Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood

PLoS One. 2012;7(10):e48215. doi: 10.1371/journal.pone.0048215. Epub 2012 Oct 25.

Abstract

Background: 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.

Methods and findings: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genomics
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Models, Genetic
  • Odds Ratio
  • Otitis Media / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Regression Analysis
  • Risk Factors
  • Surveys and Questionnaires
  • Transforming Growth Factor beta / metabolism

Substances

  • Transforming Growth Factor beta

Grants and funding

This work was supported by funds to SEJ from a Brightspark Foundation Fellowship, a Raine Medical Research Foundation Priming Grant to SEJ, and core funds to JMB from The Stan Perron Foundation, the University of Western Australia (UWA) and the Western Australian State Government. MSR is supported by an Australian Post Graduate Scholarship. The Raine Study has been supported by the National Health and Medical Research Council over the last 20 years with funding for Core Management provided by UWA, The Raine Medical Research Foundation at UWA, the UWA Faculty of Medicine, Dentistry and Health Sciences, the Telethon Institute for Child Health Research, the Women and Infants Research Foundation and Curtin University. Raine Study Illumina 660W-Quad Beadchip Data was supported by the National Health and Medical Research Council (ID 572613). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.