Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation.

GWAS PRS cross-ancestry disease disparity disease prediction genetic interactions genetics glaucoma pleiotropy transcriptomic

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
20 Feb 2024
Historique:
received: 05 01 2022
revised: 28 03 2023
accepted: 25 01 2024
medline: 22 2 2024
pubmed: 22 2 2024
entrez: 21 2 2024
Statut: ppublish

Résumé

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.

Identifiants

DOI: 10.1016/j.xcrm.2024.101430 PMID: 38382466
pubmed: 38382466
pii: S2666-3791(24)00053-3
doi: 10.1016/j.xcrm.2024.101430
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101430

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests E.R.G. received an honorarium from the journal Circulation Research of the American Heart Association as a member of the Editorial Board. S.M. is a co-founder and holds stock in Seonix Pty Ltd.

Auteurs

Valeria Lo Faro (V)

Department of Ophthalmology, Amsterdam University Medical Center (AMC), Amsterdam, the Netherlands; Department of Clinical Genetics, Amsterdam University Medical Center (AMC), Amsterdam, the Netherlands; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Arjun Bhattacharya (A)

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

Wei Zhou (W)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Dan Zhou (D)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Ying Wang (Y)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Kristi Läll (K)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Masahiro Kanai (M)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Esteban Lopera-Maya (E)

University of Groningen, UMCG, Department of Genetics, Groningen, the Netherlands.

Peter Straub (P)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Priyanka Pawar (P)

Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Ran Tao (R)

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.

Xue Zhong (X)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Shinichi Namba (S)

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.

Serena Sanna (S)

University of Groningen, UMCG, Department of Genetics, Groningen, the Netherlands; Institute for Genetics and Biomedical Research (IRGB), National Research Council (CNR), Cagliari, Italy.

Ilja M Nolte (IM)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Yukinori Okada (Y)

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka, Japan; Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan.

Nathan Ingold (N)

Statistical Genetics, QIMR Berghofer Medical Research Institute, Queensland University of Technology, Brisbane, QLD, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.

Stuart MacGregor (S)

Statistical Genetics, QIMR Berghofer Medical Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.

Harold Snieder (H)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Ida Surakka (I)

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Jonathan Shortt (J)

Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Chris Gignoux (C)

Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Nicholas Rafaels (N)

Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Kristy Crooks (K)

Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Anurag Verma (A)

Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.

Shefali S Verma (SS)

Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA.

Lindsay Guare (L)

Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Daniel J Rader (DJ)

Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Cristen Willer (C)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.

Alicia R Martin (AR)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Milam A Brantley (MA)

Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Eric R Gamazon (ER)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Nomdo M Jansonius (NM)

Department of Ophthalmology, Amsterdam University Medical Center (AMC), Amsterdam, the Netherlands.

Karen Joos (K)

Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Nancy J Cox (NJ)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Jibril Hirbo (J)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: jibril.hirbo@vumc.org.

Classifications MeSH