{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:23:48Z","timestamp":1774052628305,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T00:00:00Z","timestamp":1560816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education, Malaysia","doi-asserted-by":"publisher","award":["FRGS\/1\/2014\/SGD5\/UKM\/02\/6"],"award-info":[{"award-number":["FRGS\/1\/2014\/SGD5\/UKM\/02\/6"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004515","name":"Universiti Kebangsaan Malaysia","doi-asserted-by":"publisher","award":["DIP2018-004"],"award-info":[{"award-number":["DIP2018-004"]}],"id":[{"id":"10.13039\/501100004515","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Based on clinical observations, women with polycystic ovarian syndrome (PCOS) are prone to developing several other diseases, such as metabolic and cardiovascular diseases. However, the molecular association between PCOS and these diseases remains poorly understood. Recent studies showed that the information from protein\u2013protein interaction (PPI) network analysis are useful in understanding the disease association in detail. This study utilized this approach to deepen the knowledge on the association between PCOS and other diseases. A PPI network for PCOS was constructed using PCOS-related proteins (PCOSrp) obtained from PCOSBase. MCODE was used to identify highly connected regions in the PCOS network, known as subnetworks. These subnetworks represent protein families, where their molecular information is used to explain the association between PCOS and other diseases. Fisher\u2019s exact test and comorbidity data were used to identify PCOS\u2013disease subnetworks. Pathway enrichment analysis was performed on the PCOS\u2013disease subnetworks to identify significant pathways that are highly involved in the PCOS\u2013disease associations. Migraine, schizophrenia, depressive disorder, obesity, and hypertension, along with twelve other diseases, were identified to be highly associated with PCOS. The identification of significant pathways, such as ribosome biogenesis, antigen processing and presentation, and mitophagy, suggest their involvement in the association between PCOS and migraine, schizophrenia, and hypertension.<\/jats:p>","DOI":"10.3390\/ijms20122959","type":"journal-article","created":{"date-parts":[[2019,6,19]],"date-time":"2019-06-19T02:42:46Z","timestamp":1560912166000},"page":"2959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Protein\u2013Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome"],"prefix":"10.3390","volume":"20","author":[{"given":"Balqis","family":"Ramly","sequence":"first","affiliation":[{"name":"Centre for Bioinformatics Research, Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, UKM Bangi 43600, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0919-5126","authenticated-orcid":false,"given":"Nor","family":"Afiqah-Aleng","sequence":"additional","affiliation":[{"name":"Centre for Bioinformatics Research, Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, UKM Bangi 43600, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5386-7260","authenticated-orcid":false,"given":"Zeti-Azura","family":"Mohamed-Hussein","sequence":"additional","affiliation":[{"name":"Centre for Bioinformatics Research, Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, UKM Bangi 43600, Selangor, Malaysia"},{"name":"Centre for Frontier Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, UKM Bangi 43600, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16057","DOI":"10.1038\/nrdp.2016.57","article-title":"Polycystic ovary syndrome","volume":"2","author":"Azziz","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","first-page":"90","article-title":"Long term health consequences of polycystic ovarian syndrome: A review analysis","volume":"13","author":"Daniilidis","year":"2009","journal-title":"Hippokratia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1210\/jc.2013-2007","article-title":"Gestational diabetes and type 2 diabetes in reproductive-aged women with polycystic ovary syndrome","volume":"99","author":"Joham","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"611","DOI":"10.5812\/ijem.4020","article-title":"Cardiovascular risk in women with PCOS","volume":"10","author":"Scicchitano","year":"2012","journal-title":"Int. J. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.2147\/NDT.S91700","article-title":"Polycystic ovary syndrome and mental disorders: A systematic review and exploratory meta-analysis","volume":"12","author":"Blay","year":"2016","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40738-016-0029-2","article-title":"Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: A systematic review","volume":"2","author":"Harris","year":"2016","journal-title":"Fertil. Res. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6207","DOI":"10.1038\/s41598-017-04939-4","article-title":"Genetic and functional characterization of disease associations explains comorbidity","volume":"7","author":"Guney","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1101\/gr.071852.107","article-title":"Protein networks in disease","volume":"18","author":"Ideker","year":"2008","journal-title":"Genome Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.gdata.2016.03.008","article-title":"Genomics data genetics of PCOS: A systematic bioinformatics approach to unveil the proteins responsible for PCOS","volume":"8","author":"Panda","year":"2016","journal-title":"Genomics Data"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Babbi, G., Martelli, P.L., Profiti, G., Bovo, S., Savojardo, C., and Casadio, R. (2017). eDGAR: A database of disease-gene associations with annotated relationships among genes. BMC Genomics, 18.","DOI":"10.1186\/s12864-017-3911-3"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/1479-5876-12-99","article-title":"Unraveling human protein interaction networks underlying co-occurrences of diseases and pathological conditions","volume":"12","author":"Paik","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1257601","article-title":"Uncovering disease-disease relationships through the incomplete interactome","volume":"347","author":"Menche","year":"2015","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Suratanee, A., and Plaimas, K. (2018). Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199435"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants","volume":"45","author":"Bravo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hidalgo, C.A., Blumm, N., Barab\u00e1si, A.L., and Christakis, N.A. (2009). A dynamic network approach for the study of human phenotypes. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000353"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1093\/jmcb\/mjv014","article-title":"Ribosomal proteins: Functions beyond the ribosome","volume":"7","author":"Zhou","year":"2015","journal-title":"J. Mol. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s10815-012-9827-6","article-title":"Overexpression of ribosomal RNA in cumulus cells of patients with polycystic ovary syndrome","volume":"29","author":"Polzikov","year":"2012","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/0333102410373155","article-title":"Genomic expression patterns in medication overuse headaches","volume":"31","author":"Hershey","year":"2011","journal-title":"Cephalalgia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"39638","DOI":"10.1038\/srep39638","article-title":"Single-cell analysis of differences in transcriptomic profiles of oocytes and cumulus cells at GV, MI, MII stages from PCOS patients","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"609","DOI":"10.4103\/1673-5374.230275","article-title":"Harnessing migraines for neural regeneration","volume":"13","author":"Borkum","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7780","DOI":"10.1523\/JNEUROSCI.0762-05.2005","article-title":"Estrogen-Induced Increase in the Magnitude of Long-Term Potentiation Occurs Only When the Ratio of NMDA Transmission to AMPA Transmission Is Increased","volume":"25","author":"Smith","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_23","first-page":"142","article-title":"The polycystic ovary syndrome: An update on metabolic and hormonal mechanisms","volume":"8","author":"Dumitrescu","year":"2015","journal-title":"J. Med. Life"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fendo.2014.00192","article-title":"Estrogen biosynthesis and action in ovarian cancer","volume":"5","author":"Mungenast","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20656","DOI":"10.18632\/oncotarget.9327","article-title":"Differential DNA methylation patterns of polycystic ovarian syndrome in whole blood of Chinese women","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1038\/ng.2742","article-title":"Genome-wide association analysis identifies 14 new risk loci for schizophrenia","volume":"45","author":"Ripke","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1002\/ajmg.b.32246","article-title":"Replication and cross-phenotype study based upon schizophrenia GWASs data in the Japanese population: Support for association of MHC region with psychosis","volume":"165","author":"Saito","year":"2014","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"479","DOI":"10.4172\/2155-9899.1000479","article-title":"The major histocompability complex (MHC) in schizophrenia: A review","volume":"7","author":"Mokhtari","year":"2016","journal-title":"J. Clin. Cell. Immunol."},{"key":"ref_29","first-page":"116","article-title":"Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome","volume":"440","author":"Apostolovic","year":"2016","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1530\/REP-17-0499","article-title":"Autophagy is activated in the ovarian tissue of polycystic ovary syndrome","volume":"155","author":"Li","year":"2018","journal-title":"Reproduction"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1586\/17512433.2014.925795","article-title":"Updates on the myo-inositol plus D-chiro-inositol combined therapy in polycystic ovary syndrome","volume":"7","author":"Unfer","year":"2014","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_32","first-page":"e43695","article-title":"Metabolism and ovarian function in PCOS women: A therapeutic approach with inositols","volume":"15","author":"Rossetti","year":"2017","journal-title":"Int. J. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1507\/endocrj.EJ16-0494","article-title":"High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process","volume":"64","author":"Su","year":"2017","journal-title":"Endocr. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1757-2215-5-22","article-title":"Involvement of autophagy in ovarian cancer: A working hypothesis","volume":"5","author":"Peracchio","year":"2012","journal-title":"J. Ovarian Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/j.1468-1331.2010.03166.x","article-title":"Gene expression signature is shared by patients with Alzheimer\u2019s disease and schizophrenia at the superior temporal gyrus","volume":"18","author":"Horesh","year":"2011","journal-title":"Eur. J. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/mp.2010.52","article-title":"Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression","volume":"16","author":"Shelton","year":"2011","journal-title":"Mol. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jad.2014.02.010","article-title":"Apoptosis-related proteins and proliferation markers in the orbitofrontal cortex in major depressive disorder","volume":"158","author":"Whittom","year":"2014","journal-title":"J. Affect. Disord."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41574-018-0009-1","article-title":"Targeting autophagy in obesity: From pathophysiology to management","volume":"14","author":"Zhang","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.clindermatol.2016.10.004","article-title":"Sex hormones and acne","volume":"35","author":"Ju","year":"2017","journal-title":"Clin. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s12264-015-1548-2","article-title":"Molecular network of neuronal autophagy in the pathophysiology and treatment of depression","volume":"31","author":"Jia","year":"2015","journal-title":"Neurosci. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1016\/j.bbamcr.2013.06.001","article-title":"Crosstalk between apoptosis, necrosis and autophagy","volume":"1833","author":"Nikoletopoulou","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1515\/hsz-2012-0119","article-title":"Mitophagy: Mechanisms, pathophysiological roles, and analysis","volume":"393","author":"Ding","year":"2013","journal-title":"Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"19436","DOI":"10.1038\/srep19436","article-title":"Abnormally activated one-carbon metabolic pathway is associated with mtDNA hypermethylation and mitochondrial malfunction in the oocytes of polycystic gilt ovaries","volume":"6","author":"Jia","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ydbio.2017.04.005","article-title":"Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy","volume":"426","author":"Boudoures","year":"2017","journal-title":"Dev. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1007\/s12325-018-0810-1","article-title":"Polycystic ovary syndrome: Implication for drug metabolism on assisted reproductive techniques\u2014A literature review","volume":"35","author":"Sathyapalan","year":"2018","journal-title":"Adv. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1093\/eurheartj\/ehu436","article-title":"Mitochondrial injury and dysfunction in hypertension-induced cardiac damage","volume":"35","author":"Eirin","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1080\/15548627.2017.1280225","article-title":"Dietary spermidine for lowering high blood pressure","volume":"13","author":"Eisenberg","year":"2017","journal-title":"Autophagy"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"bax098","DOI":"10.1093\/database\/bax098","article-title":"PCOSBase: A manually curated database of polycystic ovarian syndrome","volume":"2017","author":"Harun","year":"2017","journal-title":"Database"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ymeth.2014.11.020","article-title":"DISEASES: Text mining and data integration of disease-gene associations","volume":"74","author":"Tsafou","year":"2015","journal-title":"Methods"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"D553","DOI":"10.1093\/nar\/gks1244","article-title":"The disease and gene annotations (DGA): An annotation resource for human disease","volume":"41","author":"Peng","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D1001","DOI":"10.1093\/nar\/gkt1229","article-title":"The NHGRI GWAS Catalog, a curated resource of SNP-trait associations","volume":"42","author":"Welter","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D869","DOI":"10.1093\/nar\/gkv1317","article-title":"GWASdb v2: An update database for human genetic variants identified by genome-wide association studies","volume":"44","author":"Li","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"D877","DOI":"10.1093\/nar\/gkw1012","article-title":"MalaCards: An amalgamated human disease compendium with diverse clinical and genetic annotation and structured search","volume":"45","author":"Rappaport","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"D789","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM.org: Online Mendelian Inheritance in Man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"Amberger","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1093\/bioinformatics\/bti010","article-title":"PhenomicDB: A multi-species genotype\/phenotype database for comparative phenomics","volume":"21","author":"Kahraman","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00439-013-1358-4","article-title":"The Human Gene Mutation Database: Building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine","volume":"133","author":"Stenson","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"D408","DOI":"10.1093\/nar\/gkw985","article-title":"HIPPIE v2.0: Enhancing meaningfulness and reliability of protein\u2013protein interaction networks","volume":"45","author":"Schaefer","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Bader, G.D., and Hogue, C.W.V. (2003). An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform., 4.","DOI":"10.1186\/1471-2105-4-2"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2307\/2340521","article-title":"On the interpretation of x2 from contigency tables, and the calculation of p","volume":"85","author":"Fisher","year":"1922","journal-title":"J. R. Stat. Soc."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fisher, R. (1992). A Statistical Methods for Research Workers, Springer.","DOI":"10.1007\/978-1-4612-4380-9_6"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/12\/2959\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:59:10Z","timestamp":1760187550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/12\/2959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,18]]},"references-count":62,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["ijms20122959"],"URL":"https:\/\/doi.org\/10.3390\/ijms20122959","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,18]]}}}