المؤلفون: Isa Amalie Olofsson, Ragnar P. Kristjansson, Ida Callesen, Olafur Davidsson, Bendik Winsvold, Henrik Hjalgrim, Sisse R. Ostrowski, Christian Erikstrup, Mie Topholm Bruun, Ole Birger Pedersen, Kristoffer S. Burgdorf, Karina Banasik, Erik Sørensen, Christina Mikkelsen, Maria Didriksen, Khoa Manh Dinh, Susan Mikkelsen, International Headache Genetic Consortium, DBDS Genomic Consortium, Søren Brunak, Henrik Ullum, Mona Ameri Chalmer, Jes Olesen, Lisette J. A. Kogelman, Thomas Folkmann Hansen

المصدر: Communications Biology, Vol 7, Iss 1, Pp 1-7 (2024)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Abstract Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13–1.27], p = 3.92 × 10−9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2399-3642Test

الوصول الحر: https://doaj.org/article/6ebd151e5db14c23a2d72ad9be537a6aTest

المؤلفون: Lisette J. A. Kogelman, Katrine Falkenberg, Filip Ottosson, Madeleine Ernst, Francesco Russo, Valdemar Stentoft-Hansen, Samuel Demharter, Peer Tfelt-Hansen, Arieh S. Cohen, Jes Olesen, Thomas Folkmann Hansen

المصدر: Scientific Reports, Vol 13, Iss 1, Pp 1-8 (2023)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/019b32d50c554687bdf123c45787a1b2Test

المؤلفون: Karina Banasik, Peter L. Møller, Tanya R. Techlo, Peter C. Holm, G. Bragi Walters, Andrés Ingason, Anders Rosengren, Palle D. Rohde, Lisette J. A. Kogelman, David Westergaard, Troels Siggaard, Piotr J. Chmura, Mona A. Chalmer, Ólafur Þ. Magnússon, Guðmundur Á. Þórisson, Hreinn Stefánsson, Daníel F. Guðbjartsson, Kári Stefánsson, Jes Olesen, Simon Winther, Morten Bøttcher, Søren Brunak, Thomas Werge, Mette Nyegaard, Thomas F. Hansen

المصدر: BMC Genomic Data, Vol 24, Iss 1, Pp 1-4 (2023)

مصطلحات موضوعية: Whole genome sequencing, Variant interpretation, Sequence variants, Minor allele counts, Browser, Genetics, QH426-470

الوصف: Abstract Objectives Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega.dataset:EGAD00001009756Test ) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk ). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. Data description Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2730-6844Test

الوصول الحر: https://doaj.org/article/e113e373bf77483e9c84853837f696bbTest

المؤلفون: Lisette J. A. Kogelman, Madeleine Ernst, Katrine Falkenberg, Gianluca Mazzoni, Julie Courraud, Li Peng Lundgren, Susan Svane Laursen, Arieh Cohen, Jes Olesen, Thomas Folkmann Hansen

المصدر: BMC Genomics, Vol 23, Iss 1, Pp 1-11 (2022)

مصطلحات موضوعية: Cold pressor test, Transcriptomics, Metabolomics, PCA, PLS, Systems biology, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. We hypothesize, that performing multi-omic analyses during CPT gives the opportunity to home in on molecular mechanisms involved. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken. RNA-Sequencing, steroid profiling and untargeted metabolomics were performed. Each ‘omic level was analyzed separately at both single-feature and systems-level (principal component [PCA] and partial least squares [PLS] regression analysis) and all ‘omic levels were combined using an integrative multi-omics approach, all using the paired-sample design. Results We showed that PCA was not able to discriminate time points, while PLS did significantly distinguish time points using metabolomics and/or transcriptomic data, but not using conventional physiological measures. Transcriptomic and metabolomic data revealed at feature-, systems- and integrative- level biologically relevant processes involved during CPT, e.g. lipid metabolism and stress response. Conclusion Multi-omics strategies have a great potential in pain research, both at feature- and systems- level. Therefore, they should be exploited in intervention studies, such as pain provocation tests, to gain knowledge on the biological mechanisms involved in complex traits.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2164Test

الوصول الحر: https://doaj.org/article/989a20eb70b9406b9e3f001292a71ea7Test

المؤلفون: Sanne Hage La Cour, Kiki Juhler, Lisette J. A. Kogelman, Jes Olesen, Dan Arne Klærke, David Møbjerg Kristensen, Inger Jansen-Olesen

المصدر: The Journal of Headache and Pain, Vol 23, Iss 1, Pp 1-12 (2022)

مصطلحات موضوعية: Migraine, CGRP, Xenopus Laevis oocytes, Amylin, Amylin receptor, RAMP1, Medicine

الوصف: Abstract Background The clinical use of calcitonin gene-related peptide receptor (CGRP-R) antagonists and monoclonal antibodies against CGRP and CGRP-R has offered new treatment possibilities for migraine patients. CGRP activates both the CGRP-R and structurally related amylin 1 receptor (AMY1-R). The relative effect of erenumab and the small-molecule CGRP-R antagonist, rimegepant, towards the CGRP-R and AMY-R needs to be further characterized. Methods The effect of CGRP and two CGRP-R antagonists were examined in Xenopus laevis oocytes expressing human CGRP-R, human AMY1-R and their subunits. Results CGRP administered to receptor expressing oocytes induced a concentration-dependent increase in current with the order of potency CGRP-R> > AMY1-R > calcitonin receptor (CTR). There was no effect on single components of the CGRP-R; calcitonin receptor-like receptor and receptor activity-modifying protein 1. Amylin was only effective on AMY1-R and CTR. Inhibition potencies (pIC50 values) for erenumab on CGRP induced currents were 10.86 and 9.35 for CGRP-R and AMY1-R, respectively. Rimegepant inhibited CGRP induced currents with pIC50 values of 11.30 and 9.91 for CGRP-R and AMY1-R, respectively. Conclusion Our results demonstrate that erenumab and rimegepant are potent antagonists of CGRP-R and AMY1-R with 32- and 25-times preference for the CGRP-R over the AMY1-R, respectively. It is discussed if this difference in affinity between the two receptors is the likely reason why constipation is a common and serious adverse effect during CGRP-R antagonism but less so with CGRP binding antibodies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1129-2369Test; https://doaj.org/toc/1129-2377Test

الوصول الحر: https://doaj.org/article/4da325ce717d444799c82d731c83299aTest

المؤلفون: Lisette J. A. Kogelman, Katrine Falkenberg, Alfonso Buil, Pau Erola, Julie Courraud, Susan Svane Laursen, Tom Michoel, Jes Olesen, Thomas F. Hansen

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Migraine attacks are delimited, allowing investigation of changes during and outside attack. Gene expression fluctuates according to environmental and endogenous events and therefore, we hypothesized that changes in RNA expression during and outside a spontaneous migraine attack exist which are specific to migraine. Twenty-seven migraine patients were assessed during a spontaneous migraine attack, including headache characteristics and treatment effect. Blood samples were taken during attack, two hours after treatment, on a headache-free day and after a cold pressor test. RNA-Sequencing, genotyping, and steroid profiling were performed. RNA-Sequences were analyzed at gene level (differential expression analysis) and at network level, and genomic and transcriptomic data were integrated. We found 29 differentially expressed genes between ‘attack’ and ‘after treatment’, after subtracting non-migraine specific genes, that were functioning in fatty acid oxidation, signaling pathways and immune-related pathways. Network analysis revealed mechanisms affected by changes in gene interactions, e.g. ‘ion transmembrane transport’. Integration of genomic and transcriptomic data revealed pathways related to sumatriptan treatment, i.e. ‘5HT1 type receptor mediated signaling pathway’. In conclusion, we uniquely investigated intra-individual changes in gene expression during a migraine attack. We revealed both genes and pathways potentially involved in the pathophysiology of migraine and/or migraine treatment.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/f715f3d6980b4cd2a3675cf887e67e77Test

المؤلفون: Victor A. O. Carmelo, Lisette J. A. Kogelman, Majbritt Busk Madsen, Haja N. Kadarmideen

المصدر: BMC Bioinformatics, Vol 19, Iss 1, Pp 1-7 (2018)

مصطلحات موضوعية: Epistasis, Networks, GWAS, Complex traits, WGCNA, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5

الوصف: Abstract Background Genetic epistasis is an often-overlooked area in the study of the genomics of complex traits. Genome-wide association studies are a useful tool for revealing potential causal genetic variants, but in this context, epistasis is generally ignored. Data complexity and interpretation issues make it difficult to process and interpret epistasis. As the number of interaction grows exponentially with the number of variants, computational limitation is a bottleneck. Gene Network based strategies have been successful in integrating biological data and identifying relevant hub genes and pathways related to complex traits. In this study, epistatic interactions and network-based analysis are combined in the Weighted Interaction SNP hub (WISH) method and implemented in an efficient and easy to use R package. Results The WISH R package (WISH-R) was developed to calculate epistatic interactions on a genome-wide level based on genomic data. It is easy to use and install, and works on regular genomic data. The package filters data based on linkage disequilibrium and calculates epistatic interaction coefficients between SNP pairs based on a parallelized efficient linear model and generalized linear model implementations. Normalized epistatic coefficients are analyzed in a network framework, alleviating multiple testing issues and integrating biological signal to identify modules and pathways related to complex traits. Functions for visualizing results and testing runtimes are also provided. Conclusion The WISH-R package is an efficient implementation for analyzing genome-wide epistasis for complex diseases and traits. It includes methods and strategies for analyzing epistasis from initial data filtering until final data interpretation. WISH offers a new way to analyze genomic data by combining epistasis and network based analysis in one method and provides options for visualizations. This alleviates many of the existing hurdles in the analysis of genomic interactions.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12859-018-2291-2Test; https://doaj.org/toc/1471-2105Test

الوصول الحر: https://doaj.org/article/f58d90d21f394256a55d1896a14a812bTest

المؤلفون: Prashanth eSuravajhala, Lisette J. A. Kogelman, Gianluca eMazzoni, Haja N Kadarmideen

المصدر: Frontiers in Genetics, Vol 6 (2015)

مصطلحات موضوعية: Systems Biology, protein interactions, disease association, long noncoding RNA, WGCNA, Genetics, QH426-470

الوصف: With unprecedented increase in next generation sequencing (NGS) technologies, there has been a persistent interest on transcript profiles of long noncoding RNAs (lncRNAs) and protein-coding genes forming an interaction network. Apart from protein-protein interaction (PPI), gene network models such as Weighted Gene Co-expression Network Analysis are used to functionally annotate lncRNAs in identifying their potential disease associations. To address this, studies have led to characterizing transcript structures and understanding expression profiles mediating regulatory roles. In the current exploratory analysis, we show how a lncRNA - cyp2c91 contributes to the transcriptional regulation localized to cytoplasm thereby making refractory environment for transcription. By applying network methods and pathway analyses on genes related to a disease such as obesity and systemic lupus erythematosus, we show that we can gain deeper insight in biological processes such as the perturbances in immune system, and get a better understanding of the systems biology of diseases.

وصف الملف: electronic resource

العلاقة: http://journal.frontiersin.org/Journal/10.3389/fgene.2015.00255/fullTest; https://doaj.org/toc/1664-8021Test

الوصول الحر: https://doaj.org/article/fab5fe29b04b4300947968a77e11174cTest

المؤلفون: Lisette J. A. Kogelman, Sameer D. Pant, Merete eFredholm, Haja N. Kadarmideen

المصدر: Frontiers in Genetics, Vol 5 (2014)

مصطلحات موضوعية: animal model, Systems genetics, high-throughput genotype data, WISH network, Obesity Index, Genetics, QH426-470

الوصف: Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH) and differentially wired (DW) networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g. NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g. metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic) obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways that underlie it.

وصف الملف: electronic resource

العلاقة: http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00214/fullTest; https://doaj.org/toc/1664-8021Test

الوصول الحر: https://doaj.org/article/bd33e1c2d370406ead6d11483957ea3eTest

المؤلفون: Lisette J. A. Kogelman, Haja N. Kadarmideen, Thomas eMark, Peter eKarlskov-Mortensen, Camilla S. Bruun, Susanna eCirera, Mette J. Jacobsen, Claus B. Jørgensen, Merete eFredholm

المصدر: Frontiers in Genetics, Vol 4 (2013)

مصطلحات موضوعية: Obesity, diabetes, animal model, risk prediction, F2 design, heritabilities, Genetics, QH426-470

الوصف: Obesity is a rising worldwide public health problem. Difficulties to precisely measure various obesity traits and the genetic heterogeneity in human have been major impediments to completely disentangle genetic factors causing obesity. The pig is a relevant model for studying human obesity and obesity-related (OOR) traits. Using founder breeds divergent with respect to obesity traits we have created an F2 pig resource population (454 pigs), which has been intensively phenotyped for 36 OOR traits. The main rationale for our study is to characterize the genetic architecture of OOR traits in the F2 pig design, by estimating heritabilities, genetic and phenotypic correlations using mixed- and multi-trait BLUP animal models.Our analyses revealed high coefficients of variation (15-42 per cent) and moderate to high heritabilities (0.22 - 0.81) in fatness traits, showing large phenotypic and genetic variation in the F2 population, respectively. This fulfills the purpose of creating a resource population divergent for OOR traits. Strong genetic correlations were found between weight and lean mass at dual energy x-ray absorptiometry (DXA) scanning (0.56 – 0.97). Weight and conformation also showed strong genetic correlations with slaughter traits (e.g. rg between abdominal circumference and leaf fat at slaughtering: 0.66). Genetic correlations between fat-related traits and the glucose level vary between 0.35 and 0.74 and show a strong correlation between adipose tissue and impaired glucose metabolism. Our power calculations showed a minimum of 80% power for QTL detection for all phenotypes.We revealed genetic correlations at population level, for the first time, for several difficult to measure and novel OOR traits and diseases. The results underpin the potential of the established F2 pig resource population for further genomic, systems genetics and functional investigations to unravel the genetic background of OOR traits.

وصف الملف: electronic resource

العلاقة: http://journal.frontiersin.org/Journal/10.3389/fgene.2013.00029/fullTest; https://doaj.org/toc/1664-8021Test

الوصول الحر: https://doaj.org/article/5a653de4cff5446ca71a0002ff798296Test