July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Genetic risk scores of the largest multi-trait GWAS meta-analysis on refractive errors
Author Affiliations & Notes
  • Caroline C W Klaver
    Ophthalmology and Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Milly S. Tedja
    Ophthalmology and Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Xikun Han
    Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Virginie JM Verhoeven
    Ophthalmology and Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
    Clinical Genetics, Erasmus Medical Center, Netherlands
  • Nick Ericksson
    23andMe, California, United States
  • Nick Furlotte
    23andMe, California, United States
  • Najaf Amin
    Epidemiology, Erasmus MC, Rotterdam, Netherlands
  • Cornelia van Duijn
    Epidemiology, Erasmus MC, Rotterdam, Netherlands
    Epidemiology, University of Oxford, NDPH, United Kingdom
  • Stuart MacGregor
    Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Footnotes
    Commercial Relationships   Caroline Klaver, None; Milly Tedja, None; Xikun Han, None; Virginie Verhoeven, None; Nick Ericksson, 23andMe (E); Nick Furlotte, 23andMe (E); Najaf Amin, None; Cornelia Duijn, None; Stuart MacGregor, None
  • Footnotes
    Support  ERC MYOP-PATH
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3143. doi:https://doi.org/
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    • Get Citation

      Caroline C W Klaver, Milly S. Tedja, Xikun Han, Virginie JM Verhoeven, Nick Ericksson, Nick Furlotte, Najaf Amin, Cornelia van Duijn, Stuart MacGregor; Genetic risk scores of the largest multi-trait GWAS meta-analysis on refractive errors. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3143. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Myopia is a complex genetic trait and its morbidity will become a public health issue in the near future. The explained phenotypic variance remains low (8% based on 161 loci). The aim of this study is to contribute to the missing heritability (h2) for RE by performing a multi-trait GWAS meta-analysis, and to elucidate the impact of the genetic factors by constructing genetic risk scores (GRS) for myopia risk prediction models in the case-control MYopia Study (MYST).

Methods : We performed a multi-trait GWAS meta-analysis on Spherical Equivalent (SphE), Age of Diagnosis of Myopia and Myopia Status in 620,035 participants from CREAM (N=44,710), UK Biobank (N=348,414) and 23andMe (N=134,145) using MTAG. Subsequently, we selected index variants from the genome wide significant SNPs on SphE using Plink --clump based on position (250 kb) and LD structure (>0.6). We then constructed GRS per individual in MYST (Ncases= 450; Ncontrol=591; cases with high myopia (HM) defined as spherical equivalent (SphE) ≤ -6 D and axial length (AL) ≥ 26mm): Σ(βSNP1*genotype + … + βSNP420*genotype). Finally, we calculated the variance explained (Nagelkerke r2) by GRS for HM and we constructed ROC curves comparing prediction models for HM using GRS, education level and parental myopia, with age and sex included in all models tested.

Results : The multi-trait GWAS meta-analysis yielded 420 loci associated with RE and a replication of 94% (151/161) of the previously reported loci. The 420 loci explained 9.8% of the phenotypic variance (P=4.18E-17). All prediction models for HM, except the education model (P=0.08), were significantly different from the prediction model including only age and sex. The GRS-only model (AUC 0.67), the model including education level only (AUC 0.65) or parental myopia only (AUC 0.69), the model including education level and parental myopia without GRS (AUC 0.70) and with GRS (AUC 0.69), were not significantly different from each other.

Conclusions : This large dataset enabled further identification of novel loci associated with RE and thereby contributed to solving the missing heritability. The genetic risk prediction model predicting high myopia based on all 420 risk loci performed similar to prediction models including only nongenetic risk factors (education and parental myopia). This exemplifies the complex nature of the trait.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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