Sex differences in the polygenic architecture of hearing problems in adults

Genome Medicine

Research

Sharon G. Curhan¹  Oana A. Zeleznik¹  Gary C. Curhan¹  Antonella De Lillo²  Daniel S. Tylee³  Frank R. Wendt³  Flavio De Angelis³  Gita A. Pathak³  Brenda Cabrera-Mendoza³  Renato Polimanti³  Dora Koller⁴  Royce E. Clifford⁵  Caroline M. Nievergelt⁶  Adam X. Maihofer⁶ 

[1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Department of Psychiatry, Yale University School of Medicine, 60 Temple, Suite 7A, New Haven, CT, USA;Department of Biology, University of Rome “Tor Vergata”, Rome, Italy;Department of Psychiatry, Yale University School of Medicine, 60 Temple, Suite 7A, New Haven, CT, USA;Veteran Affairs Connecticut Healthcare System, West Haven, CT, USA;Department of Psychiatry, Yale University School of Medicine, 60 Temple, Suite 7A, New Haven, CT, USA;Veteran Affairs Connecticut Healthcare System, West Haven, CT, USA;Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain;Division of Otolaryngology, Department of Surgery, University of California, San Diego, La Jolla, CA, USA;Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA;Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA;Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA;Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA;

关键词: Hearing problems;    Genome-wide association study;    Ancestry;    Polygenic risk scores;    Transcriptomic regulation;    Sex differences;    Pleiotropy;    Causal inference;    Genome-wide gene-by-environment interaction;   

DOI  :  10.1186/s13073-023-01186-3

 received in 2022-12-23, accepted in 2023-04-28,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundHearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies.MethodsLeveraging the UK Biobank, the Nurses’ Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors.ResultsWe identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes.ConclusionsThe results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.

【 授权许可】

CC BY   
© The Author(s) 2023

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