Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration

Rinki Ratnapriya; Olukayode A Sosina; Margaret R Starostik; Madeline Kwicklis; Rebecca J Kapphahn; Lars G Fritsche; Ashley Walton; Marios Arvanitis; Linn Gieser; Alexandra Pietraszkiewicz; Sandra R Montezuma; Emily Y Chew; Alexis Battle; Gonçalo R Abecasis; Deborah A Ferrington; Nilanjan Chatterjee; Anand Swaroop

doi:10.1038/s41588-019-0351-9

Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration

Nat Genet. 2019 Apr;51(4):606-610. doi: 10.1038/s41588-019-0351-9. Epub 2019 Feb 11.

Authors

Rinki Ratnapriya^#¹, Olukayode A Sosina^#^{1

2}, Margaret R Starostik^#¹, Madeline Kwicklis¹, Rebecca J Kapphahn³, Lars G Fritsche⁴, Ashley Walton¹, Marios Arvanitis⁵, Linn Gieser¹, Alexandra Pietraszkiewicz¹, Sandra R Montezuma³, Emily Y Chew⁶, Alexis Battle⁷, Gonçalo R Abecasis⁴, Deborah A Ferrington⁸, Nilanjan Chatterjee⁹, Anand Swaroop¹⁰

Affiliations

¹ Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
² Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.
⁴ Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁵ Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Departments of Biomedical Engineering and Computer Science, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA. ferri013@umn.edu.
⁹ Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. nchatte2@jhu.edu.
¹⁰ Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. swaroopa@nei.nih.gov.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Gene Expression Profiling / methods
Gene Expression Regulation / genetics
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods
Genotype
Humans
Macular Degeneration / genetics*
Phenotype
Polymorphism, Single Nucleotide / genetics
Quantitative Trait Loci / genetics*
Retina / physiopathology
Transcriptome / genetics*

Abstract

Publication types

MeSH terms

Grants and funding