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

Published on Jan 20, 2020in Nature Genetics25.455
· DOI :10.1038/S41588-019-0556-Y
Jamie E. Craig51
Estimated H-index: 51
(Flinders Medical Centre),
Ayub Qassim1
Estimated H-index: 1
(Flinders Medical Centre)
+ 56 AuthorsUk Biobank Eye1
Estimated H-index: 1
Abstract
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. Multitrait genome-wide analysis of glaucoma and related phenotypes identifies new risk loci and enables development of a polygenic risk score to predict disease susceptibility and key clinical outcomes.
  • References (49)
  • Citations (4)
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References49
Newest
#1Xikun Han (UQ: University of Queensland)H-Index: 6
#2Ayub Qassim (Flinders Medical Centre)H-Index: 1
Last. Stuart MacGregor (QIMR: QIMR Berghofer Medical Research Institute)H-Index: 66
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Optic nerve head morphology is affected by several retinal diseases. We measured the vertical optic disc diameter (DD) of the UK Biobank cohort (UKBB, N = 67 040), and performed the largest genome-wide association study (GWAS) of DD to date. We identified 81 loci (66 novel) for vertical DD. We then replicated the novel loci in International Glaucoma Genetic Consortium (IGGC, N = 22 504) and EPIC-Norfolk (N = 6005); in general the concordance in effect sizes was very high (correlation in effect s...
1 CitationsSource
#1Lulin Huang (CAS: Chinese Academy of Sciences)H-Index: 13
#2Yuhong Chen (Fudan University)H-Index: 18
Last. Zhenglin Yang (CAS: Chinese Academy of Sciences)H-Index: 34
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Intraocular pressure (IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10−7, and we formally replicated these loci. A combine...
1 CitationsSource
#1Xikun Han (UQ: University of Queensland)H-Index: 6
#2Emmanuelle Souzeau (Flinders Medical Centre)H-Index: 15
Last. Stuart MacGregor (QIMR: QIMR Berghofer Medical Research Institute)H-Index: 66
view all 21 authors...
Importance: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene ( MYOC ) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. Objectives: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). Design, Setting, and Participants: This cro...
2 CitationsSource
#1Jonathan Marchini (University of Oxford)H-Index: 58
#2Clare Bycroft (University of Oxford)H-Index: 4
Last. Peter Donnelly (University of Oxford)H-Index: 95
view all 18 authors...
The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information i...
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#1Amit KheraH-Index: 52
#2Mark Chaffin (Broad Institute)H-Index: 12
Last. Sekar KathiresanH-Index: 106
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A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2–5, it has not yet been possible to use...
257 CitationsSource
#1Stuart MacGregor (QIMR: QIMR Berghofer Medical Research Institute)H-Index: 66
#2Jue-Sheng Ong (QIMR: QIMR Berghofer Medical Research Institute)H-Index: 6
Last. Alex W. Hewitt (UTAS: University of Tasmania)H-Index: 44
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Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide. Both IOP and POAG are highly heritable. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578) that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously rep...
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#1X. Raymond Gao (UIC: University of Illinois at Chicago)H-Index: 2
#2Hua Huang (UIC: University of Illinois at Chicago)H-Index: 2
Last. Heejin Kim (UIC: University of Illinois at Chicago)H-Index: 2
view all 5 authors...
: Elevated intraocular pressure (IOP) is a significant risk factor for glaucoma, the leading cause of irreversible blindness worldwide. While previous studies have identified numerous genetic variants associated with IOP, these loci only explain a fraction of IOP heritability. Recently established of biobank repositories have resulted in large amounts of data, enabling the identification of the remaining heritability for complex traits. Here, we describe the largest genome-wide association study...
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#1Hélène Choquet (KP: Kaiser Permanente)H-Index: 20
#2Seyyedhassan Paylakhi (UCSF: University of California, San Francisco)H-Index: 2
Last. Eric Jorgenson (KP: Kaiser Permanente)H-Index: 26
view all 16 authors...
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10−8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TM...
8 CitationsSource
#1Anthony P. Khawaja (University of Cambridge)H-Index: 17
#2Jessica N. Cooke Bailey (Case Western Reserve University)H-Index: 16
Last. Pirro G. Hysi (St Thomas' Hospital)H-Index: 37
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20 CitationsSource
#1Patrick Turley (Broad Institute)H-Index: 13
#2Raymond K. Walters (Broad Institute)H-Index: 20
Last. Steven J. PittsH-Index: 10
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We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. We apply MTAG to summary statistics for depressive symptoms (N eff = 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases th...
118 CitationsSource
Cited By4
Newest
#1Fumihiko Mabuchi (University of Yamanashi)H-Index: 20
#2Nakako Mabuchi (University of Yamanashi)H-Index: 2
Last. Takeshi IwataH-Index: 22
view all 19 authors...
PURPOSE: To investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n=505) and control subjects (n=246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic varia...
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#1Ying Li (Emory University)H-Index: 4
Last. Eldon E. GeisertH-Index: 19
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PurposePreviously we identified POU6F2 as a genetic link between central corneal thickness (CCT) and risk of open-angle glaucoma. The present study is designed to characterize the POU6F2-positive retinal ganglion cells (RGCs). MethodsThe Thy1-YFP-H mouse was used to identify the structure of POU6F2-positive RGCs in the retina. In the retina of the Thy1-YFP-H mouse approximately 3% of the RGCs were labeled with yellow fluorescent protein. These retinas were stained for POU6F2 to identify the morp...
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