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Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.
Zheng, Tenghao; Ellinghaus, David; Juzenas, Simonas; Cossais, François; Burmeister, Greta; Mayr, Gabriele; Jørgensen, Isabella Friis; Teder-Laving, Maris; Skogholt, Anne Heidi; Chen, Sisi; Strege, Peter R; Ito, Go; Banasik, Karina; Becker, Thomas; Bokelmann, Frank; Brunak, Søren; Buch, Stephan; Clausnitzer, Hartmut; Datz, Christian; Degenhardt, Frauke; Doniec, Marek; Erikstrup, Christian; Esko, Tõnu; Forster, Michael; Frey, Norbert; Fritsche, Lars G; Gabrielsen, Maiken Elvestad; Gräßle, Tobias; Gsur, Andrea; Gross, Justus; Hampe, Jochen; Hendricks, Alexander; Hinz, Sebastian; Hveem, Kristian; Jongen, Johannes; Junker, Ralf; Karlsen, Tom Hemming; Hemmrich-Stanisak, Georg; Kruis, Wolfgang; Kupcinskas, Juozas; Laubert, Tilman; Rosenstiel, Philip C; Röcken, Christoph; Laudes, Matthias; Leendertz, Fabian H; Lieb, Wolfgang; Limperger, Verena; Margetis, Nikolaos; Mätz-Rensing, Kerstin; Németh, Christopher Georg.
Afiliação
  • Zheng T; School of Biological Sciences, Monash University, Clayton, Victoria, Australia.
  • Ellinghaus D; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
  • Juzenas S; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Cossais F; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Burmeister G; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Mayr G; Institute of Biotechnology, Life Science Centre, Vilnius University, Vilnius, Lithuania.
  • Jørgensen IF; Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Teder-Laving M; Department for General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.
  • Skogholt AH; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Chen S; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Strege PR; Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Ito G; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  • Banasik K; Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
  • Becker T; Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
  • Bokelmann F; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Brunak S; Institute of Advanced Research, Tokyo Medical and Dental University, Tokyo, Japan.
  • Buch S; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Clausnitzer H; Department of General-, Visceral- Transplant-, Thoracic and Pediatric Surgery, Kiel University, Kiel, Germany.
  • Datz C; Medical Office for Surgery Preetz, Preetz, Germany.
  • Degenhardt F; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Doniec M; University Hospital Schleswig-Holstein, Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, Campus Kiel & Lübeck, Kiel, Germany.
  • Erikstrup C; Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria.
  • Forster M; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Frey N; Medical office for Colo-Proctology Kiel, Kiel, Germany.
  • Fritsche LG; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
  • Gabrielsen ME; Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Gräßle T; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Gsur A; Department of Internal Medicine III, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • Gross J; Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
  • Hampe J; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany.
  • Hendricks A; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Hinz S; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  • Hveem K; Epidemiology of highly pathogenic microorganisms, Robert Koch-Institute, Berlin, Germany.
  • Jongen J; Department of Primatology, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
  • Junker R; Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
  • Karlsen TH; Department for General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.
  • Hemmrich-Stanisak G; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Kruis W; Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Germany.
  • Kupcinskas J; Department for General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.
  • Laubert T; Department for General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.
  • Rosenstiel PC; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  • Röcken C; Department of Proctological Surgery Park Klinik Kiel, Kiel, Germany.
  • Laudes M; Proctological Office Kiel, Kiel, Germany.
  • Leendertz FH; University Hospital Schleswig-Holstein, Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, Campus Kiel & Lübeck, Kiel, Germany.
  • Lieb W; Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.
  • Limperger V; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Margetis N; Faculty of Medicine, University of Cologne, Cologne, Germany.
  • Mätz-Rensing K; Department of Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Németh CG; Department of Proctological Surgery Park Klinik Kiel, Kiel, Germany.
Gut ; 2021 Apr 22.
Article em En | MEDLINE | ID: mdl-33888516
ABSTRACT

OBJECTIVE:

Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

DESIGN:

We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

RESULTS:

We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

CONCLUSION:

HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Idioma: En Ano de publicação: 2021 Tipo de documento: Article