Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-like malformation in Griffon Bruxellois dogs
Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance o...
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| creator | Lemay, Philippe Knowler, Susan P Bouasker, Samir Nédélec, Yohann Platt, Simon Freeman, Courtenay Child, Georgina Barreiro, Luis B Rouleau, Guy A Rusbridge, Clare Kibar, Zoha |
| description | Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene. |
| doi_str_mv | 10.1371/journal.pone.0089816 |
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This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0089816</identifier><identifier>PMID: 24740420</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Arnold-Chiari Malformation - genetics ; Biology and Life Sciences ; Brain ; Care and treatment ; Cerebrospinal fluid ; Complications and side effects ; Congenital defects ; Dog Diseases - genetics ; Dogs ; Etiology ; Female ; Fluid flow ; Gene mapping ; Genetic aspects ; Genetic Association Studies ; Genetic factors ; Genetic polymorphisms ; Genetic Predisposition to Disease ; Genome ; Genome-wide association studies ; Genomes ; Genotype & phenotype ; Haplotypes ; Male ; Medicine and Health Sciences ; Neural tube defects ; Neuralgia ; Neuropathy ; NMR ; Nuclear magnetic resonance ; Overcrowding ; Pain ; Parenchyma ; Patient outcomes ; Permutations ; Quantitative trait loci ; Quantitative Trait Loci - genetics ; Regression analysis ; Risk factors ; Single-nucleotide polymorphism ; Skull ; Skull - abnormalities ; Spinal cord ; Studies ; Syringomyelia ; Townes-Brocks syndrome ; Veterinary colleges</subject><ispartof>PloS one, 2014-04, Vol.9 (4), p.e89816-e89816</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Lemay et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Lemay et al 2014 Lemay et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-872d7c8068e79e1341bde961d93d8b2c7d19ba8a9a32441eb52437904c0b4c3e3</citedby><cites>FETCH-LOGICAL-c692t-872d7c8068e79e1341bde961d93d8b2c7d19ba8a9a32441eb52437904c0b4c3e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989173/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989173/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24740420$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lemay, Philippe</creatorcontrib><creatorcontrib>Knowler, Susan P</creatorcontrib><creatorcontrib>Bouasker, Samir</creatorcontrib><creatorcontrib>Nédélec, Yohann</creatorcontrib><creatorcontrib>Platt, Simon</creatorcontrib><creatorcontrib>Freeman, Courtenay</creatorcontrib><creatorcontrib>Child, Georgina</creatorcontrib><creatorcontrib>Barreiro, Luis B</creatorcontrib><creatorcontrib>Rouleau, Guy A</creatorcontrib><creatorcontrib>Rusbridge, Clare</creatorcontrib><creatorcontrib>Kibar, Zoha</creatorcontrib><title>Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-like malformation in Griffon Bruxellois dogs</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.</description><subject>Animals</subject><subject>Arnold-Chiari Malformation - genetics</subject><subject>Biology and Life Sciences</subject><subject>Brain</subject><subject>Care and treatment</subject><subject>Cerebrospinal fluid</subject><subject>Complications and side effects</subject><subject>Congenital defects</subject><subject>Dog Diseases - genetics</subject><subject>Dogs</subject><subject>Etiology</subject><subject>Female</subject><subject>Fluid flow</subject><subject>Gene mapping</subject><subject>Genetic aspects</subject><subject>Genetic Association Studies</subject><subject>Genetic factors</subject><subject>Genetic polymorphisms</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome</subject><subject>Genome-wide association studies</subject><subject>Genomes</subject><subject>Genotype & phenotype</subject><subject>Haplotypes</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Neural tube defects</subject><subject>Neuralgia</subject><subject>Neuropathy</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Overcrowding</subject><subject>Pain</subject><subject>Parenchyma</subject><subject>Patient outcomes</subject><subject>Permutations</subject><subject>Quantitative trait loci</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Regression analysis</subject><subject>Risk factors</subject><subject>Single-nucleotide polymorphism</subject><subject>Skull</subject><subject>Skull - abnormalities</subject><subject>Spinal cord</subject><subject>Studies</subject><subject>Syringomyelia</subject><subject>Townes-Brocks syndrome</subject><subject>Veterinary colleges</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk99u0zAUxiMEYmPwBggsIaHtosWO8883SKOCUanSNBjcWo59krq4cbGdansBnht3zaYG7QLlIpbz-74Tf8cnSV4TPCW0JB9WtnedMNON7WCKccUqUjxJjgmj6aRIMX16sD5KXni_wjinVVE8T47SrMxwluLj5M9VL7qggwh6Cyg4oQMyVmp0enW9OEM-9OoWaQWRaTR41NktGNRCZ9daIgettp1HwvuoEQEUChbNllo4PTH6F6C1MI1162hvO6Q7dOF008TlJ9ffgDFWe6Rs618mzxphPLwa3ifJjy-fr2dfJ4vLi_nsfDGRBUvDpCpTVcoKFxWUDAjNSK2AFUQxqqo6laUirBaVYIKmWUagztOMlgxnEteZpEBPkrd7342xng8Rek5yUrCcsqKMxHxPKCtWfOP0WrhbboXmdxvWtVy4oKUBjpuCxNKMskpkOchaFiJGXIo8diPLVfT6OFTr6zUoGVN0woxMx186veSt3fLoyEhJo8HpYODs7x584GvtZcxNdGD7u_8uqwozukPf_YM-frqBakU8gO4aG-vKnSk_p2WeVzEvEqnpI1R8FMSux_vW6Lg_EpyNBJEJcBNa0XvP59-__T97-XPMvj9glyBMWHpr-t1t8mMw24PSWe8dNA8hE8x343KfBt-NCx_GJcreHDboQXQ_H_Qvr1IQow</recordid><startdate>20140401</startdate><enddate>20140401</enddate><creator>Lemay, Philippe</creator><creator>Knowler, Susan P</creator><creator>Bouasker, Samir</creator><creator>Nédélec, Yohann</creator><creator>Platt, Simon</creator><creator>Freeman, Courtenay</creator><creator>Child, Georgina</creator><creator>Barreiro, Luis B</creator><creator>Rouleau, Guy A</creator><creator>Rusbridge, Clare</creator><creator>Kibar, Zoha</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140401</creationdate><title>Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-like malformation in Griffon Bruxellois dogs</title><author>Lemay, Philippe ; Knowler, Susan P ; Bouasker, Samir ; Nédélec, Yohann ; Platt, Simon ; Freeman, Courtenay ; Child, Georgina ; Barreiro, Luis B ; Rouleau, Guy A ; Rusbridge, Clare ; Kibar, Zoha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-872d7c8068e79e1341bde961d93d8b2c7d19ba8a9a32441eb52437904c0b4c3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Arnold-Chiari Malformation - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lemay, Philippe</au><au>Knowler, Susan P</au><au>Bouasker, Samir</au><au>Nédélec, Yohann</au><au>Platt, Simon</au><au>Freeman, Courtenay</au><au>Child, Georgina</au><au>Barreiro, Luis B</au><au>Rouleau, Guy A</au><au>Rusbridge, Clare</au><au>Kibar, Zoha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-like malformation in Griffon Bruxellois dogs</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-04-01</date><risdate>2014</risdate><volume>9</volume><issue>4</issue><spage>e89816</spage><epage>e89816</epage><pages>e89816-e89816</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24740420</pmid><doi>10.1371/journal.pone.0089816</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1516953967 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Arnold-Chiari Malformation - genetics Biology and Life Sciences Brain Care and treatment Cerebrospinal fluid Complications and side effects Congenital defects Dog Diseases - genetics Dogs Etiology Female Fluid flow Gene mapping Genetic aspects Genetic Association Studies Genetic factors Genetic polymorphisms Genetic Predisposition to Disease Genome Genome-wide association studies Genomes Genotype & phenotype Haplotypes Male Medicine and Health Sciences Neural tube defects Neuralgia Neuropathy NMR Nuclear magnetic resonance Overcrowding Pain Parenchyma Patient outcomes Permutations Quantitative trait loci Quantitative Trait Loci - genetics Regression analysis Risk factors Single-nucleotide polymorphism Skull Skull - abnormalities Spinal cord Studies Syringomyelia Townes-Brocks syndrome Veterinary colleges |
| title | Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-like malformation in Griffon Bruxellois dogs |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T11%3A48%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Quantitative%20trait%20loci%20(QTL)%20study%20identifies%20novel%20genomic%20regions%20associated%20to%20Chiari-like%20malformation%20in%20Griffon%20Bruxellois%20dogs&rft.jtitle=PloS%20one&rft.au=Lemay,%20Philippe&rft.date=2014-04-01&rft.volume=9&rft.issue=4&rft.spage=e89816&rft.epage=e89816&rft.pages=e89816-e89816&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0089816&rft_dat=%3Cgale_plos_%3EA375582431%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1516953967&rft_id=info:pmid/24740420&rft_galeid=A375582431&rft_doaj_id=oai_doaj_org_article_0f611d99398a45ecbc6a0537a508945d&rfr_iscdi=true |