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

Valeria Lo Faro; Arjun Bhattacharya; Wei Zhou; Dan Zhou; Ying Wang; Kristi Läll; Masahiro Kanai; Esteban Lopera-Maya; Peter Straub; Priyanka Pawar; Ran Tao; Xue Zhong; Shinichi Namba; Global Biobank Meta-analysis Initiative; Serena Sanna; Ilja M Nolte; Yukinori Okada; Nathan Ingold; Stuart MacGregor; Harold Snieder; Ida Surakka; Jonathan Shortt; Chris Gignoux; Nicholas Rafaels; Kristy Crooks; Anurag Verma; Shefali S Verma; Lindsay Guare; Daniel J Rader; Cristen Willer; Alicia R Martin; Milam A Brantley Jr; Eric R Gamazon; Nomdo M Jansonius; Karen Joos; Nancy J Cox; Jibril Hirbo

doi:10.1016/j.xcrm.2024.101430

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

Cell Rep Med. 2024 Feb 20;5(2):101430. doi: 10.1016/j.xcrm.2024.101430.

Authors

Valeria Lo Faro¹, Arjun Bhattacharya², Wei Zhou³, Dan Zhou⁴, Ying Wang³, Kristi Läll⁵, Masahiro Kanai⁶, Esteban Lopera-Maya⁷, Peter Straub⁴, Priyanka Pawar⁸, Ran Tao⁹, Xue Zhong⁴, Shinichi Namba¹⁰; Global Biobank Meta-analysis Initiative; Serena Sanna¹¹, Ilja M Nolte¹², Yukinori Okada¹³, Nathan Ingold¹⁴, Stuart MacGregor¹⁵, Harold Snieder¹², Ida Surakka¹⁶, Jonathan Shortt¹⁷, Chris Gignoux¹⁷, Nicholas Rafaels¹⁷, Kristy Crooks¹⁷, Anurag Verma¹⁸, Shefali S Verma¹⁹, Lindsay Guare²⁰, Daniel J Rader²¹, Cristen Willer²², Alicia R Martin³, Milam A Brantley Jr⁸, Eric R Gamazon⁴, Nomdo M Jansonius²³, Karen Joos⁸, Nancy J Cox⁴, Jibril Hirbo²⁴

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁶ 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.
⁷ University of Groningen, UMCG, Department of Genetics, Groningen, the Netherlands.
⁸ Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
¹¹ University of Groningen, UMCG, Department of Genetics, Groningen, the Netherlands; Institute for Genetics and Biomedical Research (IRGB), National Research Council (CNR), Cagliari, Italy.
¹² Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹³ 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.
¹⁴ 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.
¹⁵ Statistical Genetics, QIMR Berghofer Medical Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁶ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
¹⁸ 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.
¹⁹ Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA.
²⁰ Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA.
²¹ 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.
²² 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.
²³ Department of Ophthalmology, Amsterdam University Medical Center (AMC), Amsterdam, the Netherlands.
²⁴ 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.

Abstract

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.

Keywords: GWAS; PRS; cross-ancestry; disease disparity; disease prediction; genetic interactions; genetics; glaucoma; pleiotropy; transcriptomic.

Publication types

Meta-Analysis

MeSH terms

Biology
Cell Proliferation
Female
Genetic Predisposition to Disease* / genetics
Glaucoma, Open-Angle* / epidemiology
Glaucoma, Open-Angle* / genetics
Humans
Male
Polymorphism, Single Nucleotide