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Genetic association analysis of 77,539 genomes reveals rare disease etiologies.
Greene, Daniel; Pirri, Daniela; Frudd, Karen; Sackey, Ege; Al-Owain, Mohammed; Giese, Arnaud P J; Ramzan, Khushnooda; Riaz, Sehar; Yamanaka, Itaru; Boeckx, Nele; Thys, Chantal; Gelb, Bruce D; Brennan, Paul; Hartill, Verity; Harvengt, Julie; Kosho, Tomoki; Mansour, Sahar; Masuno, Mitsuo; Ohata, Takako; Stewart, Helen; Taibah, Khalid; Turner, Claire L S; Imtiaz, Faiqa; Riazuddin, Saima; Morisaki, Takayuki; Ostergaard, Pia; Loeys, Bart L; Morisaki, Hiroko; Ahmed, Zubair M; Birdsey, Graeme M; Freson, Kathleen; Mumford, Andrew; Turro, Ernest.
Afiliación
  • Greene D; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Frudd K; National Heart and Lung Institute, Imperial College London, London, UK.
  • Sackey E; National Heart and Lung Institute, Imperial College London, London, UK.
  • Al-Owain M; University College London Institute of Ophthalmology, University College London, London, UK.
  • Giese APJ; Molecular and Clinical Sciences Institute, St. George's University of London, London, UK.
  • Ramzan K; Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
  • Riaz S; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
  • Yamanaka I; Department of Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
  • Boeckx N; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
  • Thys C; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA.
  • Gelb BD; Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan.
  • Brennan P; Center for Medical Genetics, Antwerp University Hospital/University of Antwerp, Antwerp, Belgium.
  • Hartill V; Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
  • Harvengt J; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Kosho T; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Mansour S; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Masuno M; Northern Genetics Service, Newcastle upon Tyne Hospitals National Health Service Trust International Centre for Life, Newcastle upon Tyne, UK.
  • Ohata T; Department of Clinical Genetics, Chapel Allerton Hospital, Leeds Teaching Hospitals National Health Service Trust, Leeds, UK.
  • Stewart H; Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
  • Taibah K; Centre for Medical Genetics, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
  • Turner CLS; Department of Medical Genetics, Shinshu University School of Medicine, Nagano, Japan.
  • Imtiaz F; Center for Medical Genetics, Shinshu University Hospital, Nagano, Japan.
  • Riazuddin S; Molecular and Clinical Sciences Institute, St. George's University of London, London, UK.
  • Morisaki T; South West Thames Regional Genetics Service, St. George's University Hospitals National Health Service Foundation Trust, London, UK.
  • Ostergaard P; Department of Medical Genetics, Kawasaki Medical School Hospital, Okayama, Japan.
  • Loeys BL; Okinawa Chubu Hospital, Okinawa, Japan.
  • Morisaki H; Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK.
  • Ahmed ZM; Ear Nose and Throat Medical Centre, Riyadh, Saudi Arabia.
  • Birdsey GM; Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Exeter, UK.
  • Freson K; Department of Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
  • Mumford A; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
  • Turro E; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA.
Nat Med ; 29(3): 679-688, 2023 03.
Article en En | MEDLINE | ID: mdl-36928819
The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-ß regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Raras / Estudio de Asociación del Genoma Completo Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Raras / Estudio de Asociación del Genoma Completo Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos