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Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration
Open accessAbstract
Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD)1-3. We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets 4,5. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.
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“In the retina, S2R is expressed in several cell types including the retinal pigment epithelium cells, photoreceptors, and retinal ganglion cells [70,71,72,73,74].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [72]
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Larusdottir, A. E., Teitsdottir, U. D., Tragante, V., Pálsson, F., Kristinsdottir, A. M., Eldjárn, G. H., Stefánsdóttir, L., Oddsson, Á., Aegisdottir, H. M., Styrkársdóttir, U., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9238373/v1
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“…such as the Genotype-Tissue Expression (GTEx) project [12 ], the eQTLGen consortium [ 13 ], the Brain eQTL Alma - nac (Braineac) [ 14 ], PsychENCODE [15], the database of immune cell expression, expression quantitative trait loci and epigenomics (DICE) [ 16 ], and other eQTL resources [17 ].”
Genetic Architecture of Trans-Laminar Cribrosa Pressure Difference and Primary Open-Angle Glaucoma
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“54 The eQTL summary statistics of retinal tissue from Ratnapriya et al. (EyeGEx) 55 and Strunz et al., 56 (Supplementary Table S3) along with seven tissues from Genotype-Tissue Expression project (GTEx) version 8 57 (aorta, coronary artery, tibial artery, cultured fibroblasts, left ventricle,…”
Robust Clustering Analysis of Genes Related to Age-related Macular Degeneration using RNA-Seq
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“Retinal RNA-seq and expression quantitative trait loci (eQTL) studies have identified genes whose expression is influenced by AMD-associated variants, providing mechanistic insight into how non-coding genetic variation contributes to disease risk [1], [6].”
InfluentialSelf-citationChen, R., Lu, W., Zhu, J., Huang, L., Chen, W., Huang, G., Ren, X., Sun, Q., Hu, J., Li, J., et al. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.5.36
“29,30 Indeed, elevated PDGF-C levels were found in the retinas of AMD patients, 31 in the aqueous humor of patients with neovascular eye diseases, 32 and in mouse CNV models.”
Ren, N., Wang, L., Dutta, R. K., Umbaugh, D. S., Zhang, Q., Oh, S., Ko, D. C., Song, M., Diehl, A. M., & Du, K. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.15.731916
Chen, J., Yuan, X., Zhang, X., Huang, Q., Zhou, X., Ji, D., Zhu, W., & Duan, X. (2026) · Seminars in Ophthalmology · doi:10.1080/08820538.2026.2694713
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“The incidence of AMD was influenced by several risk factors, such as smoking (Seddon et al., 1996; Christen et al., 1996), physical activity (Mauschitz et al., 2022), lipids (Reynolds et al., 2010), and genetic predispositions (Ratnapriya et al., 2019; Fritsche et al., 2016).”
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“…genome-wide association studies, transcriptomic and expression quantitative trait locus analyses, as well as DNA methylation studies encompassing both candidate gene analyses and genome-wide methylation profiling, primarily in blood, retina, and retinal pigment epithelium 3,9–11 , 24– 28 .”
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“42,43 HEterogeneity In Dependent Instruments (HEIDI) analysis was applied within the cis -region to distinguish associations likely reflecting shared regulatory effects from those potentially driven by linkage disequilibrium or horizontal pleiotropy.”
Newton, L., Haque, B., Cheerie, D., Tsoi, C. T., Klamann, C., Sakaki, R., Qu, T., Verhaeghe, L., Liang, Y., Marks, R. M., et al. (2026) · medRxiv · doi:10.64898/2026.07.29.26359175
Wu, C., Bzikadze, A. V., Xu, T. H., Mendenhall, E. M., Chen, H., Telese, F., Polesskaya, O., Munro, D. B., Palmer, A. A., Goren, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.07.743622
“This model assumes all molecular phenotypes measured are targets of the variant of interest, whereas in practice a single trans -QTL likely only targets a subset of the phenotypes (e.g. expressed genes 39 ).”
Kurysheva, N. I., & Маслова, Е. В. (2026) · Russian Annals of Ophthalmology · doi:10.17116/oftalma2026142041112
Cheng, F., Mou, H., Liu, Z., Zhang, C.-J., Zhuang, Y., Wu, Z., Wen, X., Xue, A., Zhang, X., Yang, J., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2533682123
“Consequently, 9 genes (tagged by 12 probes) were retained with their functional annotation summarized ( SI A ppendix , Table S1), some of which, namely BLOC1S1, PILRB, and TMEM199, were previously reported using a different strategy to integrate AMD GWAS with retinal eQTL data (17).”
InfluentialDecoding Primary Open-Angle Glaucoma: A Multi-Omics Approach to Identify Druggable Effector Genes
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“26,27 The 2 datasets share 13,930 genes in common; GTEx eQTLs have 5340 genes that are unique, and EyeGEx eQTLs have 3444 unique genes.”
Wen, L., Li, F., Liu, Y., Zhang, K., Mao, A., Liu, L., Lv, X., Geng, L., Yu, F., Feng, L., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27188103
“Large-scale genome-wide association studies (GWAS) have identified dozens of susceptibility loci, underscoring the contributions of complement regulation (e.g., CFH , C3 , CFI ), lipid transport (e.g., APOE , LIPC ), and extracellular matrix remodeling (e.g., ARMS2 / HTRA1 ) [10–12].”
Multiomic Integration Reveals Novel miRNA–mRNA–Protein Expression Profile in the Aged Female Retina
Bariesheff, N. W., Wooff, Y., Blackmore, D. G., & Cioanca, A. V. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.11.37 · Cited by 1
“61,62 Here, for the first time, changes to small noncoding miRNA expression in the mouse retina at an advanced age are reported, with 91 miRNAs shown to be differentially expressed in the 30-month-old mouse retina.”
Yang, L., & Li, Z. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111243
Luthert, P. J., Faes, L., Foss, A. J. E., Fu, D. J., Hill, L. J., Huang, R., Kiel, C., Lee, W. H., Matei, Mirams, G. R., et al. (2026) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2026.101529
Pan, J., Yang, K.-T., Zhang, J.-Q., Jin, Y., & Chen, J. (2026) · Life Sciences · doi:10.1016/j.lfs.2026.124708
Xu, C.-Z., Yan, Q.-L., Feng, C., Li, Y.-Z., Li, X.-Y., Zhang, R., He, J.-W., & Wu, J.-H. (2026) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.67.12.54
“29 Genes identified through cross-cohort gene discovery and prioritization were tested for association with AMD in retinal tissue.”
Bi-Allelic PRKCZ Loss-of-Function Variants and Adult-Onset Retinitis Pigmentosa
Cordeddu, V., Sangermano, R., Mulder, S. W. M., Hussain, H. M. J., Flex, E., Mignini, L., Motta, M., Bruselles, A., Arasi, M. B., Cecchetti, S., et al. (2026) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2026.4692
Metadata
- Authors
- Ratnapriya, R., Sosina, O. A., Starostik, M. R., Kwicklis, M., Kapphahn, R. J., Fritsche, L. G., Walton, A., Arvanitis, M., Gieser, L., Pietraszkiewicz, A., Montezuma, S. R., Chew, E. Y., Battle, A., Abecasis, G. R., Ferrington, D. A., Chatterjee, N., & Swaroop, A.
- Affiliations
- National Institutes of Health (US)
- University of Minnesota (US)
- University of Michigan (US)
- Johns Hopkins University (US)
- Corresponding author
- Ferrington, Deborah A.
- Chatterjee, Nilanjan
- Swaroop, Anand
- ORCID
- Venue
- Nature Genetics
- Published
- 2019-02-11
- Volume
- 51
- Issue
- 4
- Pages
- 606-610
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6441365
- OpenAlex
- W2914762802
- Cited by
- 312
- References
- 56
- Citations by year
- 2026: 47 · 2025: 49 · 2024: 46 · 2023: 40 · 2022: 35 · 2021: 36 · 2020: 46 · 2019: 13
- FWCI
- 31.89
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-05-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Minnesota Lions Eye Bank
- University of Minnesota
- National Institutes of Health
- National Human Genome Research Institute (T32HG000040)
- National Eye Institute (ZIAEY000475, Z01EY000450, R01EY026012, ZIAEY000474, ZIAEY000450, R01EY028554)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Keywords
- age-related macular degeneration, retinal transcriptome, expression quantitative trait loci, transcriptome-wide association study, cis-eQTL, RLBP1, HIC1, PARP12, non-coding RNA, ocular genetics
- MeSH terms
- Gene Expression Regulation, Genotype, Humans, Macular Degeneration, Phenotype, Retina, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, Quantitative Trait Loci, Genome-Wide Association Study, Transcriptome
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