Rare A2ML1 variants confer susceptibility to otitis media

Regie Lyn P Santos-Cortez; Charlotte M Chiong; Ma Rina T Reyes-Quintos; Ma Leah C Tantoco; Xin Wang; Anushree Acharya; Izoduwa Abbe; Arnaud P Giese; Joshua D Smith; E Kaitlynn Allen; Biao Li; Eva Maria Cutiongco-de la Paz; Marieflor Cristy Garcia; Erasmo Gonzalo D V Llanes; Patrick John Labra; Teresa Luisa I Gloria-Cruz; Abner L Chan; Gao T Wang; Kathleen A Daly; Jay Shendure; Michael J Bamshad; Deborah A Nickerson; Janak A Patel; Saima Riazuddin; Michele M Sale; University of Washington Center for Mendelian Genomics; Tasnee Chonmaitree; Zubair M Ahmed; Generoso T Abes; Suzanne M Leal

doi:10.1038/ng.3347

Rare A2ML1 variants confer susceptibility to otitis media

Nat Genet. 2015 Aug;47(8):917-20. doi: 10.1038/ng.3347. Epub 2015 Jun 29.

Authors

Regie Lyn P Santos-Cortez¹, Charlotte M Chiong², Ma Rina T Reyes-Quintos², Ma Leah C Tantoco³, Xin Wang¹, Anushree Acharya¹, Izoduwa Abbe¹, Arnaud P Giese⁴, Joshua D Smith⁵, E Kaitlynn Allen⁶, Biao Li¹, Eva Maria Cutiongco-de la Paz⁷, Marieflor Cristy Garcia⁸, Erasmo Gonzalo D V Llanes², Patrick John Labra⁸, Teresa Luisa I Gloria-Cruz², Abner L Chan², Gao T Wang¹, Kathleen A Daly⁹, Jay Shendure⁵, Michael J Bamshad⁵, Deborah A Nickerson⁵, Janak A Patel¹⁰, Saima Riazuddin⁴, Michele M Sale¹¹; University of Washington Center for Mendelian Genomics; Tasnee Chonmaitree¹⁰, Zubair M Ahmed⁴, Generoso T Abes², Suzanne M Leal¹

Collaborators

University of Washington Center for Mendelian Genomics:
Michael J Bamshad, Jay Shendure, Deborah A Nickerson, Gonçalo R Abecasis, Peter Anderson, Marcus Annable, Mallory Beightol, Brian L Browning, Kati J Buckingham, Christina Chen, Jennifer Chin, Jessica X Chong, Gregory M Cooper, Colleen Davis, Lindsay Felker, Christopher Frazar, David Hanna, Zongxiao He, Preti Jain, Gail P Jarvik, Eric Johanson, Goo Jun, Martin Kircher, Tom Kolar, Suzanne M Leal, Daniel Luksic, Margaret J McMillin, Sean McGee, Brenton Munson, Brian J O'Roak, Bryan Paeper, Karynne Patterson, Eric Phillips, Jessica Pijoan, Christa Poel, Peggy D Robertson, Regie Santos-Cortez, Tristan Shaffer, Cindy Shephard, Deborah L Siegel, Joshua D Smith, Jeffrey C Staples, Holly K Tabor, Monica Tackett, Gao Wang, Qian Yi

Affiliations

¹ Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
² 1] Philippine National Ear Institute, University of the Philippines Manila-National Institutes of Health, Manila, Philippines. [2] Department of Otorhinolaryngology, University of the Philippines College of Medicine-Philippine General Hospital, Manila, Philippines.
³ Philippine National Ear Institute, University of the Philippines Manila-National Institutes of Health, Manila, Philippines.
⁴ Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
⁵ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
⁶ 1] Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA. [2] Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
⁷ 1] Institute of Human Genetics, University of the Philippines Manila-National Institutes of Health, Manila, Philippines. [2] Department of Pediatrics, University of the Philippines College of Medicine-Philippine General Hospital, Manila, Philippines.
⁸ Department of Otorhinolaryngology, University of the Philippines College of Medicine-Philippine General Hospital, Manila, Philippines.
⁹ Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁰ Division of Pediatric Infectious Disease and Immunology, Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.
¹¹ 1] Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA. [2] Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA. [3] Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.

PMID: 26121085
PMCID: PMC4528370
DOI: 10.1038/ng.3347

Abstract

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Child
Cochlea / metabolism
Cochlea / pathology
Exome / genetics
Family Health
Female
Gene Duplication*
Gene Frequency
Genetic Predisposition to Disease / genetics*
Genotype
Haplotypes
Humans
Male
Mice, Inbred C57BL
Models, Molecular
Otitis Media / genetics*
Otitis Media / pathology
Pedigree
Principal Component Analysis
Protein Conformation
Sequence Analysis, DNA
alpha-Macroglobulins / chemistry
alpha-Macroglobulins / genetics*

Substances

A2ML1 protein, human
alpha-Macroglobulins

Abstract

Publication types

MeSH terms

Substances

Grants and funding