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959 Publications visible to you, out of a total of 959
Towards GFO 2.0: Architecture, Modules and Applications
Onto-Med Research Group

Abstract

Not specified

Authors: Patryk Burek, Frank Loebe, Heinrich Herre

Date Published: 22nd Oct 2020

Publication Type: Journal article

The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG.
Genetical Statistics and Systems Biology

Abstract (Expand)

TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate … the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.

Authors: K. Landgraf, N. Kloting, M. Gericke, N. Maixner, E. Guiu-Jurado, M. Scholz, A. V. Witte, F. Beyer, J. T. Schwartze, M. Lacher, A. Villringer, P. Kovacs, A. Rudich, M. Bluher, W. Kiess, A. Korner

Date Published: 20th Oct 2020

Publication Type: Journal article

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.
Genetical Statistics and Systems Biology

Abstract (Expand)

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are … warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 x 10(-6)) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 x 10(-13)), bipolar disorder (1.53[1.44; 1.63]; p = 1 x 10(-43)), schizophrenia (1.36[1.28; 1.45]; p = 4 x 10(-22)), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 x 10(-12)), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 x 10(-4)), educational attainment (0.86[0.82; 0.91]; p = 2 x 10(-7)), and intelligence (0.72[0.68; 0.76]; p = 9 x 10(-29)). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Authors: A. Gialluisi, T. F. M. Andlauer, N. Mirza-Schreiber, K. Moll, J. Becker, P. Hoffmann, K. U. Ludwig, D. Czamara, B. S. Pourcain, F. Honbolygo, D. Toth, V. Csepe, G. Huguet, Y. Chaix, S. Iannuzzi, J. F. Demonet, A. P. Morris, J. Hulslander, E. G. Willcutt, J. C. DeFries, R. K. Olson, S. D. Smith, B. F. Pennington, A. Vaessen, U. Maurer, H. Lyytinen, M. Peyrard-Janvid, P. H. T. Leppanen, D. Brandeis, M. Bonte, J. F. Stein, J. B. Talcott, F. Fauchereau, A. Wilcke, H. Kirsten, B. Muller, C. Francks, T. Bourgeron, A. P. Monaco, F. Ramus, K. Landerl, J. Kere, T. S. Scerri, S. Paracchini, S. E. Fisher, J. Schumacher, M. M. Nothen, B. Muller-Myhsok, G. Schulte-Korne

Date Published: 14th Oct 2020

Publication Type: Journal article

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
Genetical Statistics and Systems Biology

Abstract (Expand)

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely … unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Authors: S. Vogelezang, J. P. Bradfield, T. S. Ahluwalia, J. A. Curtin, T. A. Lakka, N. Grarup, M. Scholz, P. J. van der Most, C. Monnereau, E. Stergiakouli, A. Heiskala, M. Horikoshi, I. O. Fedko, N. Vilor-Tejedor, D. L. Cousminer, M. Standl, C. A. Wang, J. Viikari, F. Geller, C. Iniguez, N. Pitkanen, A. Chesi, J. Bacelis, L. Yengo, M. Torrent, I. Ntalla, O. Helgeland, S. Selzam, J. M. Vonk, M. H. Zafarmand, B. Heude, I. S. Farooqi, A. Alyass, R. N. Beaumont, C. T. Have, P. Rzehak, J. R. Bilbao, T. M. Schnurr, I. Barroso, K. Bonnelykke, L. J. Beilin, L. Carstensen, M. A. Charles, B. Chawes, K. Clement, R. Closa-Monasterolo, A. Custovic, J. G. Eriksson, J. Escribano, M. Groen-Blokhuis, V. Grote, D. Gruszfeld, H. Hakonarson, T. Hansen, A. T. Hattersley, M. Hollensted, J. J. Hottenga, E. Hypponen, S. Johansson, R. Joro, M. Kahonen, V. Karhunen, W. Kiess, B. A. Knight, B. Koletzko, A. Kuhnapfel, K. Landgraf, J. P. Langhendries, T. Lehtimaki, J. T. Leinonen, A. Li, V. Lindi, E. Lowry, M. Bustamante, C. Medina-Gomez, M. Melbye, K. F. Michaelsen, C. S. Morgen, T. A. Mori, T. R. H. Nielsen, H. Niinikoski, A. J. Oldehinkel, K. Pahkala, K. Panoutsopoulou, O. Pedersen, C. E. Pennell, C. Power, S. A. Reijneveld, F. Rivadeneira, A. Simpson, P. D. Sly, J. Stokholm, K. K. Teo, E. Thiering, N. J. Timpson, A. G. Uitterlinden, C. E. M. van Beijsterveldt, B. D. C. van Schaik, M. Vaudel, E. Verduci, R. K. Vinding, M. Vogel, E. Zeggini, S. Sebert, M. V. Lind, C. D. Brown, L. Santa-Marina, E. Reischl, C. Frithioff-Bojsoe, D. Meyre, E. Wheeler, K. Ong, E. A. Nohr, T. G. M. Vrijkotte, G. H. Koppelman, R. Plomin, P. R. Njolstad, G. D. Dedoussis, P. Froguel, T. I. A. Sorensen, B. Jacobsson, R. M. Freathy, B. S. Zemel, O. Raitakari, M. Vrijheid, B. Feenstra, L. P. Lyytikainen, H. Snieder, H. Kirsten, P. G. Holt, J. Heinrich, E. Widen, J. Sunyer, D. I. Boomsma, M. R. Jarvelin, A. Korner, G. Davey Smith, J. C. Holm, M. Atalay, C. Murray, H. Bisgaard, M. I. McCarthy, V. W. V. Jaddoe, S. F. A. Grant, J. F. Felix

Date Published: 13th Oct 2020

Publication Type: Journal article

Transcriptomic Research in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives.
Genetical Statistics and Systems Biology

Abstract (Expand)

Heart failure with preserved ejection fraction (HFpEF) is increasing in incidence and has a higher prevalence compared with heart failure with reduced ejection fraction. So far, no effective treatment … of HFpEF is available, due to its complex underlying pathophysiology and clinical heterogeneity. This article aims to provide an overview and a future perspective of transcriptomic biomarker research in HFpEF. Detailed characterisation of the HFpEF phenotype and its underlying molecular pathomechanisms may open new perspectives regarding early diagnosis, improved prognostication, new therapeutic targets and tailored therapies accounting for patient heterogeneity, which may improve quality of life. A combination of cross-sectional and longitudinal study designs with sufficiently large sample sizes are required to support this concept.

Authors: S. Rosch, K. P. Rommel, M. Scholz, H. Thiele, P. Lurz

Date Published: 12th Oct 2020

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

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.
Genetical Statistics and Systems Biology

Abstract (Expand)

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large … proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (+/- 500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn’s disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn’s disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P-values \textless 0.05 (0.0040, 0.0057, 0.011, and 3.4 \times 10-6, respectively). After excluding the 20 PDAC susceptibility regions (+/- 500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn’s disease, and inflammatory bowel disease remained associated with PDAC (P-values = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P-value = 0.22) and primary sclerosing cholangitis (P-value = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.

Authors: Fangcheng Yuan, Rayjean J. Hung, Naomi Walsh, Han Zhang, Elizabeth A. Platz, William Wheeler, Lei Song, Alan A. Arslan, Laura E. Beane Freeman, Paige Bracci, Federico Canzian, Mengmeng Du, Steven Gallinger, Graham G. Giles, Phyllis J. Goodman, Charles Kooperberg, Loic Le Marchand, Rachel E. Neale, Jonas Rosendahl, Ghislaine Scelo, Xiao-Ou Shu, Kala Visvanathan, Emily White, Wei Zheng, Demetrius Albanes, Pilar Amiano, Gabriella Andreotti, Ana Babic, William R. Bamlet, Sonja I. Berndt, Paul Brennan, Bas Bueno-de-Mesquita, Julie E. Buring, Peter T. Campbell, Stephen J. Chanock, Charles S. Fuchs, J. Michael Gaziano, Michael G. Goggins, Thilo Hackert, Patricia Hartge, Manal M. Hassan, Elizabeth A. Holly, Robert N. Hoover, Verena Katzke, Holger Kirsten, Robert C. Kurtz, I-Min Lee, Nuria Malats, Roger Milne, Neil Murphy, Kimmie Ng, Ann L. Oberg, Miquel Porta, Kari G. Rabe, Francisco X. Real, Nathaniel Rothman, Howard D. Sesso, Debra T. Silverman, Ian M. Thompson, Jean Wactawski-Wende, Xiaoliang Wang, Nicolas Wentzensen, Lynne R. Wilkens, Herbert Yu, Anne Zeleniuch-Jacquotte, Jianxin Shi, Eric J. Duell, Laufey T. Amundadottir, Donghui Li, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Kai Yu, Alison P. Klein, Rachael Stolzenberg-Solomon

Date Published: 15th Sep 2020

Publication Type: Journal article

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