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A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

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Abstract

Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with P < 10−4 and 12 imputed SNPs with P < 10−4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P = 1.30 × 10−5) on chromosome 2 in the independent otitis media population (P = 4.7 × 10−5; meta-analysis P = 1.52 × 10−8). Three additional SNPs had replication P values < 0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P = 3.4 ×10−7) in KIF7 intron 7 (P = 0.072), and rs10775247, a non-synonymous SNP in TICRR exon 2 (P = 0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P = 0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.

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Acknowledgments

We thank the families for their participation. The study would not have been possible without the UMN Study recruitment team: Donna Brauer, Karen Savonna, Ruth Selvius, Ann Brauti, Cynthia Roh, Michele Bochert, Jennifer Palmer, Kendra Herrell, Judy Monroe, Norrita Rech, Kim Canfield, Heather Nelson, and JoAnn Knox. Thanks also to Kathleen Day and Pamela Hicks for technical assistance. This work was supported by National Institutes of Health grants DC003166 and DC003166-S1 (KAD). The replication work was supported primarily by the National Institutes of Health grant R01DC005630 (MLC), as well as by the National Institutes of Health General Clinical Research Center grant M01RR000084, National Institutes of Health Clinical and Translational Science Award UL1RR024153, Children’s Hospital of Pittsburgh of UPMC, and the University of Pittsburgh. Ms. Allen received support from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM008715.

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Authors and Affiliations

  1. Center for Public Health Genomics, University of Virginia, P.O. Box 800717, Charlottesville, VA, USA

    E. Kaitlynn Allen, Wei-Min Chen, Fang Chen, Xuanlin Hou, José L. Mattos, Josyf C. Mychaleckyj, Stephen S. Rich & Michèle M. Sale

  2. Department of Biochemistry and Molecular Genetics, Charlottesville, VA, USA

    E. Kaitlynn Allen & Michèle M. Sale

  3. Department of Public Health Sciences, Charlottesville, VA, USA

    Wei-Min Chen, Josyf C. Mychaleckyj & Stephen S. Rich

  4. Department of Medicine, University of Virginia, Charlottesville, Charlottesville, VA, 22908, USA

    Stephen S. Rich & Michèle M. Sale

  5. Department of Human Genetics, Pittsburgh, PA 15261, USA

    Daniel E. Weeks & Robert E. Ferrell

  6. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Daniel E. Weeks

  7. Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Fernando Segade

  8. Department of Otolaryngology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA

    Margaretha L. Casselbrant & Ellen M. Mandel

  9. Department of Otolaryngology, University of Minnesota, Minneapolis, MN, 55455, USA

    Kathleen A. Daly

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  1. E. Kaitlynn Allen
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  2. Wei-Min Chen
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  4. Fang Chen
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  9. Margaretha L. Casselbrant
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Correspondence to Michèle M. Sale.

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Allen, E.K., Chen, WM., Weeks, D.E. et al. A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2. JARO 14, 791–800 (2013). https://doi.org/10.1007/s10162-013-0411-2

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