Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.

Autor: Lee WP; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Choi SH; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA., Shea MG; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, Massachusetts, USA., Cheng PL; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Dombroski BA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Pitsillides AN; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA., Heard-Costa NL; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.; Framingham Heart Study, Framingham, Massachusetts, USA., Wang H; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Bulekova K; Research Computing Services, Information Services & Technology, Boston University, Boston, Massachusetts, USA., Kuzma AB; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Leung YY; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Farrell JJ; Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, Massachusetts, USA., Lin H; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA., Kunkle BW; John P. Hussman Institute for Human Genomics, Miami, Florida, USA.; John T. Macdonald Department of Human Genetics, Miami, Florida, USA., Naj A; Department of Biostatistics, Epidemiology, and Informatics, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Blue EE; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.; Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA., Nusetor F; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA., Wang D; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA., Boerwinkle E; Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA., Bush WS; Cleveland Institute for Computational Biology, Cleveland, Ohio, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA., Zhang X; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.; Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, Massachusetts, USA., De Jager PL; Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York, USA., Dupuis J; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada., Farrer LA; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.; Framingham Heart Study, Framingham, Massachusetts, USA.; Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, Massachusetts, USA.; Department of Ophthalmology, Department of Medicine, Boston University Medical School, Boston, Massachusetts, USA.; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA., Fornage M; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA., Martin E; John P. Hussman Institute for Human Genomics, Miami, Florida, USA.; John T. Macdonald Department of Human Genetics, Miami, Florida, USA.; University of Miami Miller School of Medicine, Miami, Florida, USA., Pericak-Vance M; John P. Hussman Institute for Human Genomics, Miami, Florida, USA.; John T. Macdonald Department of Human Genetics, Miami, Florida, USA.; University of Miami Miller School of Medicine, Miami, Florida, USA., Seshadri S; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA., Wijsman EM; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.; Department of Biostatistics, University of Washington, Seattle, Washington, USA.; Department of Genome Sciences, University of Washington, Seattle, Washington, USA., Wang LS; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Schellenberg GD; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Destefano AL; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA., Haines JL; Cleveland Institute for Computational Biology, Cleveland, Ohio, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2024 Oct 20. Date of Electronic Publication: 2024 Oct 20.
DOI: 10.1002/alz.14283
Abstrakt: Introduction: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous.
Methods: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.
Results: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10 -8 ). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10 -9 ). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10 -8 ).
Discussion: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.
Highlights: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.
(© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
Databáze: MEDLINE
Externí odkaz: