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Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

ABSTRACT: 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.

SUBMITTER: Trpchevska N

PROVIDER: S-EPMC9247887 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

Trpchevska Natalia N Freidin Maxim B MB Broer Linda L Oosterloo Berthe C BC Yao Shuyang S Zhou Yitian Y Vona Barbara B Bishop Charles C Bizaki-Vallaskangas Argyro A Canlon Barbara B Castellana Fabio F Chasman Daniel I DI Cherny Stacey S Christensen Kaare K Concas Maria Pina MP Correa Adolfo A Elkon Ran R Mengel-From Jonas J Gao Yan Y Giersch Anne B S ABS Girotto Giorgia G Gudjonsson Alexander A Gudnason Vilmundur V Heard-Costa Nancy L NL Hertzano Ronna R Hjelmborg Jacob V B JVB Hjerling-Leffler Jens J Hoffman Howard J HJ Kaprio Jaakko J Kettunen Johannes J Krebs Kristi K Kähler Anna K AK Lallemend Francois F Launer Lenore J LJ Lee I-Min IM Leonard Hampton H Li Chuan-Ming CM Lowenheim Hubert H Magnusson Patrik K E PKE van Meurs Joyce J Milani Lili L Morton Cynthia C CC Mäkitie Antti A Nalls Mike A MA Nardone Giuseppe Giovanni GG Nygaard Marianne M Palviainen Teemu T Pratt Sheila S Quaranta Nicola N Rämö Joel J Saarentaus Elmo E Sardone Rodolfo R Satizabal Claudia L CL Schweinfurth John M JM Seshadri Sudha S Shiroma Eric E Shulman Eldad E Simonsick Eleanor E Spankovich Christopher C Tropitzsch Anke A Lauschke Volker M VM Sullivan Patrick F PF Goedegebure Andre A Cederroth Christopher R CR Williams Frances M K FMK Nagtegaal Andries Paul AP

American journal of human genetics 20220516 6

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 hea ...[more]

PMID: 35580588

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Project description:BackgroundThe stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets.MethodsWe analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways.ResultsThrough the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain.ConclusionOur bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.

Dataset Information

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

Publications

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

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