Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes

Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation of human genes and identify candidate genes by ontology-seeded queries capturing the features of tendinopathy. Our BioOntological Relationship Graph database (BORG) integrates multiple sources of genomic and biomedical knowledge into an on-disk semantic network where human genes and their orthologs in mouse and rat are central concepts mapped to ontology terms. The BORG was used to screen all human genes for potential links to tendinopathy. Following further prioritisation, four strong candidate genes (COL11A2, ELN, ITGB3, LOX) were identified. These genes are differentially expressed in tendinopathy, functionally linked to features of tendinopathy and previously implicated in other connective tissue diseases. In conclusion, cross-domain semantic integration of multiple sources of biomedical knowledge, and interrogation of phenotypes and gene functions associated with disease, may significantly increase the probability of identifying strong and unobvious candidate genes in genetic association studies.

[1]  J. Cook,et al.  Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: a genetic association study. , 2013, Journal of science and medicine in sport.

[2]  Gordon K Smyth,et al.  Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2004, Statistical applications in genetics and molecular biology.

[3]  L. Soslowsky,et al.  Regulation of Collagen Fibril Nucleation and Initial Fibril Assembly Involves Coordinate Interactions with Collagens V and XI in Developing Tendon* , 2011, The Journal of Biological Chemistry.

[4]  Tim Clark,et al.  Semantic Web repositories for genomics data using the eXframe platform , 2014, Journal of Biomedical Semantics.

[5]  Willem H. Meeuwisse,et al.  Assessing Causation in Sport Injury: A Multifactorial Model , 1994 .

[6]  H. Seeherman,et al.  Regulation of gene expression in human tendinopathy , 2011, BMC musculoskeletal disorders.

[7]  A. Shapiro,et al.  Plasminogen activator inhibitor type 1 deficiency , 2008, Haemophilia : the official journal of the World Federation of Hemophilia.

[8]  James Binney.  Bigger and better , 1991, Nature.

[9]  Melinda R. Dwinell,et al.  The pathway ontology – updates and applications , 2014, Journal of Biomedical Semantics.

[10]  L. Engebretsen,et al.  International Olympic Committee consensus statement: molecular basis of connective tissue and muscle injuries in sport. , 2008, Clinics in sports medicine.

[11]  J. Cook,et al.  Investigation of variants within the COL27A1 and TNC genes and Achilles tendinopathy in two populations , 2013, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[12]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[13]  Benjamin M. Bolstad,et al.  affy - analysis of Affymetrix GeneChip data at the probe level , 2004, Bioinform..

[14]  Damian Smedley,et al.  The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data , 2014, Nucleic Acids Res..

[15]  J. Cook,et al.  The apoptosis pathway and the genetic predisposition to Achilles tendinopathy , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[16]  J. Cook,et al.  Variants within the COMP and THBS2 genes are not associated with Achilles tendinopathy in a case-control study of South African and Australian populations , 2014, Journal of sports sciences.

[17]  M. Collins,et al.  The association of genes involved in the angiogenesis‐associated signaling pathway with risk of anterior cruciate ligament rupture , 2014, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[18]  Harihara Baskaran,et al.  Conversion of Mechanical Force into TGF-β-Mediated Biochemical Signals , 2011, Current Biology.

[19]  Thomas C. Wiegers,et al.  The Comparative Toxicogenomics Database's 10th year anniversary: update 2015 , 2014, Nucleic Acids Res..

[20]  Irene Georgakoudi,et al.  Lysyl oxidase-mediated collagen crosslinks may be assessed as markers of functional properties of tendon tissue formation. , 2014, Acta biomaterialia.

[21]  M. Collins,et al.  Pathology of the tendo Achillis: do our genes contribute? , 2013, The bone & joint journal.

[22]  B. Vicenzino,et al.  Sports and exercise-related tendinopathies: a review of selected topical issues by participants of the second International Scientific Tendinopathy Symposium (ISTS) Vancouver 2012 , 2013, British Journal of Sports Medicine.

[23]  M. Collins,et al.  Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures , 2014, British Journal of Sports Medicine.

[24]  Malcolm Collins,et al.  Genetic risk factors for musculoskeletal soft tissue injuries. , 2009, Medicine and sport science.

[25]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[26]  J. Cook,et al.  Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy , 2008, British Journal of Sports Medicine.

[27]  J. Cook,et al.  Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations , 2008, British Journal of Sports Medicine.

[28]  J. Cook,et al.  Extracellular matrix proteins interact with cell‐signaling pathways in modifying risk of achilles tendinopathy , 2015, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[29]  G. Riley.  Chronic tendon pathology: molecular basis and therapeutic implications , 2005, Expert Reviews in Molecular Medicine.

[30]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[31]  A. Mitchell,et al.  Lysyl oxidase and P-ATPase-7A expression during embryonic development in the rat. , 2000, Archives of biochemistry and biophysics.

[32]  Janan T. Eppig,et al.  The Mammalian Phenotype Ontology as a unifying standard for experimental and high-throughput phenotyping data , 2012, Mammalian Genome.

[33]  L. Schriml,et al.  The Disease Ontology: fostering interoperability between biological and clinical human disease-related data , 2015, Mammalian Genome.

[34]  T D Noakes,et al.  The COL5A1 gene and Achilles tendon pathology , 2006, Scandinavian journal of medicine & science in sports.

[35]  P. Kannus,et al.  Time to abandon the “tendinitis” myth , 2002, BMJ : British Medical Journal.

[36]  J. Cook,et al.  Association of type XI collagen genes with chronic Achilles tendinopathy in independent populations from South Africa and Australia , 2013, British Journal of Sports Medicine.

[37]  M. Kjaer,et al.  Lysyl Oxidase Activity Is Required for Ordered Collagen Fibrillogenesis by Tendon Cells* , 2015, The Journal of Biological Chemistry.

[38]  J. Cook,et al.  ELN and FBN2 Gene Variants as Risk Factors for Two Sports-related Musculoskeletal Injuries , 2014, International Journal of Sports Medicine.

[39]  Lennart Martens,et al.  The Ontology Lookup Service: bigger and better , 2010, Nucleic Acids Res..

[40]  T. Noakes,et al.  The Guanine-Thymine Dinucleotide Repeat Polymorphism within the Tenascin-C Gene is Associated with Achilles Tendon Injuries , 2005, The American journal of sports medicine.

[41]  G. Mortier,et al.  Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing. , 2014, Molecular genetics and metabolism.

[42]  A. Scott,et al.  Tendons – time to revisit inflammation , 2013, British Journal of Sports Medicine.

[43]  J. Cook,et al.  A pathway-based approach investigating the genes encoding interleukin-1β, interleukin-6 and the interleukin-1 receptor antagonist provides new insight into the genetic susceptibility of Achilles tendinopathy , 2011, British Journal of Sports Medicine.

[44]  T. Byzova,et al.  Cooperation between integrin ανβ3 and VEGFR2 in angiogenesis , 2009, Angiogenesis.

[45]  Jiangang Gao,et al.  Elastic fiber homeostasis requires lysyl oxidase–like 1 protein , 2004, Nature Genetics.

[46]  Hui Yang,et al.  Phenolyzer: phenotype-based prioritization of candidate genes for human diseases , 2015, Nature Methods.

[47]  J. Karlsson,et al.  Terminology for Achilles tendon related disorders , 2011, Knee Surgery, Sports Traumatology, Arthroscopy.

[48]  K. Khan,et al.  Overuse tendon conditions: time to change a confusing terminology. , 1998, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.