Ophthalmology (Eye & Ear Hospital) - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 9 of 9
  • Item
    Thumbnail Image
    Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus
    Fan, BJ ; Chen, X ; Sondhi, N ; Sharmila, PF ; Soumittra, N ; Sripriya, S ; Sacikala, S ; Asokan, R ; Friedman, DS ; Pasquale, LR ; Gao, XR ; Vijaya, L ; Bailey, JC ; Vitart, V ; MacGregor, S ; Hammond, CJ ; Khor, CC ; Haines, JL ; George, R ; Wiggs, JL (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-05)
    PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = -0.57, 95% confidence interval [CI]: -0.78 to -0.36; P = 1.7 × 10-7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = -3.94, 95% CI: -5.23 to -2.66; P = 1.7 × 10-9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.
  • Item
    No Preview Available
    Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
    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, C-Y ; 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 ; Kraftl, P ; Howell, G ; Hauser, MA ; Pasguale, LR ; Haines, JL ; Wiggs, JL (NATURE PUBLISHING GROUP, 2016-02)
    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.
  • Item
    Thumbnail Image
    Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium
    Li, Q ; Wojciechowski, R ; Simpson, CL ; Hysi, PG ; Verhoeven, VJM ; Ikram, MK ; Hoehn, R ; Vitart, V ; Hewitt, AW ; Oexle, K ; Makela, K-M ; MacGregor, S ; Pirastu, M ; Fan, Q ; Cheng, C-Y ; St Pourcain, B ; McMahon, G ; Kemp, JP ; Northstone, K ; Rahi, JS ; Cumberland, PM ; Martin, NG ; Sanfilippo, PG ; Lu, Y ; Wang, YX ; Hayward, C ; Polasek, O ; Campbell, H ; Bencic, G ; Wright, AF ; Wedenoja, J ; Zeller, T ; Schillert, A ; Mirshahi, A ; Lackner, K ; Yip, SP ; Yap, MKH ; Ried, JS ; Gieger, C ; Murgia, F ; Wilson, JF ; Fleck, B ; Yazar, S ; Vingerling, JR ; Hofman, A ; Uitterlinden, A ; Rivadeneira, F ; Amin, N ; Karssen, L ; Oostra, BA ; Zhou, X ; Teo, Y-Y ; Tai, ES ; Vithana, E ; Barathi, V ; Zheng, Y ; Siantar, RG ; Neelam, K ; Shin, Y ; Lam, J ; Yonova-Doing, E ; Venturini, C ; Hosseini, SM ; Wong, H-S ; Lehtimaki, T ; Kahonen, M ; Raitakari, O ; Timpson, NJ ; Evans, DM ; Khor, C-C ; Aung, T ; Young, TL ; Mitchell, P ; Klein, B ; van Duijn, CM ; Meitinger, T ; Jonas, JB ; Baird, PN ; Mackey, DA ; Wong, TY ; Saw, S-M ; Parssinen, O ; Stambolian, D ; Hammond, CJ ; Klaver, CCW ; Williams, C ; Paterson, AD ; Bailey-Wilson, JE ; Guggenheim, JA (SPRINGER, 2015-02)
    To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
  • Item
    Thumbnail Image
    Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process
    Springelkamp, H ; Hoehn, R ; Mishra, A ; Hysi, PG ; Khor, C-C ; Loomis, SJ ; Bailey, JNC ; Gibson, J ; Thorleifsson, G ; Janssen, SF ; Luo, X ; Ramdas, WD ; Vithana, E ; Nongpiur, ME ; Montgomery, G ; Xu, L ; Mountain, JE ; Gharahkhani, P ; Lu, Y ; Amin, N ; Karssen, LC ; Sim, K-S ; van Leeuwen, EM ; Iglesias, AI ; Verhoeven, VJM ; Hauser, MA ; Loon, S-C ; Despriet, DDG ; Nag, A ; Venturini, C ; Sanfilippo, PG ; Schillert, A ; Kang, JH ; Landers, J ; Jonasson, F ; Cree, AJ ; van Koolwijk, LME ; Rivadeneira, F ; Souzeau, E ; Jonsson, V ; Menon, G ; Weinreb, RN ; de Jong, PTVM ; Oostra, BA ; Uitterlinden, AG ; Hofman, A ; Ennis, S ; Thorsteinsdottir, U ; Burdon, KP ; Spector, TD ; Mirshahi, A ; Saw, S-M ; Vingerling, JR ; Teo, Y-Y ; Haines, JL ; Wolfs, RCW ; Lemij, HG ; Tai, E-S ; Jansonius, NM ; Jonas, JB ; Cheng, C-Y ; Aung, T ; Viswanathan, AC ; Klaver, CCW ; Craig, JE ; Macgregor, S ; Mackey, DA ; Lotery, AJ ; Stefansson, K ; Bergen, AAB ; Young, TL ; Wiggs, JL ; Pfeiffer, N ; Wong, T-Y ; Pasquale, LR ; Hewitt, AW ; van Duijn, CM ; Hammond, CJ (NATURE PORTFOLIO, 2014-09)
    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
  • Item
    Thumbnail Image
    Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium
    Fan, Q ; Guo, X ; Tideman, JWL ; 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, C-Y ; Teo, Y-Y ; Wong, T-Y ; Ding, X ; Wojciechowski, R ; Young, TL ; Parssinen, O ; Oexle, K ; Pfeiffer, N ; Bailey-Wilson, JE ; Paterson, AD ; Klaver, CCW ; Plomin, R ; Hammond, CJ ; Mackey, DA ; He, M ; Saw, S-M ; Williams, C ; Guggenheim, JA (NATURE PORTFOLIO, 2016-05-13)
    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).
  • Item
    Thumbnail Image
    Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error
    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 (NATURE PUBLISHING GROUP, 2016-04)
    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.
  • Item
    Thumbnail Image
    Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
    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 (NATURE PUBLISHING GROUP, 2018-05-14)
    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.
  • Item
    Thumbnail Image
    Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)
    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 ; Wong, TY ; 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 (NATURE PUBLISHING GROUP, 2019-01-08)
    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.
  • Item
    Thumbnail Image
    Multi-trait genome-wide association study identifies new loci associated with optic disc parameters
    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 ; Viswanathan, AC ; 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 ; Pasquale, LR ; 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 (NATURE PUBLISHING GROUP, 2019-11-27)
    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.