Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study
| العنوان: | Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study |
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| المؤلفون: | Patricia Perez-Carpena, Patrick May, Joseph Sollini, Juan Manuel Espinosa-Sanchez, Alvaro Gallego-Martinez, Barbara Canlon, Sana Amanat, Jose A. Lopez-Escamez, Angel Batuecas-Caletrio, Andrés Soto-Varela, Christopher R. Cederroth, Ismael Aran |
| المساهمون: | Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], [Amanat,S, Gallego-Martinez,A, Perez-Carpena,P, Espinosa-Sanchez,JM, Lopez-Escamez,JA] a Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO-Centre for Genomics and Oncological Research-Pfizer/University of Granada/ Junta de Andalucía, PTS, Granada, Spain. [Sollini,J, Cederroth,CR] Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK. [Perez-Carpena,P, Lopez-Escamez,JA] c Department of Otolaryngology, Instituto de Investigacion Biosanitaria, ibs.Granada, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Aran,I] Department of Otolaryngology, Complexo Hospitalario de Pontevedra, Pontevedra, Spain. [Soto-Varela,A] e Division of Otoneurology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario, Santiago de Compostela, Spain. [Batuecas-Caletrio,A] Department of Otolaryngology, Hospital Universitario de Salamanca, IBSAL Salamanca, Spain. [Canlon,B, Cederroth,CR] Laboratory of Experimental Audiology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. [May,P] Bioinformatics Core, Luxembourg Centre for System Biomedicine, University of Luxemburg, Esch-sur-Alzette, Luxembourg. [Cederroth,CR] National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Ropewalk House, Nottingham, UK. [Lopez-Escamez,JA] Department of Surgery, Division of Otolaryngology, University of Granada, Granada, Spain, This study has been funded by H2020 MSCA-ITN-2016–722046, the H2020-SC1-2019-848261, and the GNP-182 GENDER-Net Co-Plus Fund (JALE and CRC). The project leading to these results has received funding from 'la Caixa' Foundation (ID 100010434), under agreement LCF/PR/DE18/52010002 (JALE). This project is a part of European School of Interdisciplinary Tinnitus (ESIT) research and Sana Amanat is a PhD student in Biomedicine Program at the University of Granada. CRC received additional funding from Svenska Läkaresällskapet (SLS- 779681 ), Hörselforskningsfonden (503). The data handling for STOP and SweGen cohorts were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX partially funded by the Swedish Research Council through Grant agreement No. 2018-05973 . The time provided by JS was funded by the University of Nottingham, Nottingham Research Fellowship. PM was supported by the BMBF Treat-ION Grant ( 01GM1907 ) and the DFG Research Unit FOR2715 (FNR INTER/DFG/17/ 11583046 )., Sollini, Joseph |
| المصدر: | EBioMedicine Digibug: Repositorio Institucional de la Universidad de Granada Universidad de Granada (UGR) EBioMedicine, Vol 66, Iss, Pp 103309-(2021) Digibug. Repositorio Institucional de la Universidad de Granada instname |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Exome sequencing, Medicine (General), Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology [Medical Subject Headings], Psychiatry and Psychology::Mental Disorders [Medical Subject Headings], Anatomy::Nervous System::Synapses [Medical Subject Headings], Bioinformatics, Severity of Illness Index, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Cytoskeletal Proteins [Medical Subject Headings], Mice, Tinnitus, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], Missense mutation, 050207 economics, Anatomy::Nervous System::Neurons [Medical Subject Headings], Exome, Diseases::Otorhinolaryngologic Diseases::Ear Diseases::Labyrinth Diseases::Endolymphatic Hydrops::Meniere Disease [Medical Subject Headings], education.field_of_study, 050208 finance, Geographical Locations::Geographic Locations::Europe::Scandinavia::Sweden [Medical Subject Headings], 05 social sciences, Extreme phenotype, Family aggregation, Brain, General Medicine, Axon initial segment, 3. Good health, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Health Status Indicators::Patient Acuity::Severity of Illness Index [Medical Subject Headings], Phenotype, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], 030220 oncology & carcinogenesis, Medicine, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics [Medical Subject Headings], Female, Genetics & genetic processes [F10] [Life sciences], medicine.symptom, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Génétique & processus génétiques [F10] [Sciences du vivant], Fenotipo, Research Paper, Population, Check Tags::Male [Medical Subject Headings], General Biochemistry, Genetics and Molecular Biology, Epilepsia, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], 03 medical and health sciences, R5-920, 0502 economics and business, medicine, otorhinolaryngologic diseases, Segmento inicial del axón, Animals, Humans, Genetic Predisposition to Disease, Diseases::Otorhinolaryngologic Diseases::Ear Diseases::Hearing Disorders::Tinnitus [Medical Subject Headings], Generalized epilepsy, education, Genetic studies, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Alleles, Genetic Association Studies, Phenomena and Processes::Biological Phenomena [Medical Subject Headings], Sweden, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Epilepsy, Secuenciación del exoma completo, Estudios de asociación genética, business.industry, Enfermedad de Meniere, Acúfeno, Computational Biology, Genetic Variation, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Epilepsy::Epilepsy, Generalized [Medical Subject Headings], medicine.disease, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Questionnaires::Self Report [Medical Subject Headings], 030104 developmental biology, Gene Ontology, Check Tags::Female [Medical Subject Headings], Meniere disease, Synapses, business, exome sequencing |
| الوصف: | Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons. |
| وصف الملف: | application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document; |
| تدمد: | 2352-3964 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::69b8b540fb9be7a6d76365326bd18b58Test https://pubmed.ncbi.nlm.nih.gov/33813136Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....69b8b540fb9be7a6d76365326bd18b58 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23523964 |
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