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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., (© 2023 by the American Academy of Ophthalmology.)