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1. Axial Length Distributions in Patients With Genetically Confirmed Inherited Retinal Diseases.

Author

Williams, KM, Georgiou, M, Kalitzeos, A, Chow, I, Hysi, PG, Robson, AG, Lingham, G, Chen, FK, Mackey, DA, Webster, AR, Hammond, CJ, Prokhoda, P, Carroll, J, Michaelides, M, Mahroo, OA, Williams, KM, Georgiou, M, Kalitzeos, A, Chow, I, Hysi, PG, Robson, AG, Lingham, G, Chen, FK, Mackey, DA, Webster, AR, Hammond, CJ, Prokhoda, P, Carroll, J, Michaelides, M, and Mahroo, OA

Abstract

PURPOSE: We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts. METHODS: AL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex). RESULTS: Measurements were available for 435 patients (median age, 19.5 years). Of 19 diseases, 10 had >10 participants: ABCA4 retinopathy; CNGB3- and CNGA3-associated achromatopsia; RPGR-associated disease; RPE65-associated disease; blue cone monochromacy (BCM); Bornholm eye disease (BED); TYR- and OCA2-associated oculocutaneous albinism; and GPR143-associated ocular albinism. Compared with the TwinsUK cohort (n = 322; median age, 65.1 years) and Raine Study cohort (n = 1335; median age, 19.9 years), AL distributions were wider in the IRD groups. Increased odds for longer ALs were observed for BCM, BED, RPGR, RPE65, OCA2, and TYR; increased odds for short AL were observed for RPE65, TYR, and GPR143. In subanalysis of RPGR-associated disease, longer average ALs occurred in cone-rod dystrophy (n = 5) than rod-cone dystrophy (P = 0.002). CONCLUSIONS: Several diseases showed increased odds for longer AL (highest OR with BCM); some showed increased odds for shorter AL (highest OR with GPR143). Patients with RPE65- and TYR-associated disease showed increased odds for longer and for shorter eyes. Albinism genes were associated with different effects on AL. These findings add to the phenotype of IRDs and may yield insights into mechanisms of refractive error development.

Published
2022

2. Low-concentration atropine eyedrops for myopia control in a multi-racial cohort of Australian children: A randomised clinical trial

Author

Lee, SS-Y, Lingham, G, Blaszkowska, M, Sanfilippo, PG, Koay, A, Franchina, M, Chia, A, Loughman, J, Flitcroft, DI, Hammond, CJ, Azuara-Blanco, A, Crewe, JM, Clark, A, Mackey, DA, Lee, SS-Y, Lingham, G, Blaszkowska, M, Sanfilippo, PG, Koay, A, Franchina, M, Chia, A, Loughman, J, Flitcroft, DI, Hammond, CJ, Azuara-Blanco, A, Crewe, JM, Clark, A, and Mackey, DA

Abstract

BACKGROUND: To test the hypothesis that 0.01% atropine eyedrops are a safe and effective myopia-control approach in Australian children. METHODS: Children (6-16 years; 49% Europeans, 18% East Asian, 22% South Asian, and 12% other/mixed ancestry) with documented myopia progression were enrolled into this single-centre randomised, parallel, double-masked, placebo-controlled trial and randomised to receive 0.01% atropine (n = 104) or placebo (n = 49) eyedrops (2:1 ratio) instilled nightly over 24 months (mean index age = 12.2 ± 2.5 and 11.2 ± 2.8 years, respectively). Outcome measures were the changes in spherical equivalent (SE) and axial length (AL) from baseline. RESULTS: At 12 months, the mean SE and AL change from baseline were -0.31D (95% confidence interval [CI] = -0.39 to -0.22) and 0.16 mm (95%CI = 0.13-0.20) in the atropine group and -0.53D (95%CI = -0.66 to -0.40) and 0.25 mm (95%CI = 0.20-0.30) in the placebo group (group difference p ≤ 0.01). At 24 months, the mean SE and AL change from baseline was -0.64D (95%CI = -0.73 to -0.56) and 0.34 mm (95%CI = 0.30-0.37) in the atropine group, and -0.78D (95%CI = -0.91 to -0.65) and 0.38 mm (95%CI = 0.33-0.43) in the placebo group. Group difference at 24 months was not statistically significant (p = 0.10). At 24 months, the atropine group had reduced accommodative amplitude and pupillary light response compared to the placebo group. CONCLUSIONS: In Australian children, 0.01% atropine eyedrops were safe, well-tolerated, and had a modest myopia-control effect, although there was an apparent decrease in efficacy between 18 and 24 months, which is likely driven by a higher dropout rate in the placebo group.

Published
2022

3. Time spent outdoors in childhood is associated with reduced risk of myopia as an adult

Author

Lingham, G, Yazar, S ; https://orcid.org/0000-0003-0994-6196, Lucas, RM, Milne, E, Hewitt, AW, Hammond, CJ, MacGregor, S, Rose, KA, Chen, FK, He, M, Guggenheim, JA, Clarke, MW, Saw, SM, Williams, C, Coroneo, MT ; https://orcid.org/0000-0002-3061-2011, Straker, L, Mackey, DA, Lingham, G, Yazar, S ; https://orcid.org/0000-0003-0994-6196, Lucas, RM, Milne, E, Hewitt, AW, Hammond, CJ, MacGregor, S, Rose, KA, Chen, FK, He, M, Guggenheim, JA, Clarke, MW, Saw, SM, Williams, C, Coroneo, MT ; https://orcid.org/0000-0002-3061-2011, Straker, L, and Mackey, DA

Abstract

Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.

Published
2021

4. IMI 2021 Yearly Digest

Author

Jong, M, Jonas, JB, Wolffsohn, JS, Berntsen, DA, Cho, P, Clarkson-Townsend, D, Flitcroft, DI, Gifford, KL, Haarman, AEG, Pardue, MT, Richdale, K, Sankaridurg, P, Tedja, MS, Wildsoet, CF, Bailey-Wilson, JE, Guggenheim, JA, Hammond, CJ, Kaprio, J, MacGregor, S, Mackey, DA, Musolf, AM, Klaver, CCW, Verhoeven, VJM, Vitart, V, Smith, EL, Jong, M, Jonas, JB, Wolffsohn, JS, Berntsen, DA, Cho, P, Clarkson-Townsend, D, Flitcroft, DI, Gifford, KL, Haarman, AEG, Pardue, MT, Richdale, K, Sankaridurg, P, Tedja, MS, Wildsoet, CF, Bailey-Wilson, JE, Guggenheim, JA, Hammond, CJ, Kaprio, J, MacGregor, S, Mackey, DA, Musolf, AM, Klaver, CCW, Verhoeven, VJM, Vitart, V, and Smith, EL

Abstract

PURPOSE: The International Myopia Institute (IMI) Yearly Digest highlights new research considered to be of importance since the publication of the first series of IMI white papers. METHODS: A literature search was conducted for articles on myopia between 2019 and mid-2020 to inform definitions and classifications, experimental models, genetics, interventions, clinical trials, and clinical management. Conference abstracts from key meetings in the same period were also considered. RESULTS: One thousand articles on myopia have been published between 2019 and mid-2020. Key advances include the use of the definition of premyopia in studies currently under way to test interventions in myopia, new definitions in the field of pathologic myopia, the role of new pharmacologic treatments in experimental models such as intraocular pressure-lowering latanoprost, a large meta-analysis of refractive error identifying 336 new genetic loci, new clinical interventions such as the defocus incorporated multisegment spectacles and combination therapy with low-dose atropine and orthokeratology (OK), normative standards in refractive error, the ethical dilemma of a placebo control group when myopia control treatments are established, reporting the physical metric of myopia reduction versus a percentage reduction, comparison of the risk of pediatric OK wear with risk of vision impairment in myopia, the justification of preventing myopic and axial length increase versus quality of life, and future vision loss. CONCLUSIONS: Large amounts of research in myopia have been published since the IMI 2019 white papers were released. The yearly digest serves to highlight the latest research and advances in myopia.

Published
2021

5. Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color

Author

Simcoe, M, Valdes, A, Liu, F, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, W, Kraft, P, Hammond, CJ, Shi, Y, Chen, Y, Zeng, C, Klaver, CCW, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Han, J, Mackey, DA, Martin, NG, Cheng, C-Y, Hinds, DA, Spector, TD, Kayser, M, Hysi, PG, Simcoe, M, Valdes, A, Liu, F, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, W, Kraft, P, Hammond, CJ, Shi, Y, Chen, Y, Zeng, C, Klaver, CCW, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Han, J, Mackey, DA, Martin, NG, Cheng, C-Y, Hinds, DA, Spector, TD, Kayser, M, and Hysi, PG

Abstract

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

Published
2021

6. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Author

Hauser, MA, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, Khawaja, AP, Hauser, MA, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, and Khawaja, AP

Abstract

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Published
2021

7. A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Author

Hardcastle, AJ, Liskova, P, Bykhovskaya, Y, McComish, BJ, Davidson, AE, Inglehearn, CF, Li, X, Choquet, H, Habeeb, M, Lucas, SEM, Sahebjada, S, Pontikos, N, Lopez, KER, Khawaja, AP, Ali, M, Dudakova, L, Skalicka, P, Van Dooren, BTH, Geerards, AJM, Haudum, CW, Lo Faro, V, Tenen, A, Simcoe, MJ, Patasova, K, Yarrand, D, Yin, J, Siddiqui, S, Rice, A, Farraj, LA, Chen, Y-DI, Rahi, JS, Krauss, RM, Theusch, E, Charlesworth, JC, Szczotka-Flynn, L, Toomes, C, Meester-Smoor, MA, Richardson, AJ, Mitchell, PA, Taylor, KD, Melles, RB, Aldave, AJ, Mills, RA, Cao, K, Chan, E, Daniell, MD, Wang, JJ, Rotter, JI, Hewitt, AW, MacGregor, S, Klaver, CCW, Ramdas, WD, Craig, JE, Iyengar, SK, O'Brart, D, Jorgenson, E, Baird, PN, Rabinowitz, YS, Burdon, KP, Hammond, CJ, Tuft, SJ, Hysi, PG, Hardcastle, AJ, Liskova, P, Bykhovskaya, Y, McComish, BJ, Davidson, AE, Inglehearn, CF, Li, X, Choquet, H, Habeeb, M, Lucas, SEM, Sahebjada, S, Pontikos, N, Lopez, KER, Khawaja, AP, Ali, M, Dudakova, L, Skalicka, P, Van Dooren, BTH, Geerards, AJM, Haudum, CW, Lo Faro, V, Tenen, A, Simcoe, MJ, Patasova, K, Yarrand, D, Yin, J, Siddiqui, S, Rice, A, Farraj, LA, Chen, Y-DI, Rahi, JS, Krauss, RM, Theusch, E, Charlesworth, JC, Szczotka-Flynn, L, Toomes, C, Meester-Smoor, MA, Richardson, AJ, Mitchell, PA, Taylor, KD, Melles, RB, Aldave, AJ, Mills, RA, Cao, K, Chan, E, Daniell, MD, Wang, JJ, Rotter, JI, Hewitt, AW, MacGregor, S, Klaver, CCW, Ramdas, WD, Craig, JE, Iyengar, SK, O'Brart, D, Jorgenson, E, Baird, PN, Rabinowitz, YS, Burdon, KP, Hammond, CJ, Tuft, SJ, and Hysi, PG

Abstract

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Published
2021

8. Change in the prevalence of myopia in Australian middle-aged adults across 20 years

Author

Mackey, DA, Lingham, G, Lee, SS-Y, Hunter, M, Wood, D, Hewitt, AW, Mitchell, P, Taylor, HR, Hammond, CJ, Yazar, S, Mackey, DA, Lingham, G, Lee, SS-Y, Hunter, M, Wood, D, Hewitt, AW, Mitchell, P, Taylor, HR, Hammond, CJ, and Yazar, S

Abstract

BACKGROUND: The prevalence of myopia is increasing globally including in Europe and parts of Asia but Australian data are lacking. This study aim described the change in myopia prevalence in middle-aged Australian adults over approximately a 20-year period. METHODS: Two contemporary Western Australian studies (conducted in mid-late 2010s): the coastal-regional Busselton Healthy Ageing Study (BHAS) and the urban Gen1 of the Raine Study (G1RS) were compared to two earlier studies (early-mid 1990s) in Australia: the urban Blue Mountains Eye Study (BMES) and urban/regional Melbourne Visual Impairment Project (MVIP). Refractive error was measured by autorefraction, vertometry, or subjective refraction. Participants (49-70 years) of European descent without self-reported/diagnosed cataract, corneal disease, or refractive or corneal surgery were included. RESULTS: After exclusions, data were available from 2217, 1760, 700, 2987 and 756 participants from BMES, urban MVIP, regional MVIP, BHAS, and G1RS, respectively. The mean age ranged from 57.1 ± 4.6 years in the G1RS to 60.1 ± 6.0 years in the BMES; 44-48% of participants were male. When stratified by location, the contemporary urban G1RS cohort had a higher age-standardised myopia prevalence than the urban MVIP and BMES cohorts (29.2%, 16.4%, and 23.9%, p < 0.001). The contemporary coastal-regional BHAS had a higher age-standardised myopia prevalence than the regional MVIP cohort (19.4% vs. 13.8%, p = 0.001). CONCLUSIONS: We report an increase in myopia prevalence in older adults in Australia born after World War ll compared to cohorts born before, accounting for urban/regional location. The prevalence of myopia remains relatively low in middle-aged Australian adults.

Published
2021

9. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images (vol 17, e1009497, 2021)

Author

Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, Khawaja, AP, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, and Khawaja, AP

Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Published
2021

11. Association Between Polygenic Risk Score and Risk of Myopia

Author

Mojarrad, NG, Plotnikov, D, Williams, C, Guggenheim, JA, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Keane, PA, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Mojarrad, NG, Plotnikov, D, Williams, C, Guggenheim, JA, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Keane, PA, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, K, Woodside, JV, Yates, MM, Yip, J, and Zheng, Y

Abstract

IMPORTANCE: Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. OBJECTIVES: To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. DESIGN, SETTING, AND PARTICIPANTS: Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to -0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to -5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). RESULTS: A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95%

Published
2020

12. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author

Yonova-Doing, E, Zhao, W, Igo, RP, Wang, C, Sundaresan, P, Lee, KE, Jun, GR, Alves, AC, Chai, X, Chan, ASY, Lee, MC, Fong, A, Tan, AG, Khor, CC, Chew, EY, Hysi, PG, Fan, Q, Chua, J, Chung, J, Liao, J, Colijn, JM, Burdon, KP, Fritsche, LG, Swift, MK, Hilmy, MH, Chee, ML, Tedja, M, Bonnemaijer, PWM, Gupta, P, Tan, QS, Li, Z, Vithana, EN, Ravindran, RD, Chee, S-P, Shi, Y, Liu, W, Su, X, Sim, X, Shen, Y, Wang, YX, Li, H, Tham, Y-C, Teo, YY, Aung, T, Small, KS, Mitchell, P, Jonas, JB, Wong, TY, Fletcher, AE, Klaver, CCW, Klein, BEK, Wang, JJ, Iyengar, SK, Hammond, CJ, Cheng, C-Y, Yonova-Doing, E, Zhao, W, Igo, RP, Wang, C, Sundaresan, P, Lee, KE, Jun, GR, Alves, AC, Chai, X, Chan, ASY, Lee, MC, Fong, A, Tan, AG, Khor, CC, Chew, EY, Hysi, PG, Fan, Q, Chua, J, Chung, J, Liao, J, Colijn, JM, Burdon, KP, Fritsche, LG, Swift, MK, Hilmy, MH, Chee, ML, Tedja, M, Bonnemaijer, PWM, Gupta, P, Tan, QS, Li, Z, Vithana, EN, Ravindran, RD, Chee, S-P, Shi, Y, Liu, W, Su, X, Sim, X, Shen, Y, Wang, YX, Li, H, Tham, Y-C, Teo, YY, Aung, T, Small, KS, Mitchell, P, Jonas, JB, Wong, TY, Fletcher, AE, Klaver, CCW, Klein, BEK, Wang, JJ, Iyengar, SK, Hammond, CJ, and Cheng, C-Y

Abstract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

Published
2020

13. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Q, Pozarickij, A, Tan, NYQ, Guo, X, Verhoeven, VJM, Vitart, V, Guggenheim, JA, Miyake, M, Tideman, JWL, Khawaja, AP, Zhang, L, MacGregor, S, Hoehn, R, Chen, P, Biino, G, Wedenoja, J, Saffari, SE, Tedja, MS, Xie, J, Lanca, C, Wang, YX, Sahebjada, S, Mazur, J, Mirshahi, A, Martin, NG, Yazar, S, Pennell, CE, Yap, M, Haarman, AEG, Enthoven, CA, Polling, J, Hewitt, AW, Jaddoe, VWV, van Duijn, CM, Hayward, C, Polasek, O, Tai, E-S, Yoshikatsu, H, Hysi, PG, Young, TL, Tsujikawa, A, Wang, JJ, Mitchell, P, Pfeiffer, N, Parssinen, O, Foster, PJ, Fossarello, M, Yip, SP, Williams, C, Hammond, CJ, Jonas, JB, He, M, Mackey, DA, Wong, T-Y, Klaver, CCW, Saw, S-M, Baird, PN, Cheng, C-Y, Fan, Q, Pozarickij, A, Tan, NYQ, Guo, X, Verhoeven, VJM, Vitart, V, Guggenheim, JA, Miyake, M, Tideman, JWL, Khawaja, AP, Zhang, L, MacGregor, S, Hoehn, R, Chen, P, Biino, G, Wedenoja, J, Saffari, SE, Tedja, MS, Xie, J, Lanca, C, Wang, YX, Sahebjada, S, Mazur, J, Mirshahi, A, Martin, NG, Yazar, S, Pennell, CE, Yap, M, Haarman, AEG, Enthoven, CA, Polling, J, Hewitt, AW, Jaddoe, VWV, van Duijn, CM, Hayward, C, Polasek, O, Tai, E-S, Yoshikatsu, H, Hysi, PG, Young, TL, Tsujikawa, A, Wang, JJ, Mitchell, P, Pfeiffer, N, Parssinen, O, Foster, PJ, Fossarello, M, Yip, SP, Williams, C, Hammond, CJ, Jonas, JB, He, M, Mackey, DA, Wong, T-Y, Klaver, CCW, Saw, S-M, Baird, PN, and Cheng, C-Y

Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2020

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

Author

Craig, JE, Han, X, Qassim, A, Hassall, M, Bailey, JNC, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J-S, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-Smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW, MacGregor, S, Craig, JE, Han, X, Qassim, A, Hassall, M, Bailey, JNC, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J-S, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-Smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW, and MacGregor, S

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.

Published
2020

15. Associations Between Fetal Growth Trajectories and the Development of Myopia by 20 Years of Age

Author

Dyer, KIC, Sanfilippo, PG, White, SW, Guggenheim, JA, Hammond, CJ, Newnham, JP, Mackey, DA, Yazar, S, Dyer, KIC, Sanfilippo, PG, White, SW, Guggenheim, JA, Hammond, CJ, Newnham, JP, Mackey, DA, and Yazar, S

Abstract

PURPOSE: To evaluate the contribution of genetic and early life environmental factors, as reflected by fetal anthropometric growth trajectories, toward the development of myopia during childhood and adolescence. METHODS: This analysis included 498 singleton Caucasian participants from the Raine Study, a pregnancy cohort study based in Western Australia. Serial fetal biometric measurements of these participants were collected via ultrasound scans performed at 18, 24, 28, 34, and 38 weeks' gestation. At a 20-year follow-up, the participants underwent a comprehensive ophthalmic examination, including cycloplegic autorefraction and ocular biometry measurements. Using a group-based trajectory modeling approach, we identified groups of participants with similar growth trajectories based on measurements of fetal head circumference (HC), abdominal circumference, femur length (FL), and estimated fetal weight (EFW). Differences between trajectory groups with respect to prevalence of myopia, axial length (AL), and corneal radius of curvature measured at the 20-year follow-up were evaluated via logistic regression and analysis of variance. RESULTS: Prevalence of myopia was highest among participants with consistently short or consistently long FLs (P = 0.04). There was also a trend toward increased prevalence with larger HC in late gestation, although not at a statistically significant level. Trajectory groups reflecting faster HC, FL, or EFW growth correlated with significantly flatter corneas (P = 0.03, P = 0.04, and P = 0.01, respectively) and a general, but not statistically significant, increase in AL. CONCLUSIONS: Environmental or genetic factors influencing intrauterine skeletal growth may concurrently affect ocular development, with effects persisting into adulthood.

Published
2020

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

Author

Charng, J, Simcoe, M, Sanfilippo, PG, Allingham, RR, Hewitt, AW, Hammond, CJ, Mackey, DA, Yazar, S, Charng, J, Simcoe, M, Sanfilippo, PG, Allingham, RR, Hewitt, AW, Hammond, CJ, Mackey, DA, and Yazar, S

Abstract

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.

Published
2020

17. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Hysi, PG, Choquet, H, Khawaja, AP, Wojciechowski, R, Tedja, MS, Yin, J, Simcoe, MJ, Patasova, K, Mahroo, OA, Thai, KK, Cumberland, PM, Melles, RB, Verhoeven, VJM, Vitart, V, Segre, A, Stone, RA, Wareham, N, Hewitt, AW, Mackey, DA, Klaver, CCW, MacGregor, S, Khaw, PT, Foster, PJ, Guggenheim, JA, Rahi, JS, Jorgenson, E, Hammond, CJ, Hysi, PG, Choquet, H, Khawaja, AP, Wojciechowski, R, Tedja, MS, Yin, J, Simcoe, MJ, Patasova, K, Mahroo, OA, Thai, KK, Cumberland, PM, Melles, RB, Verhoeven, VJM, Vitart, V, Segre, A, Stone, RA, Wareham, N, Hewitt, AW, Mackey, DA, Klaver, CCW, MacGregor, S, Khaw, PT, Foster, PJ, Guggenheim, JA, Rahi, JS, Jorgenson, E, and Hammond, CJ

Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Published
2020

18. Western Australia Atropine for the Treatment of Myopia (WA-ATOM) study: Rationale, methodology and participant baseline characteristics

Author

Lee, SSY, Mackey, DA, Lingham, G, Crewe, JM, Chen, FK, Charng, J, Ng, F, Flitcroft, I, Loughman, JJ, Azuara-Blanco, A, Logan, NS, Hammond, CJ, Chia, A, Richards, MD, Truong, TT, Clark, A, Lee, SSY, Mackey, DA, Lingham, G, Crewe, JM, Chen, FK, Charng, J, Ng, F, Flitcroft, I, Loughman, JJ, Azuara-Blanco, A, Logan, NS, Hammond, CJ, Chia, A, Richards, MD, Truong, TT, and Clark, A

Abstract

IMPORTANCE: Atropine eyedrops are a promising treatment for slowing myopia progression in East Asian children. However, its effects on children in Australia, including those of non-Asian background, have not been well-studied. BACKGROUND: The Western Australia Atropine for the Treatment of Myopia (WA-ATOM) study aims to determine the efficacy and long-term effects of low-dose atropine eyedrops in myopia control. This paper describes the study rationale, methodology and participant baseline characteristics. DESIGN: Single-centre, double-masked, randomized controlled trial. PARTICIPANTS: Children (6-16 years) with spherical equivalent ≤-1.50 D in each eye, astigmatism ≤1.50 D and myopia progression by ≥0.50 D/year. METHODS: Enrolled children were randomly assigned 2:1 to receive 0.01% atropine or placebo eyedrops. Participants are examined every 6 months during first 3 years of the study (2-year treatment phase followed by a 1-year washout phase), and then at a 5-year follow-up (2 years after the end of the washout phase). MAIN OUTCOME MEASURES: Annual progression rate of myopia and axial length, tolerability to eyedrops and incidence and severity of unwanted effects. RESULTS: Out of 311 children who were referred, 242 were suitable for study participation, and 153 were subsequently enrolled. The baseline characteristics of enrolled participants are presented. CONCLUSIONS AND RELEVANCE: Outcomes of the WA-ATOM study will inform on the efficacy, tolerability, safety and long-term effects of low-dose atropine eyedrops in myopia control in Australian children. The impact of ocular sun exposure, iris colour and parental myopia on the efficacy of low-dose atropine will also be assessed.

Published
2020

19. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Grp, BMES-G, Consortium, N, and Control, WTC

Subjects
Lumican, genetic structures, Fibrillin-1, General Physics and Astronomy, Gene Expression, Q1, Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, Myopia, Link (knot theory), lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Corneal Dystrophies, Hereditary, Multidisciplinary, Eye Diseases, Hereditary, symbols, NEIGHBORHOOD consortium, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Proteoglycans, Decorin, Glaucoma, Open-Angle, Science, Quantitative Trait Loci, Computational biology, Biology, Keratoconus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, symbols.namesake, Transforming Growth Factor beta2, Quantitative Trait, Heritable, Asian People, Genome-Wide Association Analysis, Humans, Author Correction, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, Human, Wellcome Trust Case Control Consortium 2, Blue Mountains Eye Study - GWAS group, General Chemistry, Mendelian Randomization Analysis, R1, eye diseases, Mendelian inheritance, Ehlers-Danlos Syndrome, lcsh:Q, sense organs, Genome-Wide Association Study
Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation., Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.

Published
2019
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20. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium

Author

Yao, Y-G, Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, V, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, Saw, S-M, Yao, Y-G, Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, V, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, and Saw, S-M

Abstract

PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). RESULTS: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. CONCLUSIONS: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

Published
2019

21. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium (vol 14, e0220143, 2019)

Author

Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, VJM, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, Saw, S-M, Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, VJM, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, and Saw, S-M

Abstract

[This corrects the article DOI: 10.1371/journal.pone.0220143.].

Published
2019

22. Associations with photoreceptor thickness measures in the UK Biobank

Author

Chua, SYL, Dhillon, B, Aslam, T, Balaskas, K, Yang, Q, Keane, PA, Tufail, A, Reisman, C, Foster, PJ, Patel, PJ, Bishop, P, Barman, SA, Barrett, JH, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Sudlow, C, Dick, AD, Egan, C, Ennis, S, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Macgillivray, T, Mackie, S, Martin, K, Mcgaughey, M, Mcguinness, B, Mckay, GJ, Mckibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnicka, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Thaung, C, Thomas, D, Trucco, E, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, J, Yates, MM, Yip, J, Zheng, Y, Tapp, R, Chua, SYL, Dhillon, B, Aslam, T, Balaskas, K, Yang, Q, Keane, PA, Tufail, A, Reisman, C, Foster, PJ, Patel, PJ, Bishop, P, Barman, SA, Barrett, JH, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Sudlow, C, Dick, AD, Egan, C, Ennis, S, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Macgillivray, T, Mackie, S, Martin, K, Mcgaughey, M, Mcguinness, B, Mckay, GJ, Mckibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnicka, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Thaung, C, Thomas, D, Trucco, E, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, J, Yates, MM, Yip, J, Zheng, Y, and Tapp, R

Abstract

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness.

Published
2019

23. IMI - Myopia Genetics Report

Author

Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, Zhou, X, Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, and Zhou, X

Abstract

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.

Published
2019

24. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author

Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, van Duijn, CM, Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, and van Duijn, CM

Abstract

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019

25. Cohort profile: design and methods in the eye and vision consortium of UK Biobank

Author

Chua, SYL, Thomas, D, Allen, N, Lotery, A, Desai, P, Patel, P, Muthy, Z, Sudlow, C, Peto, T, Khaw, PT, Foster, PJ, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Keane, PA, Khawaja, AP, Lascaratos, G, Lotery, AJ, Gillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, McKay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Chua, SYL, Thomas, D, Allen, N, Lotery, A, Desai, P, Patel, P, Muthy, Z, Sudlow, C, Peto, T, Khaw, PT, Foster, PJ, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Keane, PA, Khawaja, AP, Lascaratos, G, Lotery, AJ, Gillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, McKay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, and Zheng, Y

Abstract

PURPOSE: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. PARTICIPANTS: UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc-macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun. FINDINGS TO DATE: A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process. FUTURE PLANS: UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and sample collection will be performed in subsets of 25 000 participants every 2-3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to inves

Published
2019

26. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)

Author

Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, and Whittaker, P

Abstract

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

27. Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development

Author

Pozarickij, A, Williams, C, Hysi, PG, Guggenheim, JA, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Mac Gillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, McKay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, K, Woodside, J, Yates, MM, Yip, J, Zheng, Y, Pozarickij, A, Williams, C, Hysi, PG, Guggenheim, JA, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Mac Gillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, McKay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, K, Woodside, J, Yates, MM, Yip, J, and Zheng, Y

Abstract

A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P < 1.1 × 10-4) and 128 (88%) at nominal significance (P < 0.05). LAMA2 variant rs12193446, for example, had an effect size varying from -0.20 diopters (95% CI -0.18 to -0.23) to -0.89 diopters (95% CI -0.71 to -1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive.

Published
2019

28. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium

Author

Wong, YL, Hysi, P, Cheung, G, Tedja, Milly, Hoang, QV, Tompson, SW, Whisenhunt, KN, Verhoeven, Virginie, Zhao, WT, Hess, M, Wong, CW, Kifley, A, Hosoda, Y, Haarman, Annet, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, TY, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, CY (Ching-Yu), Yamashiro, K, Young, TL, Klaver, Caroline, Saw, SM, Wong, YL, Hysi, P, Cheung, G, Tedja, Milly, Hoang, QV, Tompson, SW, Whisenhunt, KN, Verhoeven, Virginie, Zhao, WT, Hess, M, Wong, CW, Kifley, A, Hosoda, Y, Haarman, Annet, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, TY, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, CY (Ching-Yu), Yamashiro, K, Young, TL, Klaver, Caroline, and Saw, SM

Published
2019

29. A genome-wide association study for corneal astigmatism: The CREAM Consortium

Author

Shah, Rupal, Li, Q, Zhao, W, Tedja, MS, Tideman, WL, Khawaja, A, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Pärssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Höhn, R, Baird, PN, Wong, TY, Cheng, C, Teo, YY, Mackey, DA, Williams, C, Saw, S, Klaver, CCW, Guggenheim, Jeremy, Bailey-Wilson, JE, and The CREAM Consortium

Abstract

Purpose: To identify genes and genetic markers associated with corneal astigmatism.\ud Methods: A meta-analysis was performed of genome-wide association studies (GWAS) of corneal astigmatism undertaken for 14 European ancestry (N = 22,250) and 8 Asian ancestry (N = 9,120) cohorts by the CREAM Consortium. Cases were defined as having >0.75 D of corneal astigmatism. For the meta-analysed results of European ancestry cohorts, subsequent gene-based and gene-set analyses were performed using VEGAS2 and MAGMA software. Additionally, estimates of SNP-based heritability for corneal and refractive astigmatism and spherical equivalent were calculated for Europeans using LD score regression.\ud Results: Meta-analysis of all cohorts identified a genome-wide significant locus near the gene PDGFRA (platelet derived growth factor receptor alpha): top SNP: rs7673984, odds ratio = 1.12 (95% CI: 1.08-1.16), P = 5.55 x 10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified 3 novel candidate genes for corneal astigmatism in Europeans: CLDN7 (claudin-7), ACP2 (acid phosphatase 2, lysosomal) and TNFAIP8L3 (TNF alpha induced protein 8 like 3).\ud Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified 3 novel candidate genes CLDN7, ACP2 and TNFAIP8L3 that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors to the development of astigmatism.

Published
2018

30. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author

Tedja, MS, Wojciechowski, R, Hysi, PG, Eriksson, N, Furlotte, NA, Verhoeven, VJM, Iglesias, AI, Meester-Smoor, MA, Tompson, SW, Fan, Q, Khawaja, AP, Cheng, C-Y, Höhn, R, Yamashiro, K, Wenocur, A, Grazal, C, Haller, T, Metspalu, A, Wedenoja, J, Jonas, JB, Wang, YX, Xie, J, Mitchell, P, Foster, PJ, Klein, BEK, Klein, R, Paterson, AD, Hosseini, SM, Shah, RL, Williams, C, Teo, YY, Tham, YC, Gupta, P, Zhao, W, Shi, Y, Saw, W-Y, Tai, E-S, Sim, XL, Huffman, JE, Polašek, O, Hayward, C, Bencic, G, Rudan, I, Wilson, JF, Consortium, Cream, Team, 23Andme Research, Consortium, Uk Biobank Eye And Vision, Joshi, PK, Tsujikawa, A, Matsuda, F, Whisenhunt, KN, Zeller, T, Van Der Spek, PJ, Haak, R, Meijers-Heijboer, H, Van Leeuwen, EM, Iyengar, SK, Lass, JH, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Vingerling, JR, Lehtimäki, T, Raitakari, OT, Biino, G, Concas, MP, Schwantes-An, T-H, Igo, RP, Cuellar-Partida, G, Martin, NG, Craig, JE, Gharahkhani, P, Williams, KM, Nag, A, Rahi, JS, Cumberland, PM, Delcourt, C, Bellenguez, C, Ried, JS, Bergen, AA, Meitinger, T, Gieger, C, Wong, TY, Hewitt, AW, Mackey, DA, Simpson, CL, Pfeiffer, N, Pärssinen, O, Baird, PN, Vitart, V, Amin, N, Van Duijn, CM, Bailey-Wilson, JE, Young, TL, Saw, S-M, Stambolian, D, Macgregor, S, Guggenheim, JA, Tung, JY, Hammond, CJ, Klaver, CCW, Netherlands Institute for Neuroscience (NIN), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Pediatric surgery, Tedja, Milly S [0000-0003-0356-9684], Hysi, Pirro G [0000-0001-5752-2510], Verhoeven, Virginie JM [0000-0001-7359-7862], Iglesias, Adriana I [0000-0001-5532-764X], Tompson, Stuart W [0000-0001-9788-6730], Khawaja, Anthony P [0000-0001-6802-8585], Yamashiro, Kenji [0000-0001-9354-8558], Wedenoja, Juho [0000-0002-6155-0378], Jonas, Jost B [0000-0003-2972-5227], Wang, Ya Xing [0000-0003-2749-7793], Foster, Paul J [0000-0002-4755-177X], Klein, Ronald [0000-0002-4428-6237], Shah, Rupal L [0000-0001-8789-8869], Hayward, Caroline [0000-0002-9405-9550], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Joshi, Peter K [0000-0002-6361-5059], Whisenhunt, Kristina N [0000-0003-2412-7666], Rivadeneira, Fernando [0000-0001-9435-9441], Biino, Ginevra [0000-0002-9936-946X], Gharahkhani, Puya [0000-0002-4203-5952], Williams, Katie M [0000-0003-4596-3938], Delcourt, Cécile [0000-0002-2099-0481], Bellenguez, Céline [0000-0002-1240-7874], Hewitt, Alex W [0000-0002-5123-5999], Baird, Paul N [0000-0002-1305-3502], Bailey-Wilson, Joan E [0000-0002-9153-2920], Young, Terri L [0000-0001-6994-9941], Guggenheim, Jeremy A [0000-0001-5164-340X], Hammond, Christopher J [0000-0002-3227-2620], Klaver, Caroline CW [0000-0002-2355-5258], Apollo - University of Cambridge Repository, Epidemiology, Ophthalmology, Clinical Genetics, Pathology, Internal Medicine, Graduate School, Human Genetics, Experimental Immunology, ANS - Complex Trait Genetics, and ARD - Amsterdam Reproduction and Development

Subjects
0301 basic medicine, Adult, Male, Cell type, ResearchInstitutes_Networks_Beacons/MICRA, In silico, taittovirheet, Genome-wide association study, Retinal Pigment Epithelium, Biology, Blindness, Polymorphism, Single Nucleotide, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Retina, White People, 03 medical and health sciences, HIGH-GRADE MYOPIA, RETINAL-PIGMENT EPITHELIUM, SEROTONIN PATHWAY GENES, FORM-DEPRIVATION MYOPIA, COMMON VARIANTS, OCULAR GROWTH, RETINITIS-PIGMENTOSA, GENOTYPE IMPUTATION, MISSENSE MUTATIONS, DOPAMINE-RECEPTORS, Asian People, refractive errors, Retinitis pigmentosa, Genetics, medicine, Myopia, Journal Article, Humans, Genetic Predisposition to Disease, 610 Medicine & health, Regulation of gene expression, Retinal pigment epithelium, medicine.disease, Refractive Errors, 030104 developmental biology, medicine.anatomical_structure, Manchester Institute for Collaborative Research on Ageing, Gene Expression Regulation, genetic factors, Eye disorder, Female, sense organs, geneettiset tekijät, Neuroscience, Genome-Wide Association Study, Signal Transduction
Abstract

Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300 mM SM for 1 h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50 mu M BER for 24 h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate-kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies.

Published
2018
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31. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, and MacGregor, S

Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Published
2018

32. A genome-wide association study of corneal astigmatism: The CREAM Consortium

Author

Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, Bailey-Wilson, JE, Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, and Bailey-Wilson, JE

Abstract

PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Published
2018

33. Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations

Author

Bonnemaijer, Pieter, Iglesias Gonzalez, Adriana, Nadkarni, GN, Sanyiwa, AJ, Hassan, HG, Cook, C, Simcoe, M, Taylor, KD, Schurmann, C, Belbin, GM, Kenny, EE, Bottinger, EP, van de Laar, S, Wiliams, SEI, Akafo, SK, Ashaye, AO, Zangwill, LM, Girkin, CA, Ng, MCY, Rotter, JI, Weinreb, RN, Li, Z, Allingham, RR, Nag, A, Hysi, PG, Meester - Smoor, Magda, Wiggs, JL, Hauser, MA, Hammond, CJ, Lemij, HG, Loos, RJF, Duijn, Cornelia, Thiadens, Alberta, Klaver, Caroline, Bonnemaijer, Pieter, Iglesias Gonzalez, Adriana, Nadkarni, GN, Sanyiwa, AJ, Hassan, HG, Cook, C, Simcoe, M, Taylor, KD, Schurmann, C, Belbin, GM, Kenny, EE, Bottinger, EP, van de Laar, S, Wiliams, SEI, Akafo, SK, Ashaye, AO, Zangwill, LM, Girkin, CA, Ng, MCY, Rotter, JI, Weinreb, RN, Li, Z, Allingham, RR, Nag, A, Hysi, PG, Meester - Smoor, Magda, Wiggs, JL, Hauser, MA, Hammond, CJ, Lemij, HG, Loos, RJF, Duijn, Cornelia, Thiadens, Alberta, and Klaver, Caroline

Published
2018

34. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, Macgregor, S, Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, and Macgregor, S

Published
2018

35. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author

Bailey, JNC, Loomis, SJ, Kang, JH, Allingham, RR, Gharahkhani, P, Khor, CC, Burdon, KP, Aschard, H, Chasman, DI, Igo, RP, Hysi, PG, Glastonbury, CA, Ashley-Koch, A, Brilliant, M, Brown, AA, Budenz, DL, Buil, A, Cheng, CY, Choi, H, Christen, WG, Curhan, G, De Vivo, I, Fingert, JH, Foster, PJ, Fuchs, C, Gaasterland, D, Gaasterland, T, Hewitt, AW, Hu, F, Hunter, DJ, Khawaja, AP, Lee, RK, Li, Z, Lichter, PR, Mackey, DA, McGuffin, P, Mitchell, P, Moroi, SE, Perera, SA, Pepper, KW, Qi, Q, Realini, T, Richards, JE, Ridker, PM, Rimm, E, Ritch, R, Ritchie, M, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Tamimi, RM, Topouzis, F, Viswanathan, AC, Verma, SS, Vollrath, D, Wang, JJ, Weisschuh, N, Wissinger, B, Wollstein, G, Wong, TY, Yaspan, BL, Zack, DJ, Zhang, K, Weinreb, RN, Pericak-Vance, MA, Small, K, Hammond, CJ, Aung, T, Liu, Y, Vithana, EN, MacGregor, S, Craig, JE, Kraft, P, Howell, G, Hauser, MA, and Pasquale, LR

Subjects
ANZRAG Consortium
Abstract

© 2016 Nature America, Inc. Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Published
2016
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36. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Author

Fan, Q, Guo, X, Tideman, Willem, Williams, KM, Yazar, S, Hosseini, SM, Howe, LD, St Pourcain, B, Evans, DM, Timpson, NJ, McMahon, G, Hysi, PG, Krapohl, E, Wang, YX, Jonas, JB, Baird, PN, Wang, JJ, Cheng, CY (Ching-Yu), Teo, YY, Wong, TY, Ding, X, Wojciechowski, R, Young, TL, Parssinen, O, Oexle, K, Pfeiffer, N, Bailey-Wilson, JE, Paterson, AD, Klaver, Caroline, Plomin, R, Hammond, CJ, Mackey, DA, He, MG, Saw, SM, Williams, C, Guggenheim, JA, Epidemiology, and Ophthalmology

Subjects
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Abstract

Contains fulltext : 167190.pdf (Publisher’s version ) (Open Access) Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Published
2016

37. Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study

Author

Cuellar-Partida, G, Williams, KM, Yazar, S, Guggenheim, JA, Hewitt, AW, Williams, C, Wang, JJ, Kho, P-F, Saw, SM, Cheng, C-Y, Wong, TY, Aung, T, Young, TL, Tideman, JWL, Jonas, JB, Mitchell, P, Wojciechowski, R, Stambolian, D, Hysi, P, Hammond, CJ, Mackey, DA, Lucas, RM, MacGregor, S, Cuellar-Partida, G, Williams, KM, Yazar, S, Guggenheim, JA, Hewitt, AW, Williams, C, Wang, JJ, Kho, P-F, Saw, SM, Cheng, C-Y, Wong, TY, Aung, T, Young, TL, Tideman, JWL, Jonas, JB, Mitchell, P, Wojciechowski, R, Stambolian, D, Hysi, P, Hammond, CJ, Mackey, DA, Lucas, RM, and MacGregor, S

Abstract

BACKGROUND: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. METHODS: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS. RESULTS: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. CONCLUSIONS: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.

Published
2017

38. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Author

Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, and Macgregor, S

Published
2017

39. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author

Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, Iggc, Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, and Iggc

Published
2017

41. Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Author

Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, Zeggini, E, Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, and Zeggini, E

Published
2017

42. 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

43. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author

Springelkamp, H, Mishra, A, Hysi, PG, Gharahkhani, P, Höhn, R, Khor, CC, Cooke Bailey, JN, Luo, X, Ramdas, WD, Vithana, E, Koh, V, Yazar, S, Xu, L, Forward, H, Kearns, LS, Amin, N, Iglesias, AI, Sim, KS, van Leeuwen, EM, Demirkan, A, van der Lee, S, Loon, SC, Rivadeneira, F, Nag, A, Sanfilippo, PG, Schillert, A, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Zhou, T, Burdon, KP, Spector, TD, Lackner, KJ, Saw, SM, Vingerling, JR, Teo, YY, Pasquale, LR, Wolfs, RCW, Lemij, HG, Tai, ES, Jonas, JB, Cheng, CY, Aung, T, Jansonius, NM, Klaver, CCW, Craig, JE, Young, TL, Haines, JL, Macgregor, S, Mackey, DA, Pfeiffer, N, Wong, TY, Wiggs, JL, Hewitt, AW, van Duijn, CM, Hammond, CJ, Allingham, RR, Brilliant, MH, Budenz, DL, Bailey, JNC, Christen, WG, and Fingert, J

Subjects
genetic structures, sense organs, eye diseases
Abstract

© 2015 Wiley Periodicals, Inc. Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.

Published
2015
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44. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Author

Khawaja, AP, Springelkamp, H, Creuzot-Garcher, C, Delcourt, C, Hofman, A, Höhn, R, Iglesias, AI, Wolfs, RCW, Korobelnik, J-F, Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, GHS, Cachulo, MDL, Cougnard-Grégoire, A, Dartigues, J-F, Hammond, CJ, Pfeiffer, N, Salonikiou, A, van Duijn, CM, Vingerling, JR, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, CCW, Jansonius, NM, Foster, PJ, European Eye Epidemiology (E³) Consortium, Khawaja, AP, Springelkamp, H, Creuzot-Garcher, C, Delcourt, C, Hofman, A, Höhn, R, Iglesias, AI, Wolfs, RCW, Korobelnik, J-F, Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, GHS, Cachulo, MDL, Cougnard-Grégoire, A, Dartigues, J-F, Hammond, CJ, Pfeiffer, N, Salonikiou, A, van Duijn, CM, Vingerling, JR, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, CCW, Jansonius, NM, Foster, PJ, and European Eye Epidemiology (E³) Consortium

Abstract

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.

Published
2016

45. Response: Cycloplegia in refraction: age and cycloplegics

Author

Sanfilippo, PG, Chu, B-S, Bigault, O, Kearns, LS, Boon, M-Y, Young, TL, Hammond, CJ, Hewitt, AW, Mackey, DA, Sanfilippo, PG, Chu, B-S, Bigault, O, Kearns, LS, Boon, M-Y, Young, TL, Hammond, CJ, Hewitt, AW, and Mackey, DA

Published
2016

46. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author

Fan, Q, Verhoeven, VJM, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hoehn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y, Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, X, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, T-H, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, van Leeuwen, EM, Amin, N, Uitterlinden, AG, Rivadeneira, F, Hofman, A, Vingerling, JR, Wang, YX, Wang, X, Boh, ET-H, Ikram, MK, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, E-S, Vithana, E, Mihailov, E, Khor, C-C, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, H-S, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, M, Paerssinen, O, van Duijn, CM, Wang, JJ, Williams, C, Jonas, JB, Teo, Y-Y, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, T-Y, Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, C-Y, Hammond, CJ, Klaver, CCW, Saw, S-M, Rahi, JS, Korobelnik, J-F, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, MacGregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, K-T, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, M-F, Li, X, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, JWL, Tedja, M, Deangelis, MM, Morrison, M, Farrer, L, Zhou, X, Chen, W, Mizuki, N, Meguro, A, Makela, KM, Fan, Q, Verhoeven, VJM, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hoehn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y, Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, X, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, T-H, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, van Leeuwen, EM, Amin, N, Uitterlinden, AG, Rivadeneira, F, Hofman, A, Vingerling, JR, Wang, YX, Wang, X, Boh, ET-H, Ikram, MK, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, E-S, Vithana, E, Mihailov, E, Khor, C-C, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, H-S, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, M, Paerssinen, O, van Duijn, CM, Wang, JJ, Williams, C, Jonas, JB, Teo, Y-Y, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, T-Y, Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, C-Y, Hammond, CJ, Klaver, CCW, Saw, S-M, Rahi, JS, Korobelnik, J-F, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, MacGregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, K-T, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, M-F, Li, X, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, JWL, Tedja, M, Deangelis, MM, Morrison, M, Farrer, L, Zhou, X, Chen, W, Mizuki, N, Meguro, A, and Makela, KM

Abstract

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

Published
2016

47. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E-3) Consortium

Author

Khawaja, AP, Springelkamp, Henriët, Creuzot-Garcher, C, Delcourt, C, Hofman, Bert, Hohn, R, Iglesias Gonzalez, Adriana, Wolfs, R.C.W., Korobelnik, JF, de Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, Gabriëlle, Cachulo, MD, Cougnard-Gregoire, A, Dartigues, JF, Hammond, CJ, Pfeiffer, N, Salonikiou, A, Duijn, Cornelia, Vingerling, Hans, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, Caroline, Jansonius, NM (Nomdo), Foster, PJ, Khawaja, AP, Springelkamp, Henriët, Creuzot-Garcher, C, Delcourt, C, Hofman, Bert, Hohn, R, Iglesias Gonzalez, Adriana, Wolfs, R.C.W., Korobelnik, JF, de Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, Gabriëlle, Cachulo, MD, Cougnard-Gregoire, A, Dartigues, JF, Hammond, CJ, Pfeiffer, N, Salonikiou, A, Duijn, Cornelia, Vingerling, Hans, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, Caroline, Jansonius, NM (Nomdo), and Foster, PJ

Abstract

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E-3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m(2); 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.

Published
2016

48. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia (vol 45, pg 314, 2013)

Author

Verhoeven, Virginie, Hysi, PG, Wojciechowski, R, Fan, Q, Guggenheim, JA, Hohn, R, Macgregor, S, Hewitt, AW, Nag, A, Cheng, CY (Ching-Yu), Yonova-Doing, E, Zhou, X, Ikram, Kamran, Buitendijk, Gabriëlle, McMahon, G, Kemp, JP, St Pourcain, B, Simpson, CL, Makela, KM, Lehtimaki, T, Kahonen, M, Paterson, AD, Hosseini, SM, Wong, HS, Xu, L, Jonas, JB, Parssinen, O, Wedenoja, J, Yip, SP, Ho, DWH, Pang, CP, Chen, LJ, Burdon, KP, Craig, JE, Klein, BEK, Klein, R, Haller, T, Metspalu, A, Khor, CC, Tai, ES, Aung, T, Vithana, E, Tay, WT, Barathi, VA, Chen, Peng, Li, RY, Liao, JM, Zheng, YF, Ong, RT, Doring, A, Evans, DM, Timpson, NJ, Verkerk, AJMH, Meitinger, T, Raitakari, O, Hawthorne, F, Spector, TD, Karssen, Lennart, Pirastu, M, Murgia, F, Ang, W, Mishra, A, Montgomery, GW, Pennell, CE, Cumberland, PM, Cotlarciuc, I, Mitchell, P, Wang, JJ, Schache, M, Janmahasathian, S, Igo, RP, Lass, JH, Chew, E, KIyengar, S, Gorgels, TGMF (Theo), Rudan, I, Hayward, C, Wright, AF, Polasek, O, Vatavuk, Z, Wilson, JF, Fleck, B, Zeller, T, Mirshahi, A, Müller, Caspar, Uitterlinden, André, Rivadeneira, Fernando, Vingerling, Hans, Hofman, Bert, Oostra, Ben, Amin, Najaf, Bergen, Arthur, Teo, YY, Rahi, JS, Vitart, V, Williams, C, Baird, PN, Wong, TY (Tien Yin), Oexle, K, Pfeiffer, N, Mackey, DA, Young, TL, Duijn, Cornelia, Saw, SM, Bailey-Wilson, JE, Stambolian, D, Klaver, Caroline, Hammond, CJ, Ophthalmology, Pathology, Epidemiology, Cell biology, Anesthesiology, Internal Medicine, Clinical Genetics, and Obstetrics & Gynecology

Published
2013

49. Biomarkers of skin ageing using genome wide transcriptomics

Author

Glass, D, Parts, L, Knowles, D, Nica, AC, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, A, Bell, JT, Surdulescu, G, Dimas, AS, Ingle, C, Nestle, FO, di Meglio, P, Min, JL, Wilk, A, Hammond, CJ, Hassanali, N, Yang, T-P, Montgomery, SB, Lindgren, CM, Zondervan, KT, Soranzo, N, Barroso, I, Durbin, R, Ahmadi, K, Winn, J, Bataille, V, Deloukas, P, McCarthy, MI, Spector, TD, Dermitzakis, ET, and Consortium, M

Published
2011

50. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011
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