Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss,American Journal of Human Genetics

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Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2022-05-16 , DOI: 10.1016/j.ajhg.2022.04.010
Natalia Trpchevska ₁ , Maxim B Freidin ₂ , Linda Broer ₃ , Berthe C Oosterloo ₄ , Shuyang Yao ₅ , Yitian Zhou ₁ , Barbara Vona ₆ , Charles Bishop ₇ , Argyro Bizaki-Vallaskangas ₈ , Barbara Canlon ₁ , Fabio Castellana ₉ , Daniel I Chasman ₁₀ , Stacey Cherny ₁₁ , Kaare Christensen ₁₂ , Maria Pina Concas ₁₃ , Adolfo Correa ₁₄ , Ran Elkon ₁₅ , ₁₆ , Jonas Mengel-From ₁₇ , Yan Gao ₁₈ , Anne B S Giersch ₁₉ , Giorgia Girotto ₂₀ , Alexander Gudjonsson ₂₁ , Vilmundur Gudnason ₂₂ , Nancy L Heard-Costa ₂₃ , Ronna Hertzano ₂₄ , Jacob V B Hjelmborg ₂₅ , Jens Hjerling-Leffler ₂₆ , Howard J Hoffman ₂₇ , Jaakko Kaprio ₂₈ , Johannes Kettunen ₂₉ , Kristi Krebs ₁₆ , Anna K Kähler ₅ , Francois Lallemend ₃₀ , Lenore J Launer ₃₁ , I-Min Lee ₃₂ , Hampton Leonard ₃₃ , Chuan-Ming Li ₂₇ , Hubert Lowenheim ₃₄ , Patrik K E Magnusson ₅ , Joyce van Meurs ₃ , Lili Milani ₁₆ , Cynthia C Morton ₃₅ , Antti Mäkitie ₃₆ , Mike A Nalls ₃₃ , Giuseppe Giovanni Nardone ₁₃ , Marianne Nygaard ₁₇ , Teemu Palviainen ₂₈ , Sheila Pratt ₃₇ , Nicola Quaranta ₃₈ , Joel Rämö ₂₈ , Elmo Saarentaus ₂₈ , Rodolfo Sardone ₉ , Claudia L Satizabal ₃₉ , John M Schweinfurth ₇ , Sudha Seshadri ₃₉ , Eric Shiroma ₄₀ , Eldad Shulman ₁₅ , Eleanor Simonsick ₄₁ , Christopher Spankovich ₇ , Anke Tropitzsch ₃₄ , Volker M Lauschke ₁ , Patrick F Sullivan ₄₂ , Andre Goedegebure ₄ , Christopher R Cederroth ₄₃ , Frances M K Williams ₂ , Andries Paul Nagtegaal ₄

Affiliation

Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Department of Internal Medicine, Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands.
Department of Otorhinolaryngology, Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.
Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37075 Göttingen, Germany; Department of Otolaryngology-Head & Neck Surgery, University of Tübingen Medical Center, 72076 Tübingen, Germany.
Department of Otolaryngology and Communicative Sciences, The University of Mississippi Medical Center, Jackson, MS 39216, USA.
Department of Otolaryngology, University of Tampere, 33100 Tampere, Finland; Pirkanmaan Sairaanhoitopiiri, 33520 Tampere, Finland.
Unit of Data Sciences and Technology Innovation for Population Health, National Institute of Gastroenterology "Saverio de Bellis", Research Hospital, Castellana Grotte, 70124 Bari, Italy.
Division of Preventative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Anatomy and Anthropology and Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
The Danish Twin Registry, Department of Public Health, University of Southern Denmark, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense C, Denmark.
Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, 34127 Trieste, Italy.
Jackson Heart Study, The University of Mississippi Medical Center, Jackson, MS 39216, USA.
Department of Human Molecular Genetics & Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
The Danish Twin Registry, Department of Public Health, University of Southern Denmark, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark.
Jackson Heart Study, The University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, 34127 Trieste, Italy; Department of Medicine, Surgery and Health Sciences, University of Trieste, 34139 Trieste, Italy.
Icelandic Heart Association, 201 Kopavogur, Iceland.
Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Framingham Heart Study, Framingham, MA 01702, USA.
Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland Baltimore, Baltimore, MD 21201, USA; Department of Anatomy and Neurobiology, University of Maryland Baltimore, Baltimore, MD 21201, USA; Institute for Genome Sciences, University of Maryland Baltimore, Baltimore, MD 21201, USA.
The Danish Twin Registry, Department of Public Health, University of Southern Denmark, 5000 Odense C, Denmark.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Division of Scientific Programs, Epidemiology and Statistics Program, National Institute on Deafness and Other Communications Disorders (NIDCD), NIH, Bethesda, MD 20892, USA.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.
Computational Medicine, Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland; Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; Finnish Institute for Health and Welfare, 00271 Helsinki, Finland.
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
Laboratory of Epidemiology and Population Sciences, Intramural Research Program National Institute on Aging, Bethesda, MD 20892, USA.
Division of Preventative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA.
Department of Otolaryngology-Head & Neck Surgery, University of Tübingen Medical Center, 72076 Tübingen, Germany.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Obstetrics and Gynecology and of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Manchester Centre for Audiology and Deafness, University of Manchester, Manchester M13 9PL, UK.
Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
Department of Communication Science & Disorders, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Otolaryngology Unit, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70121 Bari, Italy.
Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Framingham Heart Study, Framingham, MA 01702, USA; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases and Department of Population Health Sciences, University of Texas Health Sciences Center, San Antonio, TX 78229, USA.
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Baltimore, MD 21224, USA.
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Genetics, University of North Carolina, Chapel Hill, NC 27516, USA.
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Ropewalk House, NG1 5DU Nottingham, UK; Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, NG7 2UH Nottingham, UK.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

中文翻译：

全基因组关联荟萃分析确定了 48 种风险变异，并强调了血管纹在听力损失中的作用

听力损失是造成残疾的主要原因之一，也是痴呆症的危险因素。关于人类听力损失细胞起源的分子证据正在不断增加。在这里，我们对 723,266 名个体的临床诊断和自我报告的听力障碍进行了全基因组关联荟萃分析，并确定了 48 个显着位点，其中 10 个是新的。很大一部分关联包含错义变异，其中一半位于已知的家族性听力损失基因座内。我们使用来自小鼠耳蜗和大脑的单细胞 RNA 测序数据，并将常见变异基因组结果映射到来自血管纹的纺锤体、根和基底细胞，血管纹是耳蜗中正常听力所必需的结构。我们的研究结果表明了血管纹在听力损伤机制中的重要性，为开发听力损失治疗干预的目标提供了未来的途径。

更新日期：2022-05-16

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