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2. The Australian Eye and Ear Health Survey (AEEHS): Study protocol for a population-based cross-sectional study

Author

Senjam, SS, Kha, R, Macken, O, Mitchell, P, Liew, G, Keay, L, Waddell, C, Yang, E, Do, V, Fricke, T, Newall, J, Gopinath, B, Senjam, SS, Kha, R, Macken, O, Mitchell, P, Liew, G, Keay, L, Waddell, C, Yang, E, Do, V, Fricke, T, Newall, J, and Gopinath, B

Abstract

INTRODUCTION: Vision and hearing impairments are highly prevalent and have a significant impact on physical, psychological and social wellbeing. There is a need for accurate, contemporary national data on the prevalence, risk factors and impacts of vision and hearing loss in Australian adults. OBJECTIVES: The Australian Eye and Ear Health Survey (AEEHS) aims to determine the prevalence, risk factors and impacts of vision and hearing loss in both Aboriginal and Torres Strait Islander and non-Indigenous older adults. METHODS AND ANALYSIS: The AEEHS is a population-based cross-sectional survey which will include 5,000 participants (3250 non-Indigenous aged 50 years or older and 1750 Aboriginal and Torres Strait Islander people aged 40 years or older) from 30 sites covering urban and rural/regional geographic areas, selected using a multi-stage, random cluster sampling strategy. Questionnaires will be administered to collect data on socio-demographic, medical, ocular and ontological history. The testing battery includes assessment of blood pressure, blood sugar, anthropometry, visual acuity (presenting, unaided, pinhole and best-corrected), refraction, tonometry, slit lamp and dilated eye examination, ocular imaging including optical coherence tomography (OCT), OCT-angiography and retinal photography, and automated visual fields. Audiometry, tympanometry and video otoscopy will also be performed. The primary outcomes are age-standardised prevalence of cause-specific vision and hearing impairment. Secondary outcomes are prevalence of non-blinding eye diseases (including dry eye disease), patterns in health service utilisation, universal health coverage metrics, risk factors for vision and hearing impairment, and impact on quality of life.

Published
2024

4. Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.

Author

Moore, Anthony, Gardner, JC, Liew, G, Quan, Y-H, Ermetal, B, Ueyama, H, Davidson, AE, Schwarz, N, Kanuga, N, Chana, R, and Maher, ER

Abstract

Mutations in the OPN1LW (L-) and OPN1MW (M-)cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of color vision to progressive retinal degeneration. Genotypes of 22 families with a range of cone disorders were grouped in

Published
2014

11. Perspectives of people with late age-related macular degeneration on mental health and mental wellbeing programmes: a qualitative study

Author

Dillon, L, Gandhi, S, Tang, D, Liew, G, Hackett, M, Craig, A, Mitchell, P, Keay, L, Gopinath, B, Dillon, L, Gandhi, S, Tang, D, Liew, G, Hackett, M, Craig, A, Mitchell, P, Keay, L, and Gopinath, B

Abstract

Purpose: People with age-related macular degeneration (AMD) experience high rates of depression, but rarely engage in or have access to tailored mental wellbeing programmes. This qualitative study investigated the perspectives of those primarily with late AMD on mental health and mental wellbeing programmes. Methods: Twenty-eight people with late AMD in at least one eye, and one person with early AMD in both eyes, aged 56–87 years (mean age 78 years) attending a private eye clinic between December 2019 and January 2020 in Sydney, New South Wales, Australia, participated. Individual semi-structured interviews were conducted and analysed deductively using content analysis, following the individual level factors for health promotion interventions in the behaviour change wheel: Capability (Physical & Psychological), Opportunity (Physical & Social), and Motivation (Reflective & Automatic). Results: Six major themes were identified: Capability: (1) Impact of vision loss on mobility and leisure pursuits; (2) Adjustment to living with vision loss; Opportunity: (3) Program considerations for those with AMD; (4) Stigma and self-perception of vision loss and mental health; Motivation: (5) Accumulation of vision-related issues as a barrier to participation; (6) Examples of others living with vision loss. General personal factors relevant to delivery of a programme in this age group were also identified: Comorbidities; Limitations using technology; Isolation; Financial concerns and Beliefs that undesired effects of aging are inevitable. Conclusions: Complex individual, environmental and social factors influence the perspectives of people with late AMD on mental health, and potential participation in mental wellbeing programmes. These factors should be considered when developing and implementing mental wellbeing programmes to improve the emotional and functional rehabilitation outcomes for people with AMD.

Published
2021

12. Baseline extended zone retinal vascular calibres associate with sensory nerve abnormalities in adolescents with type 1 diabetes: A prospective longitudinal study.

Author

Velayutham, V, Benitez-Aguirre, PZ, Liew, G, Wong, TY, Jenkins, AJ, Craig, ME, Donaghue, KC, Velayutham, V, Benitez-Aguirre, PZ, Liew, G, Wong, TY, Jenkins, AJ, Craig, ME, and Donaghue, KC

Abstract

OBJECTIVE: The relationship between retinal vascular calibres (RVCs) and diabetic neuropathy is unclear. We investigated associations between RVCs and sensory nerve abnormality in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a prospective longitudinal study of 889 adolescents with type 1 diabetes with baseline mean (±SD) age 14.1 ± 1.5 years and HbA1c IFCC 69.4 ± 14.1 mmol/mol (8.6 ± 1.3%), RVCs were assessed from baseline retinal photographs: 'central zone' calibres, summarized as central retinal arteriolar (CRAE) and venular equivalents (CRVE) and 'extended zone' calibres: mean width of arterioles (MWa) and venules (MWv). Sensory nerve abnormality was defined as at least one abnormal sensory quantitative testing from two thermal and two vibration threshold tests measured at foot every 1-2 years. Associations between baseline RVC and sensory nerve function were examined using generalized estimating equations and cumulative risk by Cox regression analyses. RESULTS: During a median study follow-up of 6.2 [IQR 3.7-10.4] years, sensory nerve abnormality was found in 27% of adolescents. Narrower extended zone calibre quartiles but not CRAE or CRVE quartiles were independently associated with sensory nerve abnormality: MWa (Q1 vs. Q2-4: OR 1.35 (95% CI 1.02, 1.61) and MWv (Q1 vs. Q2-4: 1.31 (1.03, 1.7)), after adjusting for HbA1c , duration and blood pressure. Similarly, in Cox regression, the narrowest quartiles were associated with sensory nerve abnormality: MWa hazard ratio (HR) 1.5 (1.3, 1.8) and MWv 1.6 (1.4, 1.9). CONCLUSIONS: Narrower extended zone retinal calibres were associated with sensory nerve abnormality in adolescents with type 1 diabetes and may present useful biomarkers to understand the pathophysiology of neuropathy.

Published
2021

14. Age-related macular degeneration and mortality from cardiovascular disease or stroke

Author

Tan, J.S.L., Wang, J.J., Liew, G., Rochtchina, E., and Mitchell, P.

Subjects
Macular degeneration -- Patient outcomes, Macular degeneration -- Research, Cardiovascular diseases -- Patient outcomes, Cardiovascular diseases -- Research, Stroke (Disease) -- Patient outcomes, Stroke (Disease) -- Research, Mortality -- Australia, Mortality -- Research, Health
Published
2008

15. A qualitative exploration of Australian eyecare professional perspectives on Age-Related Macular Degeneration (AMD) care

Author

Jalbert, I, Rahardjo, D, Yashadhana, A, Liew, G, Gopinath, B, Jalbert, I, Rahardjo, D, Yashadhana, A, Liew, G, and Gopinath, B

Abstract

Despite the existence of evidence-based recommendations to decrease risk and progression of Age-Related Macular Degeneration (AMD) for some time, self-reported practices suggest that eyecare professionals’ advice and people with AMD’s adherence to these recommendations can be very poor. This study uses qualitative methods to explore Australian eyecare professionals’ perspective on barriers to effective AMD care. Seven focus groups involving 65 optometrists were conducted by an experienced facilitator. A nominal group technique was used to identify, prioritize and semi-quantify barriers and enablers to AMD care. Participants individually ranked their perceived top five barriers and enablers with the most important granted a score of 5 and the least important a score of 1. For each barrier or enabler, the number of votes it received and its total score were recorded. Barriers and enablers selected by at least one participant in their top 5 were then qualitatively analysed, grouped using thematic analysis and total score calculated for each consolidated barrier or enabler. In-depth individual interviews were conducted with 10 ophthalmologists and 2 optometrists. Contributions were audio-recorded, transcribed verbatim and analysed with NVivo software. One hundred and sixty-nine barriers and 51 enablers to AMD care were identified in the focus groups. Of these, 102 barriers and 42 enablers were selected as one of their top 5 by at least one participant and further consolidated into 16 barriers and 10 enablers after thematic analysis. Factors impacting AMD care identified through analysis of the transcripts were coded to three categories of influence: patient-centered, practitioner-centered, and structural factors. Eyecare professionals considered poor care pathways, people with AMD’s poor disease understanding / denial, and cost of care / lack of funding, as the most significant barriers to AMD care; they considered shared care model, access, and communication as the mos

Published
2020

25. Improving Patient Access and Reducing Costs for Glaucoma with Integrated Hospital and Community Care: A Case Study from Australia.

Author

Ford, BK, Angell, B, Liew, G, White, AJR, Keay, LJ, Ford, BK, Angell, B, Liew, G, White, AJR, and Keay, LJ

Abstract

Introduction: Glaucoma, a chronic eye disease requires regular monitoring and treatment to prevent vision-loss. In Australia, most public ophthalmology departments are overburdened. Community Eye Care is a 'collaborative' care model, involving community-based optometrist assessment and 'virtual review' by ophthalmologists to manage low-risk patients. C-EYE-C was implemented at one Australian hospital. This study aims to determine whether C-EYE-C improves access to care and better utilises resources, compared to hospital-based care. Methods: A clinical and financial audit was conducted to compare access to care and health system costs for hospital care and C-EYE-C. Attendance, wait-time, patient outcomes, and the average cost per encounter were calculated. A weighted kappa assessed agreement between the optometrist and ophthalmologist decisions. Results: There were 503 low-risk referrals, hospital (n = 182) and C-EYE-C (n = 321). C-EYE-C had higher attendance (81.6% vs 68.7%, p = 0.001); and shorter appointment wait-time (89 vs 386 days, p < 0.001). Following C-EYE-C, 57% of patients avoided hospital; with 39% requiring glaucoma management. C-EYE-C costs were 22% less than hospital care. There was substantial agreement between optometrists and ophthalmologist for diagnosis (k = 0.69, CI 0.61-0.76) and management (k = 0.66, CI 0.57-0.74). Discussion: C-EYE-C showed higher attendance, and reduced wait-times and health system costs. Conclusions: Upscale of the C-EYE-C model should be considered to further improve capacity of public eye services in Australia.

Published
2019

26. Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration

Author

Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM

Abstract

PURPOSE: Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS: We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS: We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive" the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS: We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD.

Published
2019

27. A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes

Author

Meng, W, Shah, KP, Pollack, S, Toppila, I, Hebert, HL, McCarthy, MI, Groop, L, Ahlqvist, E, Lyssenko, V, Agardh, E, Daniell, M, Kaidonis, G, Craig, JE, Mitchell, P, Liew, G, Kifley, A, Wang, JJ, Christiansen, MW, Jensen, RA, Penman, A, Hancock, HA, Chen, CJ, Correa, A, Kuo, JZ, Li, X, Chen, Y-DI, Rotter, JI, Klein, R, Klein, B, Wong, TY, Morris, AD, Doney, ASF, Colhoun, HM, Price, AL, Burdon, KP, Groop, P-H, Sandholm, N, Grassi, MA, Sobrin, L, Palmer, CNA, Meng, W, Shah, KP, Pollack, S, Toppila, I, Hebert, HL, McCarthy, MI, Groop, L, Ahlqvist, E, Lyssenko, V, Agardh, E, Daniell, M, Kaidonis, G, Craig, JE, Mitchell, P, Liew, G, Kifley, A, Wang, JJ, Christiansen, MW, Jensen, RA, Penman, A, Hancock, HA, Chen, CJ, Correa, A, Kuo, JZ, Li, X, Chen, Y-DI, Rotter, JI, Klein, R, Klein, B, Wong, TY, Morris, AD, Doney, ASF, Colhoun, HM, Price, AL, Burdon, KP, Groop, P-H, Sandholm, N, Grassi, MA, Sobrin, L, and Palmer, CNA

Abstract

PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

Published
2018

28. Automated diabetic retinopathy image assessment software: diagnostic accuracy and cost-effectiveness compared with human graders

Author

Tufail, A, Rudisill, C, Egan, C, Kapetanakis, VV, Salas-Vega, S, Owen, CG, Lee, A, Louw, V, Anderson, J, Liew, G, Bolter, L, Srinivas, S, Nittala, M, Sadda, S, Taylor, P, and Rudnicka, AR

Subjects
RE Ophthalmology
Abstract

OBJECTIVE: With the increasing prevalence of diabetes, annual screening for diabetic retinopathy (DR) by expert human grading of retinal images is challenging. Automated DR image assessment systems (ARIAS) may provide clinically effective and cost-effective detection of retinopathy. We aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders. DESIGN: Observational measurement comparison study of human graders following a national screening program for DR versus ARIAS. PARTICIPANTS: Retinal images from 20 258 consecutive patients attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013. METHODS: Retinal images were manually graded following a standard national protocol for DR screening and were processed by 3 ARIAS: iGradingM, Retmarker, and EyeArt. Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration. MAIN OUTCOME MEASURES: Screening performance (sensitivity, false-positive rate) and diagnostic accuracy (95% confidence intervals of screening-performance measures) were determined. Economic analysis estimated the cost per appropriate screening outcome. RESULTS: Sensitivity point estimates (95% confidence intervals) of the ARIAS were as follows: EyeArt 94.7% (94.2%-95.2%) for any retinopathy, 93.8% (92.9%-94.6%) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative, or proliferative), 99.6% (97.0%-99.9%) for proliferative retinopathy; Retmarker 73.0% (72.0 %-74.0%) for any retinopathy, 85.0% (83.6%-86.2%) for referable retinopathy, 97.9% (94.9%-99.1%) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading both as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost-effective. CONCLUSIONS: Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders and had sufficient specificity to make them cost-effective alternatives to manual grading alone. ARIAS have the potential to reduce costs in developed-world health care economies and to aid delivery of DR screening in developing or remote health care settings.

Published
2017

29. Five-year progression of unilateral age-related macular degeneration to bilateral involvement: the Three Continent AMD Consortium report

Author

Joachim, N., Colijn, J.M., Kifley, A., Lee, K.E., Buitendijk, G.H., Klein, B.E., Myers, C.E., Meuer, S.M., Tan, A.G., Holliday, E.G., Attia, J., Liew, G., Iyengar, S.K., Jong, p de, Hofman, A., Vingerling, J.R., Mitchell, P., Klaver, C.C.W., Klein, R., Wang, J.J., Joachim, N., Colijn, J.M., Kifley, A., Lee, K.E., Buitendijk, G.H., Klein, B.E., Myers, C.E., Meuer, S.M., Tan, A.G., Holliday, E.G., Attia, J., Liew, G., Iyengar, S.K., Jong, p de, Hofman, A., Vingerling, J.R., Mitchell, P., Klaver, C.C.W., Klein, R., and Wang, J.J.

Abstract

Item does not contain fulltext, PURPOSE: To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. DESIGN: Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. METHODS: Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. RESULTS: In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. CONCLUSION: One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.

Published
2017

30. Implementing a multi-modal support service model for the family caregivers of persons with age-related macular degeneration: A study protocol for a randomised controlled trial

Author

Gopinath, B, Craig, A, Kifley, A, Liew, G, Bloffwitch, J, Vu, KV, Joachim, N, Cummins, R, Heraghty, J, Broady, T, Hayes, A, Mitchell, P, Gopinath, B, Craig, A, Kifley, A, Liew, G, Bloffwitch, J, Vu, KV, Joachim, N, Cummins, R, Heraghty, J, Broady, T, Hayes, A, and Mitchell, P

Abstract

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. Introduction Age-related macular degeneration (AMD) is a leading cause of blindness and low vision among older adults. Previous research shows a high prevalence of distress and disruption to the lifestyle of family caregivers of persons with late AMD. This supports existing evidence that caregivers are 'hidden patients' at risk of poor health outcomes. There is ample scope for improving the support available to caregivers, and further research should be undertaken into developing services that are tailored to the requirements of family caregivers of persons with AMD. This study aims to implement and evaluate an innovative, multi-modal support service programme that aims to empower family caregivers by improving their coping strategies, enhancing hopeful feelings such as self-efficacy and helping them make the most of available sources of social and financial support. Methods and analysis A randomised controlled trial consisting of 360 caregiver-patient pairs (180 in each of the intervention and wait-list control groups). The intervention group will receive the following: (1) mail-delivered cognitive behavioural therapy designed to improve psychological adjustment and adaptive coping skills; (2) telephone-delivered group counselling sessions allowing caregivers to explore the impacts of caring and share their experiences; and (3) education on available community services/resources, financial benefits and respite services. The cognitive behavioural therapy embedded in this programme is the best evaluated and widely used psychosocial intervention. The primary outcome is a reduction in caregiver burden. Secondary outcomes include improvements in caregiver mental well-being, quality of life, fatigue and self-efficacy. Economic analysis will inform whether this intervention is cost-effective and if it is feasible to roll out this service on a larger scale. Ethics and dissem

Published
2017

31. Five-year progression of unilateral age-related macular degeneration to bilateral involvement: The Three Continent AMD Consortium report

Author

Joachim, N. (Nichole), Colijn, J.M. (Johanna), Kifley, A. (Annette), Lee, K.E. (Kristine E.), Buitendijk, G.H.S. (Gabrielle), Klein, B.E.K. (Barbara E.K.), Myers, C.E. (Chelsea), Meuer, S.M. (Stacy), Tan, A.G. (Ava G.), Holliday, E.G. (Elizabeth), Attia, J. (John), Liew, G. (Gerald), Iyengar, S.K. (Sudha), M de Jong, P.T.V. (Paulus T.V.), Hofman, A. (Albert), Vingerling, J.R. (Hans), Mitchell, P. (Paul), Klaver, C.C.W. (Caroline), Klein, R. (Ronald), Wang, J.J. (Jie Jin), Joachim, N. (Nichole), Colijn, J.M. (Johanna), Kifley, A. (Annette), Lee, K.E. (Kristine E.), Buitendijk, G.H.S. (Gabrielle), Klein, B.E.K. (Barbara E.K.), Myers, C.E. (Chelsea), Meuer, S.M. (Stacy), Tan, A.G. (Ava G.), Holliday, E.G. (Elizabeth), Attia, J. (John), Liew, G. (Gerald), Iyengar, S.K. (Sudha), M de Jong, P.T.V. (Paulus T.V.), Hofman, A. (Albert), Vingerling, J.R. (Hans), Mitchell, P. (Paul), Klaver, C.C.W. (Caroline), Klein, R. (Ronald), and Wang, J.J. (Jie Jin)

Abstract

Purpose To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. Design Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. Methods Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any

Published
2017
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35. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, L.G. (Lars), Igl, W. (Wilmar), Cooke Bailey, J.N. (Jessica N.), Grassmann, F. (Felix), Sengupta, S. (Sebanti), Bragg-Gresham, J.L. (Jennifer L.), Burdon, K.P. (Kathryn P.), Hebbring, S.J. (Scott J.), Wen, C. (Cindy), Gorski, M. (Mathias), Kim, I.K. (Ivana), Cho, D. (David), Zack, D. (Donald), Souied, E.H. (Eric), Scholl, H.P.N. (Hendrik), Bala, E. (Elisa), ELee, K. (Kristine), Hunter, D. (David), Sardell, R.J. (Rebecca J.), Mitchell, P. (Paul), Merriam, J.E. (Joanna), Cipriani, F. (Francesco), Hoffman, J.D. (Joshua D.), Schick, T. (Tina), Lechanteur, Y.T.E. (Yara T. E.), Guymer, R.H. (Robyn), Johnson, M.P. (Matthew), Jiang, Y., Stanton, C.M. (Chloe), Buitendijk, G.H.S. (Gabrielle), Zhan, X. (Xiaowei), Kwong, A.M. (Alan M.), Boleda, A. (Alexis), Brooks, M. (Matthew), Gieser, L. (Linn), Ratna Priya, R. (Rinki), Branham, K.E. (Kari), Foerster, J.R. (Johanna R.), Heckenlively, J.R. (John), Othman, M.I. (Mohammad), Vote, B.J. (Brendan J.), Liang, H.H. (Helena Hai), Souzeau, E. (Emmanuelle), McAllister, I.L. (Ian L.), Isaacs, T. (Timothy), Hall, J. (Janette), Lake, S. (Stewart), Mackey, D.A. (David), Constable, I.J. (Ian J.), Craig, J.E. (Jamie E.), Kitchner, T.E. (Terrie E.), Yang, Z. (Zhenglin), Su, Z. (Zhiguang), Luo, H. (Hongrong), Chen, D. (Daniel), Ouyang, H. (Hong), Flagg, K. (Ken), Lin, D. (Danni), Mao, G. (Guanping), Ferreyra, H.A. (Henry), Stark, K. (Klaus), Strachwitz, C. (Claudia) von, Wolf, A. (Armin), Brandl, C. (Caroline), Rudolph, G. (Guenther), Olden, M. (Matthias), Morrison, M.A. (Margaux), Morgan, D.J. (Denise), Schu, M. (Matthew), Ahn, J. (Jeeyun), Silvestri, G. (Giuliana), Tsironi, E.E. (Evangelia), Park, K.H. (Kyu Hyung), Farrer, L.A. (Lindsay), Orlin, A. (Anton), Brucker, A. (Alexander), Curcio, C.A. (Christine A.), Mohand-Sa'd, S. (Saddek), Sahel, J.-A. (José-Alain), Audo, I. (Isabelle), Benchaboune, M. (Mustapha), Cree, A.J. (Angela), Rennie, C.A. (Christina A.), Goverdhan, S.V. (Srinivas V.), Grunin, M. (Michelle), Hagbi-Levi, S. (Shira), Campochiaro, B. (Betsy), Katsanis, N. (Nicholas), Holz, F.G. (Frank), Blond, F. (Frédéric), Blanché, H. (Hél'ne), Deleuze, J.-F. (Jean-Fran'ois), Igo Jr., R.P. (Robert), Truitt, B.J. (Barbara), Peachey, N.S. (Neal ), Meuer, S.M. (Stacy), Myers, C.E. (Chelsea), Moore, E.L. (Emily L.), Klein, R. (Ronald), Hauser, M.A. (Michael), Postel, E.A. (Eric), Courtenay, M.D. (Monique D.), Schwartz, S.M. (Stephen), Kovach, J.L. (Jaclyn), Scott, W.K. (William), Liew, G. (Gerald), Tan, A.G. (Ava G.), Gopinath, B. (Bamini), Smith, T. (Tim), Khan, J.C. (Jane), Shahid, M. (Mohammad), Moore, A.T. (Anthony), McGrath, J.A. (J Allie), Laux, R. (Reneé), Brantley, M.A. (Milam), Agarwal, A. (Anita), Ersoy, L. (Lebriz), Caramoy, A. (Albert), Langmann, T. (Thomas), Saksens, N.T.M. (Nicole T.), Jong, E.K. (Eiko Kde), Hoyng, C.B. (Carel), Cain, M.S. (Melinda), Richardson, A.J. (Andrea), Martin, T.M. (Tammy M.), Blangero, J. (John), Weeks, D.E. (Daniel), Dhillon, B. (Bal), Duijn, C.M. (Cornelia) van, Doheny, K.F. (Kimberly), Romm, J. (Jane), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Gorin, M.B. (Michael B.), Klein, M.L. (Michael), Baird, P.N. (Paul), Hollander, A.I. (Anneke), Fauser, S. (Sascha), WYates, J.R. (John R.), Allikmets, R. (Rando), Wang, J.J. (Jie Jin), Schaumberg, D.A. (Debra), Klein, B.E.K. (Barbara), Hagstrom, S.A. (Stephanie), Chowers, Y. (Yehuda), Lotery, A.J. (Andrew), Léveillard, T. (Thierry), Zhang, K. (Kang), Brilliant, M.H. (Murray H.), Hewit, A.W. (Alex), Swaroop, A. (Anand), Chew, E.Y. (Emily Y.), Pericak-Vance, M.A. (Margaret), DeAngelis, M.M. (Margaret), Stambolian, D. (Dwight), Haines, J.L. (Jonathan), Iyengar, S.K. (Sudha), Weber, B.H.F. (Bernhard), Abecasis, G.R. (Gonçalo), Heid, I.M. (Iris), Li, M. (Mingyao), Fritsche, L.G. (Lars), Igl, W. (Wilmar), Cooke Bailey, J.N. (Jessica N.), Grassmann, F. (Felix), Sengupta, S. (Sebanti), Bragg-Gresham, J.L. (Jennifer L.), Burdon, K.P. (Kathryn P.), Hebbring, S.J. (Scott J.), Wen, C. (Cindy), Gorski, M. (Mathias), Kim, I.K. (Ivana), Cho, D. (David), Zack, D. (Donald), Souied, E.H. (Eric), Scholl, H.P.N. (Hendrik), Bala, E. (Elisa), ELee, K. (Kristine), Hunter, D. (David), Sardell, R.J. (Rebecca J.), Mitchell, P. (Paul), Merriam, J.E. (Joanna), Cipriani, F. (Francesco), Hoffman, J.D. (Joshua D.), Schick, T. (Tina), Lechanteur, Y.T.E. (Yara T. E.), Guymer, R.H. (Robyn), Johnson, M.P. (Matthew), Jiang, Y., Stanton, C.M. (Chloe), Buitendijk, G.H.S. (Gabrielle), Zhan, X. (Xiaowei), Kwong, A.M. (Alan M.), Boleda, A. (Alexis), Brooks, M. (Matthew), Gieser, L. (Linn), Ratna Priya, R. (Rinki), Branham, K.E. (Kari), Foerster, J.R. (Johanna R.), Heckenlively, J.R. (John), Othman, M.I. (Mohammad), Vote, B.J. (Brendan J.), Liang, H.H. (Helena Hai), Souzeau, E. (Emmanuelle), McAllister, I.L. (Ian L.), Isaacs, T. (Timothy), Hall, J. (Janette), Lake, S. (Stewart), Mackey, D.A. (David), Constable, I.J. (Ian J.), Craig, J.E. (Jamie E.), Kitchner, T.E. (Terrie E.), Yang, Z. (Zhenglin), Su, Z. (Zhiguang), Luo, H. (Hongrong), Chen, D. (Daniel), Ouyang, H. (Hong), Flagg, K. (Ken), Lin, D. (Danni), Mao, G. (Guanping), Ferreyra, H.A. (Henry), Stark, K. (Klaus), Strachwitz, C. (Claudia) von, Wolf, A. (Armin), Brandl, C. (Caroline), Rudolph, G. (Guenther), Olden, M. (Matthias), Morrison, M.A. (Margaux), Morgan, D.J. (Denise), Schu, M. (Matthew), Ahn, J. (Jeeyun), Silvestri, G. (Giuliana), Tsironi, E.E. (Evangelia), Park, K.H. (Kyu Hyung), Farrer, L.A. (Lindsay), Orlin, A. (Anton), Brucker, A. (Alexander), Curcio, C.A. (Christine A.), Mohand-Sa'd, S. (Saddek), Sahel, J.-A. (José-Alain), Audo, I. (Isabelle), Benchaboune, M. (Mustapha), Cree, A.J. (Angela), Rennie, C.A. (Christina A.), Goverdhan, S.V. (Srinivas V.), Grunin, M. (Michelle), Hagbi-Levi, S. (Shira), Campochiaro, B. (Betsy), Katsanis, N. (Nicholas), Holz, F.G. (Frank), Blond, F. (Frédéric), Blanché, H. (Hél'ne), Deleuze, J.-F. (Jean-Fran'ois), Igo Jr., R.P. (Robert), Truitt, B.J. (Barbara), Peachey, N.S. (Neal ), Meuer, S.M. (Stacy), Myers, C.E. (Chelsea), Moore, E.L. (Emily L.), Klein, R. (Ronald), Hauser, M.A. (Michael), Postel, E.A. (Eric), Courtenay, M.D. (Monique D.), Schwartz, S.M. (Stephen), Kovach, J.L. (Jaclyn), Scott, W.K. (William), Liew, G. (Gerald), Tan, A.G. (Ava G.), Gopinath, B. (Bamini), Smith, T. (Tim), Khan, J.C. (Jane), Shahid, M. (Mohammad), Moore, A.T. (Anthony), McGrath, J.A. (J Allie), Laux, R. (Reneé), Brantley, M.A. (Milam), Agarwal, A. (Anita), Ersoy, L. (Lebriz), Caramoy, A. (Albert), Langmann, T. (Thomas), Saksens, N.T.M. (Nicole T.), Jong, E.K. (Eiko Kde), Hoyng, C.B. (Carel), Cain, M.S. (Melinda), Richardson, A.J. (Andrea), Martin, T.M. (Tammy M.), Blangero, J. (John), Weeks, D.E. (Daniel), Dhillon, B. (Bal), Duijn, C.M. (Cornelia) van, Doheny, K.F. (Kimberly), Romm, J. (Jane), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Gorin, M.B. (Michael B.), Klein, M.L. (Michael), Baird, P.N. (Paul), Hollander, A.I. (Anneke), Fauser, S. (Sascha), WYates, J.R. (John R.), Allikmets, R. (Rando), Wang, J.J. (Jie Jin), Schaumberg, D.A. (Debra), Klein, B.E.K. (Barbara), Hagstrom, S.A. (Stephanie), Chowers, Y. (Yehuda), Lotery, A.J. (Andrew), Léveillard, T. (Thierry), Zhang, K. (Kang), Brilliant, M.H. (Murray H.), Hewit, A.W. (Alex), Swaroop, A. (Anand), Chew, E.Y. (Emily Y.), Pericak-Vance, M.A. (Margaret), DeAngelis, M.M. (Margaret), Stambolian, D. (Dwight), Haines, J.L. (Jonathan), Iyengar, S.K. (Sudha), Weber, B.H.F. (Bernhard), Abecasis, G.R. (Gonçalo), Heid, I.M. (Iris), and Li, M. (Mingyao)

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10 -8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10 -10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016
Full Text
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36. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016

37. Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo

Author

Ikram MK, Sim X, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, Wang JJ, Klein R, Klein BE, Breteler MM, Cheung N, Liew G, Mitchell P, Uitterlinden AG, Rivadeneira F, Hofman A, de Jong PT, van Duijn CM, Kao L, Cheng CY, Smith AV, Glazer NL, Lumley T, McKnight B, Psaty BM, Jonasson F, Eiriksdottir G, Aspelund T, Newton Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar S, Zhao JH, Heath SC, Eyheramendy S, Wallace C, Chambers JC, Khaw KT, Polidoro S, Grobbee DE, Onland Moret NC, Allione A, Di Gregorio A, Guarrera S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, O'Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder P, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Galan P, Gut IV, Hercberg S, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bandinelli S, Ferrucci L, Watkins H, Tuomilehto J, Altshuler D, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RFJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB, Harris TB, Launer LJ, Taylor KD, Li X, Iyengar SK, Xi Q, Sivakumaran TA, Mackey DA, Macgregor S, Martin NG, Young TL, Bis JC, Wiggins KL, Heckbert SR, Hammond CJ, Andrew T, Fahy S, Attia J, Holliday EG, Scott RJ, Islam FM, Rotter JI, McAuley AK, Boerwinkle E, Tai ES, Gudnason V, Siscovick DS, Vingerling JR, Wong TY, PANICO, SALVATORE, Ophthalmology, Epidemiology, Internal Medicine, Faculteit der Geneeskunde, Ikram, Mk, Xueling, S, Jensen, Ra, Cotch, Mf, Hewitt, Aw, Ikram, Ma, Wang, Jj, Klein, R, Klein, Be, Breteler, Mm, Cheung, N, Liew, G, Mitchell, P, Uitterlinden, Ag, Rivadeneira, F, Hofman, A, de Jong, Pt, van Duijn, Cm, Kao, L, Cheng, Cy, Smith, Av, Glazer, Nl, Lumley, T, Mcknight, B, Psaty, Bm, Jonasson, F, Eiriksdottir, G, Aspelund, T, Panico, Salvatore, Global BPgen, Consortium, Harris, Tb, Launer, Lj, Taylor, Kd, Li, X, Iyengar, Sk, Xi, Q, Sivakumaran, Ta, Mackey, Da, Macgregor, S, Martin, Ng, Young, Tl, Bis, Jc, Wiggins, Kl, Heckbert, Sr, Hammond, Cj, Andrew, T, Fahy, S, Attia, J, Holliday, Eg, Scott, Rj, Islam, Fm, Rotter, Ji, Mcauley, Ak, Boerwinkle, E, Tai, E, Gudnason, V, Siscovick, D, Vingerling, Jr, 2010 Oct 28, Wong T. Y. PLoS G. e. n. e. t., 6:e1001184, Sim, X, Newton Cheh, C, Johnson, T, Gateva, V, Tobin, Md, Bochud, M, Coin, L, Najjar, S, Zhao, Jh, Heath, Sc, Eyheramendy, S, Wallace, C, Chambers, Jc, Khaw, Kt, Polidoro, S, Grobbee, De, Onland Moret, Nc, Allione, A, Di Gregorio, A, Guarrera, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, O'Reilly, Pf, Peltonen, L, Pouta, A, de Jong, Pe, Snieder, P, Tognoni, G, Lakatta, Eg, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Galan, P, Gut, Iv, Hercberg, S, van der Schouw, Yt, Numans, Me, Matullo, G, Navis, G, Berglund, G, Bandinelli, S, Ferrucci, L, Watkins, H, Tuomilehto, J, Altshuler, D, Wareham, Nj, Uda, M, Jarvelin, Mr, Mooser, V, Melander, O, Loos, Rfj, Elliott, P, Abecasis, Gr, Caulfield, M, Munroe, Pb, Wong, Ty, Medical Research Council (MRC), and Department of Public Health

Subjects
Male, Cancer Research, Pathology, VESSEL DIAMETERS, Genome-wide association study, 030204 cardiovascular system & hematology, QH426-470, DISEASE, Pathogenesis, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Cardiovascular Disorders/Vascular Biology, Child, Genetics (clinical), Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, Middle Aged, 314 Health sciences, 3. Good health, Cardiovascular Diseases, Child, Preschool, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Female, Research Article, Adult, medicine.medical_specialty, Adolescent, ANTIHYPERTENSIVE DRUG THERAPIES, Population, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, ATHEROSCLEROSIS RISK, Biology, Polymorphism, Single Nucleotide, White People, Microcirculation, 03 medical and health sciences, Young Adult, AGE, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Genetics and Genomics/Population Genetics, medicine, SNP, Humans, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, Global BPgen Consortium, 030304 developmental biology, Aged, 0604 Genetics, Chromosomes, Human, Pair 12, Retinal Vessels, Retinal, CHARGE CONSORTIUM, RETINAL VASCULAR CALIBER, chemistry, Genetic Loci, Ophthalmology/Retinal Disorders, genome-wide association study, microcirculation, GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK, Chromosomes, Human, Pair 19, Developmental Biology, Genome-Wide Association Study
Abstract

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p, Author Summary The microcirculation plays an important role in the development of cardiovascular diseases. Retinal vascular caliber changes reflect early microvascular disease and predict incident cardiovascular events. In order to identify genetic variants associated with retinal vascular caliber, we performed a genome-wide association study and analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). We found evidence for association of four loci with retinal venular caliber: on chromosomes 19q13 within the RASIP1 locus, 6q24 adjacent to the VTA1 and NMBR loci, 12q24 in the region of ATXN2,SH2B3 and PTPN11 loci, and 5q14 adjacent to the MEF2C locus. In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. In the present study, we demonstrate that four novel loci were associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. Our findings will help focus research on novel genes and pathways involving the microcirculation and its role in the development of cardiovascular disease.

Published
2010

41. Three Different Cone Opsin Gene Array Mutational Mechanisms with Genotype-Phenotype Correlation and Functional Investigation of Cone Opsin Variants

Author

Gardner, JC, Liew, G, Quan, Y-H, Ermetal, B, Ueyama, H, Davidson, AE, Schwarz, N, Kanuga, N, Chana, R, Maher, ER, Webster, AR, Holder, GE, Robson, AG, Cheetham, ME, Liebelt, J, Ruddle, JB, Moore, AT, Michaelides, M, Hardcastle, AJ, Gardner, JC, Liew, G, Quan, Y-H, Ermetal, B, Ueyama, H, Davidson, AE, Schwarz, N, Kanuga, N, Chana, R, Maher, ER, Webster, AR, Holder, GE, Robson, AG, Cheetham, ME, Liebelt, J, Ruddle, JB, Moore, AT, Michaelides, M, and Hardcastle, AJ

Abstract

Mutations in the OPN1LW (L-) and OPN1MW (M-)cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of color vision to progressive retinal degeneration. Genotypes of 22 families with a range of cone disorders were grouped into three classes: deletions of the locus control region (LCR); missense mutation (p.Cys203Arg) in an L-/M-hybrid gene; and exon 3 single-nucleotide polymorphism (SNP) interchange haplotypes in an otherwise normal gene array. Moderate-to-high myopia was observed in all mutation categories. Individuals with LCR deletions or p.Cys203Arg mutations were more likely to have nystagmus and poor vision, with disease progression in some p.Cys203Arg patients. Three disease-associated exon 3 SNP haplotypes encoding LIAVA, LVAVA, or MIAVA were identified in our cohort. These patients were less likely to have nystagmus but more likely to show progression, with all patients over the age of 40 years having marked macular abnormalities. Previously, the haplotype LIAVA has been shown to result in exon 3 skipping. Here, we show that haplotypes LVAVA and MIAVA also result in aberrant splicing, with a residual low level of correctly spliced cone opsin. The OPN1LW/OPN1MW:c.532A>G SNP, common to all three disease-associated haplotypes, appears to be principally responsible for this mutational mechanism.

Published
2014

42. Complete Blood Count and Retinal Vessel Calibers

Author

Stitt, A, Liew, G, Wang, JJ, Rochtchina, E, Wong, TY, Mitchell, P, Stitt, A, Liew, G, Wang, JJ, Rochtchina, E, Wong, TY, and Mitchell, P

Abstract

OBJECTIVE: The influence of hematological indices such as complete blood count on microcirculation is poorly understood. Retinal microvasculature can be directly visualized and vessel calibers are associated with a range of ocular and systemic diseases. We examined the association of complete blood count with retinal vessel calibers. METHODS: Cross-sectional population-based Blue Mountains Eye Study, n = 3009, aged 49+ years. Complete blood count was measured from fasting blood samples taken at baseline examination, 1992-4. Retinal arteriolar and venular calibers were measured from digitized retinal photographs using a validated semi-automated computer program. RESULTS: All analyses adjusted for age, sex, systolic blood pressure, diabetes, smoking and fellow vessel caliber. Higher hematocrit, white cell count and platelet count were associated with narrower arteriolar caliber (p = 0.02, 0.03 and 0.001 respectively), while higher hemoglobin, hematocrit, red cell count, white cell count and platelet count were associated with wider venular caliber (p<0.0001 for all). Each quintile increase in hematocrit, white cell count and platelet count was associated with approximately 0.5 µm narrower arteriolar caliber; whereas each quintile increase in all of the complete blood count components was associated with approximately 1-2 µm wider venular caliber. CONCLUSIONS: These associations show that elevated levels of hematological indices can have adverse effects on the microcirculation.

Published
2014

43. Retinal vascular fractal dimension and risk of early diabetic retinopathy: A prospective study of children and adolescents with type 1 diabetes

Author

Jenkins, AJ, Shueh, WL, Cheung, N, Wang, JJ, Donaghue, KC, Liew, G, Islam, FMA, and Wong, TY

Subjects
Retinal Vessels - Physiopathology, Adolescent, Incidence, Patient Selection, Diabetes Mellitus, Type 1 - Complications - Physiopathology, Functional Laterality, Young Adult, Diabetic Retinopathy - Epidemiology - Physiopathology, Fractals, Risk Factors, Photography, Humans, Regression Analysis, Prospective Studies, Child, Follow-Up Studies, Proportional Hazards Models
Abstract

OBJECTIVE - To examine the prospective association of retinal vascular fractal dimension with diabetic retinopathy risk in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS - This was a hospital-based prospective study of 590 patients aged 12-20 years with type 1 diabetes free of retinopathy at baseline. All patients had seven-field retinal photographs taken of both eyes. Incident retinopathy was ascertained from retinal photographs taken at follow-up visits. Fractal dimension was measured from baseline photographs using a computer-based program following a standardized protocol. RESULTS - Over a mean ± SD follow-up period of 2.9 ± 2.0 years, 262 participants developed mild nonproliferative diabetic retinopathy (15.0 per 100 person-years). After adjusting for age, sex, diabetes duration, A1C, and other risk factors, we found no association between retinal vascular fractal dimension and incident retinopathy. CONCLUSIONS - Retinal vascular fractal dimension was not associated with incident early diabetic retinopathy in this sample of children and adolescents with type 1 diabetes. © 2009 by the American Diabetes Association., link_to_OA_fulltext

Published
2009

46. Left main coronary arterial endothelial function and heterogenous segmental epicardial vasomotor reactivity in vivo: novel insights with intravascular ultrasonography

Author

Puri, R., primary, Nicholls, S. J., additional, Brennan, D. M., additional, Andrews, J., additional, King, K. L., additional, Liew, G. Y., additional, Carbone, A., additional, Copus, B., additional, Nelson, A. J., additional, Kapadia, S. R., additional, Tuzcu, E. M., additional, Beltrame, J. F., additional, Worthley, S. G., additional, and Worthley, M. I., additional

Published
2014
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47. Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis

Author

Holliday, E.G. (Elizabeth), Smith, A.V. (Davey), Cornes, B.K. (Belinda), Buitendijk, G.H.S. (Gabrielle), Jensen, R.A. (Richard), Sim, X. (Xueling), Aspelund, T. (Thor), Aung, T. (Tin), Baird, P.N. (Paul), Boerwinkle, E.A. (Eric), Cheng, C-Y. (Ching-Yu), Duijn, C.M. (Cornelia) van, Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Hewit, A.W. (Alex), Inouye, M. (Michael), Jonasson, F. (Fridbert), Klein, B.E.K. (Barbara), Launer, L.J. (Lenore), Li, X. (Xiaohui), Liew, G. (Gerald), Lumley, T. (Thomas), McElduff, P. (Patrick), McKnight, B. (Barbara), Mitchell, P. (Paul), Psaty, B.M. (Bruce), Rochtchina, E. (Elena), Rotter, J.I. (Jerome), Scott, R.J. (Rodney), Tay, W.-T. (Wan-Ting), Taylor, K. (Kent), Teo, Y.Y. (Yik Ying), Uitterlinden, A.G. (André), Viswanathan, A. (Anand), Xie, S. (Sophia), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Tai, E.S. (Shyong), Siscovick, D.S. (David), Klein, R. (Ronald), Cotch, M.F. (Mary Frances), Wong, T.Y. (Tien Yin), Attia, J. (John), Wang, J.J. (Jie Jin), Holliday, E.G. (Elizabeth), Smith, A.V. (Davey), Cornes, B.K. (Belinda), Buitendijk, G.H.S. (Gabrielle), Jensen, R.A. (Richard), Sim, X. (Xueling), Aspelund, T. (Thor), Aung, T. (Tin), Baird, P.N. (Paul), Boerwinkle, E.A. (Eric), Cheng, C-Y. (Ching-Yu), Duijn, C.M. (Cornelia) van, Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Hewit, A.W. (Alex), Inouye, M. (Michael), Jonasson, F. (Fridbert), Klein, B.E.K. (Barbara), Launer, L.J. (Lenore), Li, X. (Xiaohui), Liew, G. (Gerald), Lumley, T. (Thomas), McElduff, P. (Patrick), McKnight, B. (Barbara), Mitchell, P. (Paul), Psaty, B.M. (Bruce), Rochtchina, E. (Elena), Rotter, J.I. (Jerome), Scott, R.J. (Rodney), Tay, W.-T. (Wan-Ting), Taylor, K. (Kent), Teo, Y.Y. (Yik Ying), Uitterlinden, A.G. (André), Viswanathan, A. (Anand), Xie, S. (Sophia), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Tai, E.S. (Shyong), Siscovick, D.S. (David), Klein, R. (Ronald), Cotch, M.F. (Mary Frances), Wong, T.Y. (Tien Yin), Attia, J. (John), and Wang, J.J. (Jie Jin)

Published
2013
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48. Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Author

Jensen, R.A. (Richard), Sim, X. (Xueling), Li, X. (Xiaohui), Cotch, M.F. (Mary Frances), Ikram, M.K. (Kamran), Holliday, E.G. (Elizabeth), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Jonasson, F. (Fridbert), Klein, B.E.K. (Barbara), Launer, L.J. (Lenore), Smith, A.V. (Albert Vernon), Boerwinkle, E.A. (Eric), Cheung, N. (Ning), Hewit, A.W. (Alex), Liew, G. (Gerald), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Attia, J. (John), Scott, R.J. (Rodney), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K. (Kent), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Tay, W.-T. (Wan-Ting), Teo, Y.Y. (Yik Ying), Seielstad, M. (Mark), Liu, J. (Jianjun), Cheng, C-Y. (Ching-Yu), Saw, S-M. (Seang-Mei), Aung, T. (Tin), Ganesh, S.K. (Santhi), O'Donnell, C.J. (Christopher), Nalls, M.A. (Michael), Wiggins, K.L. (Kerri), Kuo, J.Z. (Jane), Duijn, C.M. (Cornelia) van, Gudnason, V. (Vilmundur), Klein, R. (Ronald), Siscovick, D.S. (David), Rotter, J.I. (Jerome), Tai, E.S. (Shyong), Vingerling, J.R. (Hans), Wong, T.Y. (Tien Yin), Jensen, R.A. (Richard), Sim, X. (Xueling), Li, X. (Xiaohui), Cotch, M.F. (Mary Frances), Ikram, M.K. (Kamran), Holliday, E.G. (Elizabeth), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Jonasson, F. (Fridbert), Klein, B.E.K. (Barbara), Launer, L.J. (Lenore), Smith, A.V. (Albert Vernon), Boerwinkle, E.A. (Eric), Cheung, N. (Ning), Hewit, A.W. (Alex), Liew, G. (Gerald), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Attia, J. (John), Scott, R.J. (Rodney), Glazer, N.L. (Nicole), Lumley, T. (Thomas), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K. (Kent), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Tay, W.-T. (Wan-Ting), Teo, Y.Y. (Yik Ying), Seielstad, M. (Mark), Liu, J. (Jianjun), Cheng, C-Y. (Ching-Yu), Saw, S-M. (Seang-Mei), Aung, T. (Tin), Ganesh, S.K. (Santhi), O'Donnell, C.J. (Christopher), Nalls, M.A. (Michael), Wiggins, K.L. (Kerri), Kuo, J.Z. (Jane), Duijn, C.M. (Cornelia) van, Gudnason, V. (Vilmundur), Klein, R. (Ronald), Siscovick, D.S. (David), Rotter, J.I. (Jerome), Tai, E.S. (Shyong), Vingerling, J.R. (Hans), and Wong, T.Y. (Tien Yin)

Abstract

Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, 21.360.23 (beta 6 standard error), p=6.661029. Evidence suggests this was a false positive finding. The minor allele frequency was low (,2%), the quality of the imputation was moderate (r2 ,0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. Conclusions: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Published
2013
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49. Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Author

Mittal, B, Jensen, RA, Sim, X, Li, X, Cotch, MF, Ikram, MK, Holliday, EG, Eiriksdottir, G, Harris, TB, Jonasson, F, Klein, BEK, Launer, LJ, Smith, AV, Boerwinkle, E, Cheung, N, Hewitt, AW, Liew, G, Mitchell, P, Wang, JJ, Attia, J, Scott, R, Glazer, NL, Lumley, T, McKnight, B, Psaty, BM, Taylor, K, Hofman, A, de Jong, PTVM, Rivadeneira, F, Uitterlinden, AG, Tay, W-T, Teo, YY, Seielstad, M, Liu, J, Cheng, C-Y, Saw, S-M, Aung, T, Ganesh, SK, O'Donnell, CJ, Nalls, MA, Wiggins, KL, Kuo, JZ, van Duijn, CM, Gudnason, V, Klein, R, Siscovick, DS, Rotter, JI, Tai, ES, Vingerling, J, Wong, TY, Mittal, B, Jensen, RA, Sim, X, Li, X, Cotch, MF, Ikram, MK, Holliday, EG, Eiriksdottir, G, Harris, TB, Jonasson, F, Klein, BEK, Launer, LJ, Smith, AV, Boerwinkle, E, Cheung, N, Hewitt, AW, Liew, G, Mitchell, P, Wang, JJ, Attia, J, Scott, R, Glazer, NL, Lumley, T, McKnight, B, Psaty, BM, Taylor, K, Hofman, A, de Jong, PTVM, Rivadeneira, F, Uitterlinden, AG, Tay, W-T, Teo, YY, Seielstad, M, Liu, J, Cheng, C-Y, Saw, S-M, Aung, T, Ganesh, SK, O'Donnell, CJ, Nalls, MA, Wiggins, KL, Kuo, JZ, van Duijn, CM, Gudnason, V, Klein, R, Siscovick, DS, Rotter, JI, Tai, ES, Vingerling, J, and Wong, TY

Abstract

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Published
2013

50. Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Author

Jensen, RA, Sim, XL, Li, XH, Cotch, MF, Ikram, Kamran, Holliday, EG, Eiriksdottir, G, Harris, TB, Jonasson, F, Klein, BEK, Launer, LJ (Lenore), Smith, AV, Boerwinkle, E, Cheung, N, Hewitt, AW, Liew, G, Mitchell, P, Wang, JJ, Attia, J, Scott, R, Glazer, NL, Lumley, T, McKnight, B, Psaty, BM, Taylor, K, Hofman, Bert, de Jong, PTVM (Paulus), Rivadeneira, Fernando, Uitterlinden, André, Tay, WT, Teo, YY, Seielstad, M, Liu, JJ, Cheng, CY (Ching-Yu), Saw, SM, Aung, T, Ganesh, SK, O'Donnell, CJ, Nalls, MA, Wiggins, KL, Kuo, JZ, Duijn, Cornelia, Gudnason, V, Klein, R, Siscovick, DS, Rotter, JI, Tai, ES, Vingerling, Hans, Wong, TY (Tien Yin), Jensen, RA, Sim, XL, Li, XH, Cotch, MF, Ikram, Kamran, Holliday, EG, Eiriksdottir, G, Harris, TB, Jonasson, F, Klein, BEK, Launer, LJ (Lenore), Smith, AV, Boerwinkle, E, Cheung, N, Hewitt, AW, Liew, G, Mitchell, P, Wang, JJ, Attia, J, Scott, R, Glazer, NL, Lumley, T, McKnight, B, Psaty, BM, Taylor, K, Hofman, Bert, de Jong, PTVM (Paulus), Rivadeneira, Fernando, Uitterlinden, André, Tay, WT, Teo, YY, Seielstad, M, Liu, JJ, Cheng, CY (Ching-Yu), Saw, SM, Aung, T, Ganesh, SK, O'Donnell, CJ, Nalls, MA, Wiggins, KL, Kuo, JZ, Duijn, Cornelia, Gudnason, V, Klein, R, Siscovick, DS, Rotter, JI, Tai, ES, Vingerling, Hans, and Wong, TY (Tien Yin)

Published
2013

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