Identification and functional validation of an enhancer variant in the 9p21.3 locus associated with glaucoma risk and elevated expression of p16INK4a |
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Authors: | Yizhou Zhu Cagdas Tazearslan Michael G. Rosenfeld Andras Fiser Yousin Suh |
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Affiliation: | 1. Department of Obstetrics and Gynecology, Columbia University, New York, New York, USA;2. Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA;3. Department of Medicine, School of Medicine, University of California, La Jolla, California, USA Howard Hughes Medical Institute, University of California, La Jolla, California, USA;4. Department of Systems & Computational Biology, Albert Einstein College of Medicine, New York, New York, USA Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA |
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Abstract: | Glaucoma is a leading cause of irreversible blindness, with advanced age being the single most significant risk factor. However, the mechanisms underlying the relationship between aging and glaucoma remain unclear. Genome-wide association studies (GWAS) have successfully identified genetic variants strongly associated with increased glaucoma risk. Understanding how these variants function in pathogenesis is crucial for translating genetic associations into molecular mechanisms and, ultimately, clinical applications. The chromosome 9p21.3 locus is among the most replicated glaucoma risk loci discovered by GWAS. Nonetheless, the absence of protein-coding genes in the locus makes interpreting the disease association challenging, leaving the causal variant and molecular mechanism elusive. In this study, we report the identification of a functional glaucoma risk variant, rs6475604. By employing computational and experimental methods, we demonstrated that rs6475604 resides in a repressive regulatory element. Risk allele of rs6475604 disrupts the binding of YY1, a transcription factor known to repress the expression of a neighboring gene in 9p21.3, p16INK4A, which plays a crucial role in cellular senescence and aging. These findings suggest that the glaucoma disease variant contributes to accelerated senescence, providing a molecular link between glaucoma risk and an essential cellular mechanism for human aging. |
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Keywords: | 9p21 cellular senescence genome-wide association study glaucoma molecular genetics p16INK4A YY1 |
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