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Large-scale rare variant burden testing in Parkinson's disease.
Makarious, Mary B; Lake, Julie; Pitz, Vanessa; Ye Fu, Allen; Guidubaldi, Joseph L; Solsberg, Caroline Warly; Bandres-Ciga, Sara; Leonard, Hampton L; Kim, Jonggeol Jeffrey; Billingsley, Kimberley J; Grenn, Francis P; Jerez, Pilar Alvarez; Alvarado, Chelsea X; Iwaki, Hirotaka; Ta, Michael; Vitale, Dan; Hernandez, Dena; Torkamani, Ali; Ryten, Mina; Hardy, John; Scholz, Sonja W; Traynor, Bryan J; Dalgard, Clifton L; Ehrlich, Debra J; Tanaka, Toshiko; Ferrucci, Luigi; Beach, Thomas G; Serrano, Geidy E; Real, Raquel; Morris, Huw R; Ding, Jinhui; Gibbs, J Raphael; Singleton, Andrew B; Nalls, Mike A; Bhangale, Tushar; Blauwendraat, Cornelis.
Afiliación
  • Makarious MB; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Lake J; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
  • Pitz V; UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK.
  • Ye Fu A; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Guidubaldi JL; Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Solsberg CW; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Bandres-Ciga S; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
  • Leonard HL; Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Kim JJ; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Billingsley KJ; Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.
  • Grenn FP; Pharmaceutical Sciences and Pharmacogenomics, University of California San Francisco, San Francisco, CA 94143, USA.
  • Jerez PA; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Alvarado CX; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Iwaki H; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Ta M; Data Tecnica International, Washington, DC 20812, USA.
  • Vitale D; Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Hernandez D; Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
  • Torkamani A; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Ryten M; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Hardy J; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Scholz SW; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Traynor BJ; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Dalgard CL; Data Tecnica International, Washington, DC 20812, USA.
  • Ehrlich DJ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Tanaka T; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Ferrucci L; Data Tecnica International, Washington, DC 20812, USA.
  • Beach TG; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Serrano GE; Data Tecnica International, Washington, DC 20812, USA.
  • Real R; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • Morris HR; Data Tecnica International, Washington, DC 20812, USA.
  • Ding J; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
  • Gibbs JR; Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
  • Singleton AB; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK.
  • Nalls MA; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Bhangale T; UK Dementia Research Institute and Department of Neurodegenerative Disease and Reta Lila Weston Institute, UCL Queen Square Institute of Neurology and UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK.
  • Blauwendraat C; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
Brain ; 146(11): 4622-4632, 2023 11 02.
Article en En | MEDLINE | ID: mdl-37348876
Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Brain Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Brain Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido