Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.,Nature Genetics

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Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.
Nature Genetics ( IF 30.8 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41588-019-0556-y
Jamie E Craig ₁ , Xikun Han _{2,

3} , Ayub Qassim ₁ , Mark Hassall ₁ , Jessica N Cooke Bailey ₄ , Tyler G Kinzy ₄ , Anthony P Khawaja ₅ , Jiyuan An ₂ , Henry Marshall ₁ , Puya Gharahkhani ₂ , Robert P Igo ₄ , Stuart L Graham ₆ , Paul R Healey _{7,

8} , Jue-Sheng Ong ₂ , Tiger Zhou ₁ , Owen Siggs ₁ , Matthew H Law ₂ , Emmanuelle Souzeau ₁ , Bronwyn Ridge ₁ , Pirro G Hysi ₉ , Kathryn P Burdon ₁₀ , Richard A Mills ₁ , John Landers ₁ , Jonathan B Ruddle ₁₁ , Ashish Agar ₁₂ , Anna Galanopoulos ₁₃ , Andrew J R White _{7,

8} , Colin E Willoughby _{14,

15} , Nicholas H Andrew ₁ , Stephen Best ₁₆ , Andrea L Vincent ₁₇ , Ivan Goldberg ₁₈ , Graham Radford-Smith ₂ , Nicholas G Martin ₂ , Grant W Montgomery ₁₉ , Veronique Vitart ₂₀ , Rene Hoehn _{21,

22} , Robert Wojciechowski _{23,

24} , Jost B Jonas ₂₅ , Tin Aung ₂₆ , Louis R Pasquale ₂₇ , Angela Jane Cree ₂₈ , Sobha Sivaprasad ₂₉ , Neeru A Vallabh _{30,

31} , , , Ananth C Viswanathan ₅ , Francesca Pasutto ₃₂ , Jonathan L Haines ₄ , Caroline C W Klaver ₃₃ , Cornelia M van Duijn ₃₄ , Robert J Casson ₃₅ , Paul J Foster ₅ , Peng Tee Khaw ₅ , Christopher J Hammond ₉ , David A Mackey _{10,

36} , Paul Mitchell ₃₇ , Andrew J Lotery ₂₈ , Janey L Wiggs ₃₈ , Alex W Hewitt ₁₀ , Stuart MacGregor ₂

Affiliation

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia.
Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
Clinical Ophthalmology & Eye Health, Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.
Department of Ophthalmology, King's College London, St. Thomas' Hospital, London, UK.
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia.
Department of Ophthalmology, Prince of Wales Hospital Randwick, Sydney, New South Wales, Australia.
South Australian Institute of Ophthalmology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Biomedical Sciences Research Institute, Ulster University, Coleraine, UK.
Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK.
Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
Discipline of Ophthalmology, Faculty of Medicine and Health, University of Sydney, Sydney Eye Hospital, Sydney, New South Wales, Australia.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Department of Ophthalmology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland.
Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
National Institute for Health Research Moorfields Biomedical Research Centre, London, UK.
Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia.
Lions Eye Institute, Centre for Ophthalmology and Vision Sciences, University of Western Australia, Perth, Western Australia, Australia.
Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

中文翻译：

青光眼的多性状分析确定了新的风险位点，并能够对疾病的易感性和进展进行多基因预测。

青光眼是一种以视神经进行性退化为特征的疾病，可以通过及时诊断和治疗来预防。我们对 67,040 名英国生物银行参与者的视神经照片进行了表征，并使用多性状遗传模型来识别青光眼的风险位点。青光眼多基因风险评分 (PRS) 能够对未选择的青光眼病例进行有效的风险分层，并修改编码 p.Gln368Ter 的 MYOC 变体的外显率，这是最常见的青光眼相关肌纤蛋白变体。在未选择的青光眼人群中，PRS 最高十分位的个体比最低十分位的人患青光眼的绝对风险提前 10 年，并且发生晚期青光眼的风险增加了 15 倍（最高 10% 与剩余 90%，优势比 = 4.20 ）。PRS 在前瞻性监测中预测青光眼进展，早期明显青光眼病例 (P = 0.004) 和晚期疾病的手术干预 (P = 3.6 × 10-6)。这种青光眼 PRS 将有助于开发一种个性化的方法来早期治疗高危个体，而对低危人群进行较少的密集监测和治疗。

更新日期：2020-01-20

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