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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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Age-related macular degeneration
Fleckenstein, M., Keenan, T. D. L., Guymer, R. H., Chakravarthy, U., Schmitz-Valckenberg, S., Klaver, C. C. W., Wong, W. T., & Chew, E. Y. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00265-2 · Cited by 1,093
Self-citationGharahkhani, P., Jorgenson, E., Hysi, P. G., Khawaja, A. P., Pendergrass, S. A., Han, X., Ong, J., Hewitt, A. W., Segrè, A. V., Rouhana, J. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20851-4 · Cited by 459
Cao, C., Wang, J., Kwok, D., Cui, F., Zhang, Z., Da, Z., Li, M. J., & Zou, Q. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab957 · Cited by 365
“Biologists have used these emerging TWAS software packages to identify and interpret causal genes in multiple diseases and domains, such as calcific aortic valve stenosis (19), high-grade serous ovarian cancer (20), breast cancer (21), macular degeneration (22) and schizophrenia (23–26).”
MethodHysi, P. G., Choquet, H., Khawaja, A. P., Wojciechowski, R., Tedja, M. S., Yin, J., Simcoe, M. J., Patasova, K., Mahroo, O. A., Thai, K. K., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0599-0 · Cited by 334
Advancing the use of genome-wide association studies for drug repurposing
Reay, W. R., & Cairns, M. J. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00387-z · Cited by 284
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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