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

• Published in: PLoS 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
• Language: English
• 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
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1010584

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.