Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration

Orozco, Luz D.; Chen, Hsu-Hsin; Cox, Christian L.; Katschke, Kenneth J.; Arceo, Rommel; Espiritu, Carmina; Caplazi, Patrick; Nghiem, Sarajane Saturnio; Chen, Ying-Jiun; Modrušan, Zora; Dressen, Amy; Goldstein, Leonard D.; Clarke, Christine L.; Bhangale, Tushar; Yaspan, Brian L.; Jeanne, Marion; Townsend, Michael J.; Campagne, Menno van Lookeren; Hackney, Jason A.

doi:10.1016/j.celrep.2019.12.082

Cited by 166 publications

(209 citation statements)

References 69 publications

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“…Ratnapriya et al (2019) were the first to perform eQTL and TWAS analyses in 406 retinal samples [ 25 ]. This was followed by a study of Orozco et al (2020) that calculated eQTL in 121 retinae and additionally in RPE/choroid samples [ 28 ]. Both studies included, apart from control retinae, additionally AMD patient samples to a variable extend.…”

Section: Resultsmentioning

confidence: 99%

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Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

Strunz

Kiel

Sauerbeck

et al. 2020

Cells

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Over the last 15 years, genome-wide association studies (GWAS) have greatly advanced our understanding of the genetic landscape of complex phenotypes. Nevertheless, causal interpretations of GWAS data are challenging but crucial to understand underlying mechanisms and pathologies. In this review, we explore to what extend the research community follows up on GWAS data. We have traced the scientific activities responding to the two largest GWAS conducted on age-related macular degeneration (AMD) so far. Altogether 703 articles were manually categorized according to their study type. This demonstrates that follow-up studies mainly involve “Review articles” (33%) or “Genetic association studies” (33%), while 19% of publications report on findings from experimental work. It is striking to note that only three of 16 AMD-associated loci described de novo in 2016 were examined in the four-year follow-up period after publication. A comparative analysis of five studies on gene expression regulation in AMD-associated loci revealed consistent gene candidates for 15 of these loci. Our random survey highlights the fact that functional follow-up studies on GWAS results are still in its early stages hampering a significant refinement of the vast association data and thus a more accurate insight into mechanisms and pathways.

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Section: Resultsmentioning

confidence: 99%

“…Orozco et al (2020) [ 28 ] investigated eQTL in a total of 121 samples from retinal and combined RPE and choroid (RPE/choroid) tissue. Further, they distinguished between macular and non-macular tissue and applied a Benjamini and Hochberg FDR threshold of 0.05 [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

Strunz

Kiel

Sauerbeck

et al. 2020

Cells

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“…By profiling 119,520 single cells, we provided detailed single-cell transcriptomes of adult and aged primate retinae with regional information. The retinal transcriptome at single-cell or single-nuclei level has been reported [3,[9][10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…The molecular differences between the foveal and peripheral retina are important for understanding human visual function. To date, multiple analyses in primates have demonstrated the regionspecific retinal transcriptomes in developing and adult foveal and peripheral retina, suggesting distinct transcriptional regulations in the two regions [3,[9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

A single-cell transcriptome atlas of the aging human and macaque retina

Lü

Zhong

et al. 2020

Preprint

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The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119,520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting the distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type- specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A- rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region- specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understand the molecular and cellular mechanisms underlying human retinal diseases. Together, these datasets are valuable for understanding the molecular characteristics of primate retina, as well as the molecular regulation of aging progression and related diseases.

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“…Some of the published studies on eQTL and pQTL have not identified pleiotropic regions because they have focused on cis-associations 16,[24][25][26] . Our results indicate that protein expression is regulated at multiple levels and in coordination with other independent proteins, which are likely part of the same signaling pathway.…”

Section: Pleiotropic Locimentioning

confidence: 99%

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

Cruchaga¹,

Yang²,

Farias³

et al. 2020

Preprint

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Understanding the tissue-specific genetic architecture of protein levels is instrumental to understand the biology of health and disease. We generated a genomic atlas of protein levels in multiple neurologically relevant tissues (380 brain, 835 cerebrospinal fluid (CSF) and 529 plasma), by profiling thousands of proteins (713 CSF, 931 plasma and 1079 brain) in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. cis-pQTL were more likely to be shared across tissues but trans-pQTL tend to be tissue-specific. Between 44% to 68.2% of the pQTL do not colocalize with expression, splicing, methylation or histone QTLs, indicating that protein levels have a different genetic architecture to those that regulate gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. Here we present the first multi-tissue study yielding hundred of novel pQTLs. This data will be instrumental to identify the functional gene from GWAS signals, identify novel biological protein-protein interactions, identify novel potential biomarkers and drug targets for complex traits.

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Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration

Cited by 166 publications

References 69 publications

Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

A single-cell transcriptome atlas of the aging human and macaque retina

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

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