Gene burden analysis identifies genes associated with increased risk and severity of adult-onset hearing loss in a diverse hospital-based cohort

Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and...

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Published inPLoS genetics Vol. 19; no. 1; p. e1010584
Main Authors Hui, Daniel, Mehrabi, Shadi, Quimby, Alexandra E., Chen, Tingfang, Chen, Sixing, Park, Joseph, Li, Binglan, Ruckenstein, Michael J., Rader, Daniel J., Ritchie, Marylyn D., Brant, Jason A., Epstein, Douglas J., Mathieson, Iain
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 19.01.2023
Public Library of Science (PLoS)
Subjects
Adult
Age
Biobanks
Biology and Life Sciences
Computer and Information Sciences
Craniofacial dysostosis
Deafness
Deafness - genetics
Electronic health records
Electronic medical records
Genes
Genetic aspects
Genetic disorders
Genetic variation
Genetics
Health care
Hearing
Hearing loss
Hearing Loss - genetics
Hearing Loss, Sensorineural - genetics
Humans
Life span
Medical records
Medical research
Medicine and Health Sciences
Medicine, Experimental
Multifactorial Inheritance
Mutation
People and places
Polygenic inheritance
Risk factors
Statistics
United States
United Kingdom > UK
Online AccessGet full text
ISSN1553-7404
1553-7390
1553-7404
DOI10.1371/journal.pgen.1010584

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Abstract Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank–a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene– TCOF1 , responsible for a syndromic form of congenital hearing loss–in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes ( COL5A1 , HMMR , RAPGEF3 , and NNT ) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.
AbstractList Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank-a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene-TCOF1, responsible for a syndromic form of congenital hearing loss-in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes (COL5A1, HMMR, RAPGEF3, and NNT) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.
Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank-a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene-TCOF1, responsible for a syndromic form of congenital hearing loss-in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes (COL5A1, HMMR, RAPGEF3, and NNT) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank-a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene-TCOF1, responsible for a syndromic form of congenital hearing loss-in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes (COL5A1, HMMR, RAPGEF3, and NNT) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.
Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank–a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene– TCOF1 , responsible for a syndromic form of congenital hearing loss–in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes ( COL5A1 , HMMR , RAPGEF3 , and NNT ) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases. Age-related hearing loss is relatively common and has a genetic component to risk, though little is known about specific genes that are involved. Here, we study participants in the Penn Medicine BioBank to identify factors that increase risk of hearing loss. We show that loss-of-function variants in genes that are known to cause Mendelian forms of hearing loss also increase risk of age-related hearing loss. Because many such genes have been identified, they can be used to interpret the results of genome-wide association studies and to investigate the biological basis of age-related hearing loss. Our results also emphasize that many reported Mendelian hearing loss variants are incompletely penetrant and may act cumulatively. Finally, our study shows how hospital-recruited biobank cohorts can aid in the study of common conditions like hearing loss, even when those conditions are not the primary reason for contact with the health system.
Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank–a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene– TCOF1 , responsible for a syndromic form of congenital hearing loss–in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes ( COL5A1 , HMMR , RAPGEF3 , and NNT ) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.
Audience Academic
Author Park, Joseph
Brant, Jason A.
Chen, Sixing
Hui, Daniel
Mehrabi, Shadi
Rader, Daniel J.
Ritchie, Marylyn D.
Chen, Tingfang
Quimby, Alexandra E.
Ruckenstein, Michael J.
Li, Binglan
Mathieson, Iain
Epstein, Douglas J.
AuthorAffiliation 2 Department of Otolaryngology, University of Michigan, Ann Arbor, Michigan, United States of America
3 Department of Otolaryngology–Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
1 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
6 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
8 Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
4 Department of Biomedical Data Science, Stanford University, Stanford, California, United States of America
7 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
9 Department of Otolaryngology–Head and Neck Surgery, Corporal Michael J
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– name: University of California San Diego, UNITED STATES
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36656851$$D View this record in MEDLINE/PubMed
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crossref_primary_10_1186_s13073_024_01372_x
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Copyright Copyright: © 2023 Hui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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License Copyright: © 2023 Hui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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A full list of contributors is available in S1 Note.
I have read the journal’s policy and the authors of this manuscript have the following competing interests: Regeneron Genetics Center is part of Regeneron Pharmaceuticals. The other authors have declared that no competing interests exist.
ORCID 0000-0002-3492-0679
0000-0002-4256-3982
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Snippet Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are...
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SubjectTerms Adult
Age
Biobanks
Biology and Life Sciences
Computer and Information Sciences
Craniofacial dysostosis
Deafness
Deafness - genetics
Electronic health records
Electronic medical records
Genes
Genetic aspects
Genetic disorders
Genetic variation
Genetics
Health care
Hearing
Hearing loss
Hearing Loss - genetics
Hearing Loss, Sensorineural - genetics
Humans
Life span
Medical records
Medical research
Medicine and Health Sciences
Medicine, Experimental
Multifactorial Inheritance
Mutation
People and places
Polygenic inheritance
Risk factors
Statistics
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Title Gene burden analysis identifies genes associated with increased risk and severity of adult-onset hearing loss in a diverse hospital-based cohort
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