Identification of Rare Variants Involved in High Myopia Unraveled by Whole Genome Sequencing

Annechien E G Haarman; Caroline C W Klaver; Milly S Tedja; Susanne Roosing; Galuh Astuti; Christian Gilissen; Lies H Hoefsloot; Marianne van Tienhoven; Tom Brands; Frank J Magielsen; Bert H J F M M Eussen; Annelies de Klein; Erwin Brosens; Virginie J M Verhoeven

doi:10.1016/j.xops.2023.100303

Identification of Rare Variants Involved in High Myopia Unraveled by Whole Genome Sequencing

Ophthalmol Sci. 2023 Apr 6;3(4):100303. doi: 10.1016/j.xops.2023.100303. eCollection 2023 Dec.

Authors

Annechien E G Haarman^{1

2}, Caroline C W Klaver^{1

2

3

4}, Milly S Tedja^{1

2}, Susanne Roosing^{5

6}, Galuh Astuti⁵, Christian Gilissen⁵, Lies H Hoefsloot⁷, Marianne van Tienhoven⁷, Tom Brands⁷, Frank J Magielsen⁷, Bert H J F M M Eussen⁷, Annelies de Klein⁷, Erwin Brosens⁷, Virginie J M Verhoeven^{1

7}

Affiliations

¹ Erasmus MC, Department of Ophthalmology, Rotterdam, The Netherlands.
² Erasmus MC, Department of Epidemiology, Rotterdam, The Netherlands.
³ Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland.
⁵ Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
⁶ Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷ Erasmus MC, Department of Clinical Genetics, Rotterdam, The Netherlands.

Abstract

Purpose: Myopia (nearsightedness) is a condition in which a refractive error (RE) affects vision. Although common variants explain part of the genetic predisposition (18%), most of the estimated 70% heritability is missing. Here, we investigate the contribution of rare genetic variation because this might explain more of the missing heritability in the more severe forms of myopia. In particular, high myopia can lead to blindness and has a tremendous impact on a patient and at the societal level. The exact molecular mechanisms behind this condition are not yet completely unraveled, but whole genome sequencing (WGS) studies have the potential to identify novel (rare) disease genes, explaining the high heritability.

Design: Cross-sectional study performed in the Netherlands.

Participants: We investigated 159 European patients with high myopia (RE > -10 diopters).

Methods: We performed WGS using a stepwise filtering approach and burden analysis. The contribution of common variants was calculated as a genetic risk score (GRS).

Main outcome measures: Rare variant burden, GRS.

Results: In 25% (n = 40) of these patients, there was a high (> 75th percentile) contribution of common predisposing variants; that is, these participants had higher GRSs. In 7 of the remaining 119 patients (6%), deleterious variants in genes associated with known (ocular) disorders, such as retinal dystrophy disease (prominin 1 [PROM1]) or ocular development (ATP binding cassette subfamily B member 6 [ABCB6], TGFB induced factor homeobox 1 [TGIF1]), were identified. Furthermore, without using a gene panel, we identified a high burden of rare variants in 8 novel genes associated with myopia. The genes heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) (proportion in study population vs. the Genome Aggregation Database (GnomAD) 0.14 vs. 0.03, P = 4.22E-17), RNA binding motif protein 20 (RBM20) (0.15 vs. 0.06, P = 4.98E-05), and MAP7 domain containing 1 (MAP7D1) (0.19 vs. 0.06, P = 1.16E-10) were involved in the Wnt signaling cascade, melatonin degradation, and ocular development and showed most biologically plausible associations.

Conclusions: We found different contributions of common and rare variants in low and high grade myopia. Using WGS, we identified some interesting candidate genes that could explain the high myopia phenotype in some patients.

Financial disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Keywords: Blindness; Complex genetics; Genetic risk score; Mendelian diseases.