Centre for Eye Research Australia (CERA) - Research Publications

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Author: Craig, Jamie × End date: 2021 × Start date: 2020 × Type: Journal Article ×

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    The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort
    Siggs, OM ; Awadalla, MS ; Souzeau, E ; Staffieri, SE ; Kearns, LS ; Laurie, K ; Kuot, A ; Qassim, A ; Edwards, TL ; Coote, MA ; Mancel, E ; Walland, MJ ; Dondey, J ; Galanopoulous, A ; Casson, RJ ; Mills, RA ; MacArthur, DG ; Ruddle, JB ; Burdon, KP ; Craig, JE (WILEY, 2020-05)
    Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.
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    Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression
    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 (NATURE PORTFOLIO, 2020-02)
    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.
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    Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error
    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 (NATURE PORTFOLIO, 2020-03-19)
    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.