Predicting the Future of Genetic Risk Profiling of Glaucoma

Han, Xikun; Hewitt, Alex W.; MacGregor, Stuart

doi:10.1001/jamaophthalmol.2020.5404

Cited by 15 publications

(12 citation statements)

References 79 publications

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“…Note that the QTL on mouse chromosome 5 identified by ( Chintalapudi et al, 2017 ) is not synthetic with the QTL on rat chromosome 5 that was identified in our study. Research of genetic underpinning of IOP in humans include multiple GWAS studies, however, most of them have a case-control design, and are not designed to studying the genetics of the normal variation of IOP (reviewed in ( Youngblood et al, 2019 ; Sakurada et al, 2020 ; Han et al, 2021 )). This study is the first to use HS outbred rats in a GWAS analysis to investigate IOP.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study finds multiple loci associated with intraocular pressure in HS rats

et al. 2023

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Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. Increased IOP is a major risk factor for most types of glaucoma, including primary open angle glaucoma (POAG). Investigating the genetic basis of IOP may lead to a better understanding of the molecular mechanisms of POAG. The goal of this study was to identify genetic loci involved in regulating IOP using outbred heterogeneous stock (HS) rats. HS rats are a multigenerational outbred population derived from eight inbred strains that have been fully sequenced. This population is ideal for a genome-wide association study (GWAS) owing to the accumulated recombinations among well-defined haplotypes, the relatively high allele frequencies, the accessibility to a large collection of tissue samples, and the large allelic effect size compared to human studies. Both male and female HS rats (N = 1,812) were used in the study. Genotyping-by-sequencing was used to obtain ∼3.5 million single nucleotide polymorphisms (SNP) from each individual. SNP heritability for IOP in HS rats was 0.32, which agrees with other studies. We performed a GWAS for the IOP phenotype using a linear mixed model and used permutation to determine a genome-wide significance threshold. We identified three genome-wide significant loci for IOP on chromosomes 1, 5, and 16. Next, we sequenced the mRNA of 51 whole eye samples to find cis-eQTLs to aid in identification of candidate genes. We report 5 candidate genes within those loci: Tyr, Ctsc, Plekhf2, Ndufaf6 and Angpt2. Tyr, Ndufaf6 and Angpt2 genes have been previously implicated by human GWAS of IOP-related conditions. Ctsc and Plekhf2 genes represent novel findings that may provide new insight into the molecular basis of IOP. This study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential candidate genes for future functional testing.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study finds multiple loci associated with intraocular pressure in HS rats

et al. 2023

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“…Finally, the recent development of efficient sequencing techniques has enabled AI applications on multi-omics data for basic glaucoma research. For instance, genome-wide association studies (GWAS) have revealed hundreds of POAG-related genetic loci with consistent effects across ancestries ( 23 , 110 , 111 ); and whole-genome-based polygenic risk score enables the prediction of future glaucoma risks ( 112 ). Furthermore, multi-omics investigations can help identify the molecular signature for glaucoma predisposition ( 113 ), patient-specific tear composition ( 114 ), mechanical stress-derived trabecular meshwork cytoskeletal changes ( 115 ), and risk factors for IOP elevation ( 116 ).…”

Section: Discussionmentioning

confidence: 99%

Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications

Pasquale

Girard

et al. 2023

Front. Ophthalmol.

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Artificial intelligence (AI) has been approved for biomedical research in diverse areas from bedside clinical studies to benchtop basic scientific research. For ophthalmic research, in particular glaucoma, AI applications are rapidly growing for potential clinical translation given the vast data available and the introduction of federated learning. Conversely, AI for basic science remains limited despite its useful power in providing mechanistic insight. In this perspective, we discuss recent progress, opportunities, and challenges in the application of AI in glaucoma for scientific discoveries. Specifically, we focus on the research paradigm of reverse translation, in which clinical data are first used for patient-centered hypothesis generation followed by transitioning into basic science studies for hypothesis validation. We elaborate on several distinctive areas of research opportunities for reverse translation of AI in glaucoma including disease risk and progression prediction, pathology characterization, and sub-phenotype identification. We conclude with current challenges and future opportunities for AI research in basic science for glaucoma such as inter-species diversity, AI model generalizability and explainability, as well as AI applications using advanced ocular imaging and genomic data.

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“…55 Indeed, considering glaucoma in a general population context, even variants previously thought to confer large increases in risk (such as the MYOC 368 Stop mutation), may only make modest contributions [odds ratio (OR) ∼4, rather than OR > 10 56 ] to the overall genetic burden of glaucoma, with most of the genetic risk attributable to a large number of genetic variants of individually small effect. 57 The identification of specific disease risk genes is particularly important for the discovery and development of new drug targets ("new biology"), as it has been shown that when a drug target is supported by genetic evidence, the probability of its clinical approval is more than double, with enormous economic savings in the drug development pipeline. 58,59 In the field of glaucoma, several potential targets have been identified, either IOPdriven, or VCDR-driven (neuroprotective agents), summarized in Table 2, and future studies are needed to translate these discoveries into clinical practice.…”

Section: Geneticsmentioning

confidence: 99%

“…While a PRS is not a diagnostic test for the disease, it represents a risk-stratifying score able to identify subjects at higher risk for POAG and associated with clinical outcomes, with a high potential in terms of clinical applicability. [50][51][52][53][54][55][56][57][58][59][60] As POAG represents one of the most heritable diseases (with first-degree relatives with a lifetime risk of developing the disease almost 10 times higher than controls [46][47][48] ), a genetics-based score has excellent potential to identify subjects who will benefit from targeted screening, early diagnosis, and prompt treatment. Future studies including larger sample sizes bringing together all the genetics and clinical data available globally will allow further discoveries in this field and improve disease predictions.…”

Section: Geneticsmentioning

confidence: 99%

Lessons From The Glaucoma Foundation Think Tank 2023: A Patient-Centric Approach to Glaucoma

Harris,

Verticchio Vercellin,

Weinreb

et al. 2023

Journal of Glaucoma

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Purpose: To summarize the main topics discussed during the 28th Annual Glaucoma Foundation Think Tank Meeting “A Patient-Centric Approach to Glaucoma” held in New York on June 9th and 10th 2023. Methods: The highlights of the sessions on BIG DATA, genetics, modifiable lifestyle risk factors, female sex hormones, and neuroprotection in the field of primary open-angle glaucoma (POAG) were summarized. Results: The researchers discussed the importance of BIG DATA repositories available at national and international levels for POAG research, including the United Kingdom Biobank. Combining genotyped large cohorts worldwide, facilitated by artificial intelligence (AI) and machine learning approaches, led to the milestone discovery of 312 genome-wide significant disease loci for POAG. While these loci could be combined into a polygenic risk score with clinical utility, Think Tank meeting participants also provided analytical epidemiological evidence that behavioral risk factors modify POAG polygenetic risk, citing specific examples related to caffeine and alcohol use. The impact of female sex hormones on POAG pathophysiology was discussed, as was neuroprotection and the potential use of AI to help mitigate specific challenges faced in clinical trials and speed approval of neuroprotective agents. Conclusion: The experts agreed on the importance of genetics in defining individual POAG risk and highlighted the additional crucial role of lifestyle, gender, blood pressure, and vascular risk factors. The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease.

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Predicting the Future of Genetic Risk Profiling of Glaucoma

Cited by 15 publications

References 79 publications

Genome-wide association study finds multiple loci associated with intraocular pressure in HS rats

Genome-wide association study finds multiple loci associated with intraocular pressure in HS rats

Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications

Lessons From The Glaucoma Foundation Think Tank 2023: A Patient-Centric Approach to Glaucoma

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