropometric data, which were further processed by machine learning to stratify the participants into body types. We here applied this body typing concept to describe the diversity of body shapes in an aging population and its association with physical activity and selected health and lifestyle factors. We find that aging results in similar reshaping of female and male bodies despite the large diversity of body types observed in the study. Slim body shapes remain slim and partly tend to become even more lean and fragile, while obese body shapes remain obese. Female body shapes change more strongly than male ones. The incidence of the different body types changes with characteristic Life Course trajectories. Physical activity is inversely related to the body mass index and decreases with age, while self-reported incidence for myocardial infarction shows overall the inverse trend. We discuss health risks factors in the context of body shape and its relation to obesity. Body typing opens options for personalized anthropometry to better estimate health risk in epidemiological research and future clinical applications.

Authors: A. Frenzel, H. Binder, N. Walter, K. Wirkner, M. Loeffler, H. Loeffler-Wirth

Date Published: 29th Mar 2020

Publication Type: Not specified

Sex-Specific Differences in Circumpapillary Retinal Nerve Fiber Layer Thickness.
LIFE Adult

Abstract (Expand)

PURPOSE: To investigate the role of sex on retinal nerve fiber layer (RNFL) thickness at 768 circumpapillary locations based on OCT findings. DESIGN: Population-based cross-sectional study. PARTICIPANTS: … We investigated 5646 eyes of 5646 healthy participants from the Leipzig Research Centre for Civilization Diseases (LIFE)-Adult Study of a predominantly white population. METHODS: All participants underwent standardized systemic assessments and ocular imaging. Circumpapillary RNFL (cRNFL) thickness was measured at 768 points equidistant from the optic nerve head using spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). To control ocular magnification effects, the true scanning radius was estimated by scanning focus. Student t test was used to evaluate sex differences in cRNFL thickness globally and at each of the 768 locations. Multivariable linear regression and analysis of variance were used to evaluate individual contributions of various factors to cRNFL thickness variance. MAIN OUTCOME MEASURES: Difference in cRNFL thickness between males and females. RESULTS: Our population consisted of 54.8% females. The global cRNFL thickness was 1 mum thicker in females (P < 0.001). However, detailed analysis at each of the 768 locations revealed substantial location specificity of the sex effects, with RNFL thickness difference ranging from -9.98 to +8.00 mum. Females showed significantly thicker RNFLs in the temporal, superotemporal, nasal, inferonasal, and inferotemporal regions (43.6% of 768 locations), whereas males showed significantly thicker RNFLs in the superior region (13.2%). The results were similar after adjusting for age, body height, and scanning radius. The superotemporal and inferotemporal RNFL peaks shifted temporally in females by 2.4 degrees and 1.9 degrees , respectively. On regions with significant sex effects, sex explained more RNFL thickness variance than age, whereas the major peak locations and interpeak angle explained most of the RNFL thickness variance unexplained by sex. CONCLUSIONS: Substantial sex effects on cRNFL thickness were found at 56.8% of all 768 circumpapillary locations, with specific patterns for different sectors. Over large regions, sex was at least as important in explaining the cRNFL thickness variance as was age, which is well established to have a substantial impact on cRNFL thickness. Including sex in the cRNFL thickness norm could therefore improve glaucoma diagnosis and monitoring.

Authors: D. Li, F. G. Rauscher, E. Y. Choi, M. Wang, N. Baniasadi, K. Wirkner, T. Kirsten, J. Thiery, C. Engel, M. Loeffler, T. Elze

Date Published: 17th Nov 2019

Publication Type: Journal article

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated … in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.

Authors: Michael T. Parsons, Emma Tudini, Hongyan Li, Eric Hahnen, Barbara Wappenschmidt, Lidia Feliubadaló, Cora M. Aalfs, Simona Agata, Kristiina Aittomäki, Elisa Alducci, María Concepción Alonso-Cerezo, Norbert Arnold, Bernd Auber, Rachel Austin, Jacopo Azzollini, Judith Balmaña, Elena Barbieri, Claus R. Bartram, Ana Blanco, Britta Blümcke, Sandra Bonache, Bernardo Bonanni, Åke Borg, Beatrice Bortesi, Joan Brunet, Carla Bruzzone, Karolin Bucksch, Giulia Cagnoli, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Mariarosaria Calvello, Gabriele L. Capone, Sandrine M. Caputo, Ileana Carnevali, Estela Carrasco, Virginie Caux-Moncoutier, Pietro Cavalli, Giulia Cini, Edward M. Clarke, Paola Concolino, Elisa J. Cops, Laura Cortesi, Fergus J. Couch, Esther Darder, Miguel de La Hoya, Michael Dean, Irmgard Debatin, Jesús Del Valle, Capucine Delnatte, Nicolas Derive, Orland Diez, Nina Ditsch, Susan M. Domchek, Véronique Dutrannoy, Diana M. Eccles, Hans Ehrencrona, Ute Enders, D. Gareth Evans, Ulrike Faust, Ute Felbor, Irene Feroce, Miriam Fine, Henrique C. R. Galvao, Gaetana Gambino, Andrea Gehrig, Francesca Gensini, Anne-Marie Gerdes, Aldo Germani, Jutta Giesecke, Viviana Gismondi, Carolina Gómez, Encarna B. Gómez Garcia, Sara González, Elia Grau, Sabine Grill, Eva Gross, Aliana Guerrieri-Gonzaga, Marine Guillaud-Bataille, Sara Gutiérrez-Enríquez, Thomas Haaf, Karl Hackmann, Thomas v. O. Hansen, Marion Harris, Jan Hauke, Tilman Heinrich, Heide Hellebrand, Karen N. Herold, Ellen Honisch, Judit Horvath, Claude Houdayer, Verena Hübbel, Silvia Iglesias, Angel Izquierdo, Paul A. James, Linda A. M. Janssen, Udo Jeschke, Silke Kaulfuß, Katharina Keupp, Marion Kiechle, Alexandra Kölbl, Sophie Krieger, Torben A. Kruse, Anders Kvist, Fiona Lalloo, Mirjam Larsen, Vanessa L. Lattimore, Charlotte Lautrup, Susanne Ledig, Elena Leinert, Alexandra L. Lewis, Joanna Lim, Markus Loeffler, Adrià López-Fernández, Emanuela Lucci-Cordisco, Nicolai Maass, Siranoush Manoukian, Monica Marabelli, Laura Matricardi, Alfons Meindl, Rodrigo D. Michelli, Setareh Moghadasi, Alejandro Moles-Fernández, Marco Montagna, Gemma Montalban, Alvaro N. Monteiro, Eva Montes, Luigi Mori, Lidia Moserle, Clemens R. Müller, Christoph Mundhenke, Nadia Naldi, Katherine L. Nathanson, Matilde Navarro, Heli Nevanlinna, Cassandra B. Nichols, Dieter Niederacher, Henriette R. Nielsen, Kai-Ren Ong, Nicholas Pachter, Edenir I. Palmero, Laura Papi, Inge Sokilde Pedersen, Bernard Peissel, Pedro Pérez-Segura, Katharina Pfeifer, Marta Pineda, Esther Pohl-Rescigno, Nicola K. Poplawski, Berardino Porfirio, Anne S. Quante, Juliane Ramser, Rui M. Reis, Françoise Revillion, Kerstin Rhiem, Barbara Riboli, Julia Ritter, Daniela Rivera, Paula Rofes, Andreas Rump, Monica Salinas, Ana María Sánchez de Abajo, Gunnar Schmidt, Ulrike Schoenwiese, Jochen Seggewiß, Ares Solanes, Doris Steinemann, Mathias Stiller, Dominique Stoppa-Lyonnet, Kelly J. Sullivan, Rachel Susman, Christian Sutter, Sean V. Tavtigian, Soo H. Teo, Alex Teulé, Mads Thomassen, Maria Grazia Tibiletti, Silvia Tognazzo, Amanda E. Toland, Eva Tornero, Therese Törngren, Sara Torres-Esquius, Angela Toss, Alison H. Trainer, Christi J. van Asperen, Marion T. van Mackelenbergh, Liliana Varesco, Gardenia Vargas-Parra, Raymonda Varon, Ana Vega, Ángela Velasco, Anne-Sophie Vesper, Alessandra Viel, Maaike P. G. Vreeswijk, Sebastian A. Wagner, Anke Waha, Logan C. Walker, Rhiannon J. Walters, Shan Wang-Gohrke, Bernhard H. F. Weber, Wilko Weichert, Kerstin Wieland, Lisa Wiesmüller, Isabell Witzel, Achim Wöckel, Emma R. Woodward, Silke Zachariae, Valentina Zampiga, Christine Zeder-Göß, Conxi Lázaro, Arcangela de Nicolo, Paolo Radice, Christoph Engel, Rita K. Schmutzler, David E. Goldgar, Amanda B. Spurdle

Date Published: 1st Sep 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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

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