Lee Kyoung A Viola, Aboobakar Inas F, Jain Ashish, Tesdahl Corey D, Jin Kimberly, Oke Isdin, Whitman Mary C
Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts; University of South Florida Morsani College of Medicine, Tampa, Florida.
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Ophthalmology. 2025 Jul;132(7):758-766. doi: 10.1016/j.ophtha.2025.01.013. Epub 2025 Jan 20.
Amblyopia is characterized by decreased visual acuity due to abnormal visual experience during development. It affects approximately 3% of the population and is associated with abnormal development of the visual cortex. Despite treatment, many patients have residual visual acuity deficits. This study aimed to explore the genetic contributions to amblyopia.
Case-control.
The All of Us Research Program includes genotypic and phenotypic data from a diverse population of adults (age ≥ 18 years) across the United States. A total of 764 subjects with amblyopia (based on International Classification of Diseases and Systematized Nomenclature of Medicine codes) and 122 305 controls with no record of amblyopia and with whole genome sequencing data were compared. Only participants of European genetic ancestry were included because of small numbers of affected participants in other ancestral groups.
Genome-wide association study (GWAS) of common variants (minor allele frequency > 1%) and rare variant association study (RVAS) at the gene level for amblyopia of participants in the All of Us Research Program.
Individual single nucleotide polymorphisms (SNPs) significantly associated with amblyopia and genes with significant burden of rare variants in amblyopia.
The GWAS revealed 4 loci that approached statistical significance defined as P < 5e-8: rs56105618, rs1349660, rs7958343, and rs138693522. Each of the variants is an expression quantitative trait locus (eQTL) for a gene expressed in the brain or related to neural development. This RVAS revealed 15 genes with a statistically significant (P < 5e-05) different burden of variants: DCP1B, OR12D2, PCDHA4, ALKBH8, NMUR2, OR52P1P, NEU1, CACNB2, PSMA7, LRR1, ZNF831, FSIP2, ZNF654, CES5A, and MPV17, several of which have known roles in neurodevelopment.
The identification of genes linked to amblyopia with roles in neurodevelopment suggests that the neurodevelopmental changes in amblyopia are not only secondary to abnormal visual experience but also may result from the interaction of primary neurodevelopmental deficits with abnormal experience. This potentially explains why some children develop amblyopia and others do not with the same ocular risk factors, may explain differences in treatment outcomes, and suggests new avenues for amblyopia treatment.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
弱视的特征是由于发育过程中异常的视觉体验导致视力下降。它影响约3%的人口，并与视觉皮层的异常发育有关。尽管进行了治疗，许多患者仍有残余视力缺陷。本研究旨在探索弱视的遗传因素。
病例对照研究。
“我们所有人”研究项目包括来自美国不同成年人群体（年龄≥18岁）的基因型和表型数据。比较了764名弱视患者（基于国际疾病分类和医学系统命名法代码）和122305名无弱视记录且有全基因组测序数据的对照者。由于其他祖先群体中受影响的参与者数量较少，仅纳入了欧洲遗传血统的参与者。
对“我们所有人”研究项目参与者的弱视进行全基因组常见变异（次要等位基因频率>1%）关联研究（GWAS）和基因水平的罕见变异关联研究（RVAS）。
与弱视显著相关的个体单核苷酸多态性（SNP）以及弱视中具有显著罕见变异负担的基因。
GWAS揭示了4个接近统计学显著性（定义为P<5e-8）的位点：rs56105618、rs1349660、rs7958343和rs138693522。每个变异都是在大脑中表达或与神经发育相关的基因的表达数量性状位点（eQTL）。该RVAS揭示了15个基因，其变异负担在统计学上有显著差异（P<5e-05）：DCP1B、OR12D2、PCDHA4、ALKBH8、NMUR2、OR52P1P、NEU1、CACNB2、PSMA7、LRR1、ZNF831、FSIP2、ZNF654、CES5A和MPV17，其中一些在神经发育中具有已知作用。
鉴定出与弱视相关且在神经发育中起作用的基因表明，弱视中的神经发育变化不仅继发于异常的视觉体验，还可能是原发性神经发育缺陷与异常体验相互作用的结果。这可能解释了为什么一些儿童会患弱视而其他具有相同眼部危险因素的儿童却不会，可能解释治疗结果的差异，并为弱视治疗提供新的途径。
专有或商业披露信息可在参考文献之后找到。
