Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Craig, Jamie E; Han, Xikun; Qassim, Ayub; Hassall, Mark; Bailey, Jessica N. Cooke; Kinzy, Tyler G.; Khawaja, Anthony P.; An, Jiyuan; Marshall, Henry; Gharahkhani, Puya; Igo, Robert P.; Graham, Stuart; Healey, Paul R.; Ong, Jue‐Sheng; Zhou, Tiger; Siggs, Owen M.; Law, Matthew H.; Souzeau, Emmanuelle; Ridge, Bronwyn; Hysi, Pirro G.; Burdon, Kathryn P.; Mills, Richard A.; Landers, John; Ruddle, Jonathan B; Agar, Ashish; Galanopoulos, Anna; White, Andrew; Willoughby, Colin E.; Andrew, Nicholas H; Best, Stephen; Vincent, Andrea L.; Goldberg, Ivan; Radford‐Smith, Graham; Martin, Nicholas G.; Montgomery, Grant W.; Vitart, Véronique; Hoehn, René; Wojciechowski, Robert; Jonas, Jost B.; Aung, Tin; Pasquale, Louis R.; Cree, Angela J.; Sivaprasad, Sobha; Vallabh, Neeru A.; Viswanathan, Ananth C.; Pasutto, Francesca; Haines, Jonathan L.; Klaver, Caroline C W; Duijn, Cornelia M. van; Casson, Robert J.; Foster, Paul J.; Khaw, Peng Tee; Hammond, Christopher J; Mackey, David A.; Mitchell, Paul; Lotery, Andrew; Wiggs, Janey L.; Hewitt, Alex W.; MacGregor, Stuart

doi:10.1038/s41588-019-0556-y

Cited by 226 publications

(288 citation statements)

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“…More recently, polygenic scores have been developed that integrate the effects of many common genetic variants on disease risk 2 – 5 . While the common variants have small individual effects on disease risk, they can cumulatively have large effects—producing, in some individuals, risks equivalent to the strong monogenic variants 6 , 7 . A key question is how monogenic and polygenic risk interact: can disease risk from a monogenic variant that causes major disruption to a specific pathway be meaningfully modified by polygenic risk factors that involve small perturbations to a wide range of cellular pathways?…”

Section: Introductionmentioning

confidence: 99%

“…Recent work has suggested that common variant background modifies the age of disease onset among carriers of high-risk trinucleotide repeats predisposing to Huntington’s disease, the p.Gln368Ter MYOC variant predisposing to glaucoma, and continuous measures, such as height, body mass index, and cholesterol levels among those with rare monogenic mutations 6 , 8 – 10 . With respect to common diseases such as cancer, the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) studied a large number of BRCA1/2 monogenic risk variant carriers recruited from cancer genetics clinics, noting a relationship between a polygenic score comprised of genome-wide significant loci and the risk of breast, ovarian, and prostate cancer 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

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Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

et al. 2020

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Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditionsfamilial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic backgroundthe probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

et al. 2020

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“…Among these, the rs10483727 variant in the SIX1 region was significantly associated with POAG diagnosis and progression in a quantitative trait GWA study 4 and with risk of POAG in a later case-control GWA study 3 . More importantly, the rs10483727 variant was associated with POAG across different ethnicities 2 , 5 – 8 . However, to date, no causal variants driving its association with POAG have been identified.…”

Section: Introductionmentioning

confidence: 94%

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Charng

Simcoe

Sanfilippo

et al. 2020

Sci Rep

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SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6. However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life. Genome-wide association (GWA) studies have identified multiple genetic variants that increase susceptibility to Primary Open-Angle Glaucoma (POAG) 1-3. Among these, the rs10483727 variant in the SIX1 region was significantly associated with POAG diagnosis and progression in a quantitative trait GWA study 4 and with risk of POAG in a later case-control GWA study 3. More importantly, the rs10483727 variant was associated with POAG across different ethnicities 2,5-8. However, to date, no causal variants driving its association with POAG have been identified. Similarly, the effect of rs10483727 on protein function remains unknown. The missense variant rs33912345 (Asn141His), found in the SIX6 locus 9 , is in strong linkage disequilibrium with rs10483727. It is also associated with POAG and has been shown to alter the function of the SIX6 protein 10. SIX6 is involved in the differentiation and survival of retinal ganglion cells 11,12 , which are the primary cells affected in POAG. Both SIX1 and SIX6 belong to the family of sine oculis (SIX) transcription factors with six members in mammals (SIX1 to SIX6). All members of the family are characterized by the presence of two highly conserved domains: a homeobox domain and a SIX domain 13,14. SIX1 is expressed in several tissues, including the optic vesicles and the limb mesenchyme, but it is poorly expressed in the eye. In contrast, studies in different species, including humans, have shown that SIX6 is highly expressed in the developing retina, especially in the retinal ganglion and the amacrine cells 11,15,16. Genetic inactivation of SIX6 has been shown to result in hypoplasia of the mice retina, which subsequently lead to absence of the optic nerves 16. It is well established that POAG results in thinning of the retinal nerve fibre layer (RNFL) 17,18 , thus RNFL assessment has become indispensable in POAG management 19. Polymorphisms in SIX6 and SIX1 have been reported to result in significant RNFL thinning but the region of RNFL thinning has varied depending on the study. More specifically, each...

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“…It can be difficult for DL, and humans, to classify glaucoma in the eyes with less severe disease manifestations or multiple comorbid eye conditions, especially high myopia ( Li et al, 2018 ; Masumoto et al, 2018a ), which requires a larger image database. Furthermore, in order to develop a more dependable screening method, other clinical parameters, including IOP, central corneal thickness and glaucoma genetic informativity biomarkers ( Craig et al, 2020 ) should be integrated. Finally, the application and validation of these advanced methods in a real-world screening setting need additional investigations to bolster its support.…”

Section: Digital Innovations For Eye Diseasesmentioning

confidence: 99%

Digital technology, tele-medicine and artificial intelligence in ophthalmology: A global perspective

Liu

Ting

et al. 2021

Progress in Retinal and Eye Research

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The simultaneous maturation of multiple digital and telecommunications technologies in 2020 has created an unprecedented opportunity for ophthalmology to adapt to new models of care using tele-health supported by digital innovations. These digital innovations include artificial intelligence (AI), 5th generation (5G) telecommunication networks and the Internet of Things (IoT), creating an inter-dependent ecosystem offering opportunities to develop new models of eye care addressing the challenges of COVID-19 and beyond. Ophthalmology has thrived in some of these areas partly due to its many image-based investigations. Tele-health and AI provide synchronous solutions to challenges facing ophthalmologists and healthcare providers worldwide. This article reviews how countries across the world have utilised these digital innovations to tackle diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, glaucoma, refractive error correction, cataract and other anterior segment disorders. The review summarises the digital strategies that countries are developing and discusses technologies that may increasingly enter the clinical workflow and processes of ophthalmologists. Furthermore as countries around the world have initiated a series of escalating containment and mitigation measures during the COVID-19 pandemic, the delivery of eye care services globally has been significantly impacted. As ophthalmic services adapt and form a “new normal”, the rapid adoption of some of telehealth and digital innovation during the pandemic is also discussed. Finally, challenges for validation and clinical implementation are considered, as well as recommendations on future directions.

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Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Abstract: Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Cited by 226 publications

References 60 publications

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Digital technology, tele-medicine and artificial intelligence in ophthalmology: A global perspective

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