{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:45:24Z","timestamp":1789685124022,"version":"4.0.1"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T00:00:00Z","timestamp":1653523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Cryptorchidism is the most common congenital sex development disorder in dogs. Despite this, little progress has been made in understanding its genetic background. Extensive genetic testing of dogs through consumer and veterinary channels using a high-density SNP genotyping microarray coupled with links to clinical records presents the opportunity for a large-scale genome-wide association study to elucidate the molecular risk factors associated with cryptorchidism in dogs. Using an inter-breed genome-wide association study approach, a significant statistical association on canine chromosome 10 was identified, with the top SNP pinpointing a variant of <jats:italic>HMGA2<\/jats:italic> previously associated with adult weight variance. In further analysis we show that incidence of cryptorchidism is skewed towards smaller dogs in concordance with the identified variant\u2019s previous association with adult weight. This study represents the first putative variant to be associated with cryptorchidism in dogs.<\/jats:p>","DOI":"10.1371\/journal.pone.0267604","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T17:31:56Z","timestamp":1653586316000},"page":"e0267604","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Large scale across-breed genome-wide association study reveals a variant in HMGA2 associated with inguinal cryptorchidism risk in dogs"],"prefix":"10.1371","volume":"17","author":[{"given":"Matthew","family":"Blades","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0223-8747","authenticated-orcid":true,"given":"Jamie","family":"Freyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9874-8484","authenticated-orcid":true,"given":"Jonas","family":"Donner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Chodroff Foran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2817-2165","authenticated-orcid":true,"given":"Oliver P.","family":"Forman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,5,26]]},"reference":[{"key":"pone.0267604.ref001","first-page":"325","volume":"30","author":"Nappier M Cryptorchidism","year":"2008","journal-title":"Compend Contin Educ Vet"},{"key":"pone.0267604.ref002","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.2460\/ajvr.2001.62.1198","article-title":"Heritability estimations for diseases, coat color, body weight, and height in a birth cohort of Boxers","volume":"62","author":"AL Nielen","year":"2001","journal-title":"Am J Vet Res"},{"key":"pone.0267604.ref003","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.anireprosci.2008.07.004","article-title":"Relationship of cryptorchidism with sex ratios and litter sizes in 12 dog breeds","volume":"113","author":"EJ Gubbels","year":"2009","journal-title":"Anim Reprod Sci"},{"key":"pone.0267604.ref004","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1136\/vr.152.16.502","article-title":"Incidence of cryptorchidism in dogs and cats","volume":"152","author":"D Yates","year":"2003","journal-title":"Vet Rec"},{"key":"pone.0267604.ref005","doi-asserted-by":"crossref","first-page":"105201","DOI":"10.1016\/j.prevetmed.2020.105201","article-title":"A five-year cohort study on testicular tumors from a population-based canine cancer registry in central Italy (Umbria)","volume":"185","author":"E Manuali","year":"2020","journal-title":"Prev Vet Med"},{"key":"pone.0267604.ref006","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/tera.1420320108","article-title":"Canine cryptorchism and subsequent testicular neoplasia: case-control study with epidemiologic update","volume":"32","author":"HM Hayes","year":"1985","journal-title":"Teratology"},{"key":"pone.0267604.ref007","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1097\/00000658-194512260-00012","article-title":"Bilateral Adrenalectomy in Prostatic Cancer: Clinical Features and Urinary Excretion of 17-Ketosteroids and Estrogen","volume":"122","author":"C Huggins","year":"1945","journal-title":"Ann Surg"},{"key":"pone.0267604.ref008","first-page":"1054","article-title":"Estrogen-induced myelotoxicity in dogs: A review","volume":"50","author":"HB Sontas","year":"2009","journal-title":"Can Vet J"},{"key":"pone.0267604.ref009","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/MED.0b013e32835ffc7d","article-title":"Cryptorchidism","volume":"20","author":"PA Lee","year":"2013","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"pone.0267604.ref010","doi-asserted-by":"crossref","first-page":"906","DOI":"10.3389\/fendo.2019.00906","article-title":"Hypogonadism and Cryptorchidism","volume":"10","author":"W Rodprasert","year":"2019","journal-title":"Front Endocrinol"},{"key":"pone.0267604.ref011","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1111\/andr.12217","article-title":"Molecular mechanisms of cryptorchidism development: update of the database, disease comorbidity, and initiative for standardization of reporting in scientific literature","volume":"4","author":"K Urh","year":"2016","journal-title":"Andrology"},{"key":"pone.0267604.ref012","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/ng.2310","article-title":"Genome-wide efficient mixed-model analysis for association studies","volume":"44","author":"X Zhou","year":"2012","journal-title":"Nat Genet"},{"key":"pone.0267604.ref013","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/jbg.12064","article-title":"A genome-wide association study for canine cryptorchidism in Siberian Huskies","volume":"131","author":"X Zhao","year":"2014","journal-title":"J Anim Breed Genet Z Tierzuchtung Zuchtungsbiologie"},{"key":"pone.0267604.ref014","first-page":"92","article-title":"Polymorphisms of MAMLD1, SRD5A2, and AR Candidate Genes in Seven Dogs (78,XY; SRY-Positive) Affected by Hypospadias or Cryptorchidism","volume":"13","author":"P Krzemi\u0144ska","year":"2019","journal-title":"Sex Dev Genet Mol Biol Evol Endocrinol Embryol Pathol Sex Determ Differ"},{"key":"pone.0267604.ref015","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.theriogenology.2020.08.029","article-title":"Analysis of transcript and methylation levels of INSL3 and RXFP2 in undescended and descended dog testes suggested promising biomarkers associated with cryptorchidism","volume":"157","author":"J Nowacka-Woszuk","year":"2020","journal-title":"Theriogenology"},{"key":"pone.0267604.ref016","doi-asserted-by":"crossref","first-page":"e1007361","DOI":"10.1371\/journal.pgen.1007361","article-title":"Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs","volume":"14","author":"J Donner","year":"2018","journal-title":"PLoS Genet"},{"key":"pone.0267604.ref017","doi-asserted-by":"crossref","first-page":"e0161005","DOI":"10.1371\/journal.pone.0161005","article-title":"Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders","volume":"11","author":"J Donner","year":"2016","journal-title":"PloS One"},{"key":"pone.0267604.ref018","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"S Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"key":"pone.0267604.ref019","doi-asserted-by":"crossref","first-page":"731","DOI":"10.21105\/joss.00731","article-title":"qqman: an R package for visualizing GWAS results using Q-Q and manhattan plots","volume":"3","author":"SD Turner","year":"2018","journal-title":"J Open Source Softw"},{"key":"pone.0267604.ref020","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-98141-3","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"H. Wickham","year":"2009"},{"key":"pone.0267604.ref021","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1101\/gr.157339.113","article-title":"Derived variants at six genes explain nearly half of size reduction in dog breeds","volume":"23","author":"M Rimbault","year":"2013","journal-title":"Genome Res"},{"key":"pone.0267604.ref022","doi-asserted-by":"crossref","first-page":"5420","DOI":"10.1073\/pnas.1721630115","article-title":"High mobility group A2 (HMGA2) deficiency in pigs leads to dwarfism, abnormal fetal resource allocation, and cryptorchidism","volume":"115","author":"J Chung","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0267604.ref023","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/ng0895-436","article-title":"Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours","volume":"10","author":"EF Schoenmakers","year":"1995","journal-title":"Nat Genet"},{"key":"pone.0267604.ref024","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.cancergencyto.2008.07.009","article-title":"A microRNA encoded in a highly conserved part of the mammalian HMGA2 gene","volume":"187","author":"I von Ahsen","year":"2008","journal-title":"Cancer Genet Cytogenet"},{"key":"pone.0267604.ref025","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1186\/s12864-015-1702-2","article-title":"Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds","volume":"16","author":"MT Webster","year":"2015","journal-title":"BMC Genomics"},{"key":"pone.0267604.ref026","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1242\/bio.20146759","article-title":"Hmga1\/Hmga2 double knock-out mice display a \u201csuperpygmy\u201d phenotype","volume":"3","author":"A Federico","year":"2014","journal-title":"Biol Open"},{"key":"pone.0267604.ref027","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/oxfordjournals.jhered.a106143","article-title":"PYGMY, A DWARFING GENE IN THE HOUSE MOUSE","volume":"41","author":"JWB King","year":"1950","journal-title":"J Hered"},{"key":"pone.0267604.ref028","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1186\/s12864-016-2936-3","article-title":"Genetic mapping of canine fear and aggression","volume":"17","author":"I Zapata","year":"2016","journal-title":"BMC Genomics"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0267604","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T17:32:25Z","timestamp":1653586345000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0267604"}},"subtitle":[],"editor":[{"given":"Carlos E.","family":"Ambr\u00f3sio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,5,26]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0267604","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,26]]}}}