Genetic variation affects morphological retinal phenotypes extracted from UK Biobank Optical Coherence Tomography images

Currant, Hannah; Hysi, Pirro G.; Fitzgerald, Tomas; Gharahkhani, Puya; Bonnemaijer, Pieter W.M.; Eye, UK Biobank; Atan, Denize; Aung, Tin; Charng, Jason; Choquet, Hélène; Craig, Jamie E; Hewitt, Alex W.; Khaw, Peng Tee; Klaver, Caroline C W; Kubo, Michiaki; Ong, Jue‐Sheng; Pasquale, Louis R.; Reisman, Charles; Simcoe, Mark James; Thiadens, Alberta A H J; Duijn, Cornelia M. van; Yazar, Seyhan; Jorgenson, Eric; MacGregor, Stuart; Hammond, Chris; Mackey, David A.; Wiggs, Janey L.; Foster, Paul J.; Patel, Praveen J; Birney, Ewan; Khawaja, Anthony P

doi:10.1101/2020.07.20.20157180

Cited by 4 publications

(4 citation statements)

References 77 publications

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“…We discovered 9 loci associated with Df with similar effect across European, Asian, and African UKBB participants. Most of these genetic variants are relevant to multiple traits and diseases; for instance, the one located near HERC2 has been previously associated with hair 34 , skin 35 , and eye colour 36 ; but recent studies also suggest a strong effect in AMD 37 , glaucoma 38 , intraocular pressure 39 , visual acuity 40 , retinal arterial width 41 and arterial and venular retinal tortuosity 11,14 . Another interesting associated SNP is the one near the SLC12A9 gene as it has been reported in pigmentation [34][35][36] , mean arterial pressure 42 , and resting heart rate 43 GWAS.…”

Section: Discussionmentioning

confidence: 99%

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Velasco

Engelmann

Rawlik

et al. 2021

Preprint

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There is increasing evidence that the complexity of the retinal vasculature (measured as fractal dimension, Df) might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present here a genome-wide association study (GWAS) aimed to elucidate the genetic component of Df and to analyse its relationship with CAD. To this end, we obtained Df from retinal fundus images and genotyping information from ∼38,000 white-British participants in the UK Biobank. We discovered 9 loci associated with Df, previously reported in pigmentation, retinal width and tortuosity, hypertension, and CAD studies. Significant negative genetic correlation estimates endorse the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD fatal outcomes. This strong association motivated us to developing a MI predictive model combining clinical information, Df, a CAD polygenic risk score and using a random forest algorithm. Internal cross validation evidenced a considerable improvement in the area under the curve (AUC) of our predictive model (AUC=0.770) when comparing with an established risk model, SCORE, (AUC=0.719). Our findings shed new light on the genetic basis of Df, unveiling a common control with CAD, and highlights the benefits of its application in individualised MI risk prediction.

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Section: Discussionmentioning

confidence: 99%

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Velasco

Engelmann

Rawlik

et al. 2021

Preprint

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“…Interestingly, two of these loci, OCA2-HERC2 (Figure 4D; rs12913832, p ¼ 2.2 3 10 À66 ) and TYR (rs1126809, p ¼ 5.8 3 10 À13 ), have been previously associated with macular inner retinal thickness (retinal nerve fiber layer and ganglion cell inner plexiform layer) as derived from UKB optical coherence tomography images. 57 These inner retinal parameters have diagnostic utility for glaucoma that is considered complementary to VCDR and may be particularly efficacious at detecting early glaucoma. 58 Moreover, it is not currently possible to ascertain the thickness of the inner retina from fundus images, which are two-dimensional.…”

Section: Relationship Of Primary Open-angle Glaucoma and Vcdrmentioning

confidence: 99%

Large-scale machine-learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology

Alipanahi

Hormozdiari

Behsaz

et al. 2021

The American Journal of Human Genetics

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Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p % 5 3 10 À8 ) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort.

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“…The software provides an image quality score and segmentation indicators which was used for quality control. Segmentation indicators included the Inner Limiting Membrane (ILM) Indicator, a measure of the minimum localized edge strength around the ILM boundary across the scan, which can be used to identify blinks, scans that contain regions of signal fading, and errors in segmentation 20 . We excluded all images with image quality less than 40 and images representing the poorest 10% of ILM indicator.…”

Section: Retinal Optical Coherence Tomography (Oct) and Retinal Layer Segmentationmentioning

confidence: 99%

Photoreceptor layer thinning is an early biomarker for age-related macular degeneration development: Epidemiological and genetic evidence from UK Biobank optical coherence tomography data

Zekavat¹,

Sekimitsu

et al. 2021

Preprint

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Introduction: Age-related macular degeneration (AMD) is a blinding condition for which there is currently no early-stage clinical biomarker. AMD is characterized by thinning of the outer retina and drusen formation leading to thickening of the Bruch's membrane and RPE complex, but the timing between these two events, as well as the role of genetic variants in these processes, are unclear. Here, we jointly analyzed genomic, electronic health record, and optical coherence tomography (OCT) data across 44,823 individuals from the UK Biobank to characterize the epidemiological and genetic associations between retinal layer thicknesses and AMD. Methods: The Topcon Advanced Boundary Segmentation algorithm was used for automated retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model, and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we tested the association of AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age^2, sex, smoking status, and principal components of ancestry. Results: Photoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed and accelerated at age 45, while retinal pigment epithelium and Bruch's membrane complex (RPE+BM) thickening started after age 57. Each standard deviation (SD) of PS thinning and RPE+BM thickening were associated with prevalent AMD (PS: OR 1.37, 95% CI 1.25-1.49, P=2.5x10-12; RPE+BM: OR=1.34, 95% CI 1.27-1.41, P=8.4x10^-28) and incident AMD (PS: HR 1.35, 95% CI 1.23-1.47, P=3.7x10^-11; RPE+BM: HR 1.14, 95% CI 1.06-1.22, P=0.00024). An AMD polygenic risk score (PRS) was associated with PS thinning (Beta -0.21 SD per 2-fold genetically increased risk of AMD, 95% CI -0.23 to -0.19, P=2.8x10^-74), and its association with RPE+BM was U-shaped (thinning with AMD PRS<92nd percentile and thickening with AMD PRS>92nd percentile suggestive of drusen formation). The loci with strongest support were AMD risk-raising variants CFH:rs570618-T, CFH:10922109-C, and ARMS2/HTRA1:rs3750846-C on PS thinning, and SYN3/TIMP3:rs5754227-T on RPE+BM thickening. Conclusions: Epidemiologically, PS thinning precedes RPE+BM thickening by decades, and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage clinical biomarker for future AMD development.

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Genetic variation affects morphological retinal phenotypes extracted from UK Biobank Optical Coherence Tomography images

Cited by 4 publications

References 77 publications

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Large-scale machine-learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology

Photoreceptor layer thinning is an early biomarker for age-related macular degeneration development: Epidemiological and genetic evidence from UK Biobank optical coherence tomography data

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