Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries.

Autor: Gorman BR; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.; Booz Allen Hamilton, McLean, VA, USA., Voloudakis G; Center for Disease Neurogenomics, Department of Psychiatry; Friedman Brain Institute; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Center for Precision Medicine and Translational Therapeutics, VISN 2 Mental Illness Research, Education, and Clinical Center (MIRECC), James J. Peters Veterans Affairs Medical Center, New York/New Jersey VA Health Care Network, Bronx, NY, USA., Igo RP Jr; Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA., Kinzy T; Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA., Halladay CW; Center of Innovation in Long Term Services and Supports, VA Providence Healthcare System, Providence, RI, USA., Bigdeli TB; Research Service, VA New York Harbor Healthcare System, Brooklyn, NY, USA.; Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA., Zeng B; Center for Disease Neurogenomics, Department of Psychiatry; Friedman Brain Institute; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Venkatesh S; Center for Disease Neurogenomics, Department of Psychiatry; Friedman Brain Institute; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Center for Precision Medicine and Translational Therapeutics, VISN 2 Mental Illness Research, Education, and Clinical Center (MIRECC), James J. Peters Veterans Affairs Medical Center, New York/New Jersey VA Health Care Network, Bronx, NY, USA., Cooke Bailey JN; Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.; Department of Genetics & Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Crawford DC; Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.; Department of Genetics & Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Markianos K; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA., Dong F; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.; Booz Allen Hamilton, McLean, VA, USA., Schreiner PA; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.; Booz Allen Hamilton, McLean, VA, USA., Zhang W; Center for Disease Neurogenomics, Department of Psychiatry; Friedman Brain Institute; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Hadi T; Eye Clinic, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.; Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Cleveland, OH, USA., Anger MD; Eye Clinic, VA Western NY Healthcare System, Buffalo, NY, USA.; Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA., Stockwell A; Department of Human Genetics, Genentech, South San Francisco, CA, USA., Melles RB; Department of Ophthalmology, Kaiser Permanente Northern California, Redwood City, CA, USA., Yin J; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA., Choquet H; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA., Kaye R; Southampton Eye Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK.; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Patasova K; Section of Ophthalmology, School of Life Course Sciences, King's College London, London, UK.; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK., Patel PJ; National Institute for Health and Care Research Biomedical Research Centre, Moorfields Eye Hospital National Health Service Foundation Trust, London, UK.; Institute of Ophthalmology, University College London, London, UK., Yaspan BL; Department of Human Genetics, Genentech, South San Francisco, CA, USA., Jorgenson E; Regeneron Genetics Center, Tarrytown, NY, USA., Hysi PG; Section of Ophthalmology, School of Life Course Sciences, King's College London, London, UK.; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.; UCL Great Ormond Street Institute of Child Health, King's College London, London, UK.; Sørlandet Sykehus Arendal, Arendal Hospital, Arendal, Norway., Lotery AJ; Southampton Eye Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK.; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Gaziano JM; Million Veteran Program Coordinating Center, VA Boston Healthcare System, Boston, MA, USA.; Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Tsao PS; VA Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Fliesler SJ; Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA.; Research Service, VA Western NY Healthcare System, Buffalo, NY, USA.; Biochemistry, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA.; Graduate Program in Neurosciences, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA., Sullivan JM; Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA.; Research Service, VA Western NY Healthcare System, Buffalo, NY, USA.; Graduate Program in Neurosciences, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA., Greenberg PB; Section of Ophthalmology, VA Providence Healthcare System, Providence, RI, USA.; Division of Ophthalmology, Alpert Medical School, Brown University, Providence, RI, USA., Wu WC; Section of Cardiology, Medical Service, VA Providence Healthcare System, Providence, RI, USA.; Division of Cardiology, Department of Medicine, Alpert Medical School, Brown University, Providence, RI, USA., Assimes TL; VA Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Pyarajan S; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Roussos P; Center for Disease Neurogenomics, Department of Psychiatry; Friedman Brain Institute; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Center for Precision Medicine and Translational Therapeutics, VISN 2 Mental Illness Research, Education, and Clinical Center (MIRECC), James J. Peters Veterans Affairs Medical Center, New York/New Jersey VA Health Care Network, Bronx, NY, USA. panagiotis.roussos@mssm.edu., Peachey NS; Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA. neal.peachey@va.gov.; Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. neal.peachey@va.gov.; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA. neal.peachey@va.gov., Iyengar SK; Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA. ski@case.edu.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. ski@case.edu.; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA. ski@case.edu.; Department of Genetics & Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. ski@case.edu.; Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Cleveland, OH, USA. ski@case.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Dec; Vol. 56 (12), pp. 2659-2671. Date of Electronic Publication: 2024 Dec 02.
DOI: 10.1038/s41588-024-01764-0
Abstrakt: To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.
Competing Interests: Competing interests: A.S. and B.L.Y. are employees of Genentech/Roche and hold stock and stock options in Roche. E.J. is an employee and a stockholder of Regeneron Genetics Center. The other authors declare no competing interests.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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