title: Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity.
abstract: Klinefelter syndrome (KS) (47,XXY) is the most common male sex chromosome aneuploidy. Diagnosis and clinical supervision remain a challenge due to varying phenotypic presentation and insufficient characterization of the syndrome. Here we combine health data-driven epidemiology and molecular level systems biology to improve the understanding of KS and the molecular interplay influencing its comorbidities. In total, 78 overrepresented KS comorbidities were identified using in- and out-patient registry data from the entire Danish population covering 6.8 million individuals. The comorbidities extracted included both clinically well-known (e.g. infertility and osteoporosis) and still less established KS comorbidities (e.g. pituitary gland hypofunction and dental caries). Several systems biology approaches were applied to identify key molecular players underlying KS comorbidities: Identification of co-expressed modules as well as central hubs and gene dosage perturbed protein complexes in a KS comorbidity network build from known disease proteins and their protein-protein interactions. The systems biology approaches together pointed to novel aspects of KS disease phenotypes including perturbed Jak-STAT pathway, dysregulated genes important for disturbed immune system (IL4), energy balance (POMC and LEP) and erythropoietin signalling in KS. We present an extended epidemiological study that links KS comorbidities to the molecular level and identify potential causal players in the disease biology underlying the identified comorbidities.
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Belling
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Russo
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders B
authors.initials: AB
authors.lastname: Jensen
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Marlene D
authors.initials: MD
authors.lastname: Dalgaard
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: David
authors.initials: D
authors.lastname: Westergaard
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebæk
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
mesh_terms: D000782:Aneuploidy; D041321:Chromosomes, Human, X / Q000235:genetics*; D015897:Comorbidity; D003718:Denmark; D003731:Dental Caries / Q000235:genetics / Q000473:pathology; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D053613:Janus Kinase 1 / Q000235:genetics; D007713:Klinefelter Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D043484:Proprotein Convertases / Q000235:genetics; D050791:STAT Transcription Factors / Q000235:genetics; D049490:Systems Biology; D013739:Testosterone / Q000235:genetics
chemical_list: C508598:IL4 protein, human; D050791:STAT Transcription Factors; D015847:Interleukin-4; D013739:Testosterone; D053613:Janus Kinase 1; D043484:Proprotein Convertases