Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood
Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ≥ 3 months) is 40-70% heritable. Few underlying genes have been identified to da...
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| Veröffentlicht in: | PloS one 2012-10, Vol.7 (10), p.e48215-e48215 |
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| creator | Rye, Marie S Warrington, Nicole M Scaman, Elizabeth S H Vijayasekaran, Shyan Coates, Harvey L Anderson, Denise Pennell, Craig E Blackwell, Jenefer M Jamieson, Sarra E |
| description | Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ≥ 3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported.
Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA) |
| doi_str_mv | 10.1371/journal.pone.0048215 |
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Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS.
This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0048215</identifier><identifier>PMID: 23133572</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age ; Biology ; Breastfeeding & lactation ; Case-Control Studies ; Child ; Child, Preschool ; Childhood ; Children ; Children & youth ; Childrens health ; Chromosome 19 ; Chromosome 20 ; Chromosome Mapping ; Clusters ; Cohort Studies ; Diseases ; Ear diseases ; Effusion ; Epidemiology ; Families & family life ; Family ; Family studies ; Female ; Genes ; Genetic aspects ; Genetic Predisposition to Disease ; Genetics ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Genomics ; Genotype ; Genotype & phenotype ; Hospitals ; Humans ; Infant ; Infant, Newborn ; Inflammation ; Male ; Medical research ; Medicine ; Middle ear ; Models, Genetic ; Odds Ratio ; Otitis media ; Otitis Media - genetics ; Otolaryngology ; Otology ; Phenotype ; Polymorphism, Single Nucleotide ; Pregnancy ; Principal components analysis ; Regression Analysis ; Replication ; Risk Factors ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Studies ; Surgery ; Surveys and Questionnaires ; Transforming Growth Factor beta - metabolism ; Transforming growth factors</subject><ispartof>PloS one, 2012-10, Vol.7 (10), p.e48215-e48215</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Rye et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>2012 Rye et al 2012 Rye et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-26c22acb23ace1f43c51c46e29f7641e6e60092798d77f947cb8c7d5d271a0193</citedby><cites>FETCH-LOGICAL-c692t-26c22acb23ace1f43c51c46e29f7641e6e60092798d77f947cb8c7d5d271a0193</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/PMC3485007/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485007/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23133572$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Timpson, Nicholas John</contributor><creatorcontrib>Rye, Marie S</creatorcontrib><creatorcontrib>Warrington, Nicole M</creatorcontrib><creatorcontrib>Scaman, Elizabeth S H</creatorcontrib><creatorcontrib>Vijayasekaran, Shyan</creatorcontrib><creatorcontrib>Coates, Harvey L</creatorcontrib><creatorcontrib>Anderson, Denise</creatorcontrib><creatorcontrib>Pennell, Craig E</creatorcontrib><creatorcontrib>Blackwell, Jenefer M</creatorcontrib><creatorcontrib>Jamieson, Sarra E</creatorcontrib><title>Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ≥ 3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported.
Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS.
This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.</description><subject>Age</subject><subject>Biology</subject><subject>Breastfeeding & lactation</subject><subject>Case-Control Studies</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Childhood</subject><subject>Children</subject><subject>Children & youth</subject><subject>Childrens health</subject><subject>Chromosome 19</subject><subject>Chromosome 20</subject><subject>Chromosome Mapping</subject><subject>Clusters</subject><subject>Cohort Studies</subject><subject>Diseases</subject><subject>Ear diseases</subject><subject>Effusion</subject><subject>Epidemiology</subject><subject>Families & family life</subject><subject>Family</subject><subject>Family studies</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Inflammation</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Middle ear</subject><subject>Models, Genetic</subject><subject>Odds Ratio</subject><subject>Otitis media</subject><subject>Otitis Media - genetics</subject><subject>Otolaryngology</subject><subject>Otology</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Pregnancy</subject><subject>Principal components analysis</subject><subject>Regression Analysis</subject><subject>Replication</subject><subject>Risk Factors</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>Studies</subject><subject>Surgery</subject><subject>Surveys and Questionnaires</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming growth 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E</au><au>Blackwell, Jenefer M</au><au>Jamieson, Sarra E</au><au>Timpson, Nicholas John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-10-25</date><risdate>2012</risdate><volume>7</volume><issue>10</issue><spage>e48215</spage><epage>e48215</epage><pages>e48215-e48215</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ≥ 3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported.
Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS.
This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23133572</pmid><doi>10.1371/journal.pone.0048215</doi><tpages>e48215</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-10, Vol.7 (10), p.e48215-e48215 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1327131474 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) Journals Open Acc |
| subjects | Age Biology Breastfeeding & lactation Case-Control Studies Child Child, Preschool Childhood Children Children & youth Childrens health Chromosome 19 Chromosome 20 Chromosome Mapping Clusters Cohort Studies Diseases Ear diseases Effusion Epidemiology Families & family life Family Family studies Female Genes Genetic aspects Genetic Predisposition to Disease Genetics Genome-wide association studies Genome-Wide Association Study Genomes Genomics Genotype Genotype & phenotype Hospitals Humans Infant Infant, Newborn Inflammation Male Medical research Medicine Middle ear Models, Genetic Odds Ratio Otitis media Otitis Media - genetics Otolaryngology Otology Phenotype Polymorphism, Single Nucleotide Pregnancy Principal components analysis Regression Analysis Replication Risk Factors Single nucleotide polymorphisms Single-nucleotide polymorphism Studies Surgery Surveys and Questionnaires Transforming Growth Factor beta - metabolism Transforming growth factors |
| title | Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood |
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