Ophthalmology (Eye & Ear Hospital) - Research Publications

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Author: Baird, Paul × Author: Mackey, David × Start date: 2020 ×

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    A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration
    Strunz, T ; Lauwen, S ; Kiel, C ; den Hollander, A ; Weber, BHF (NATURE PORTFOLIO, 2020-01-31)
    Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.
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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.