Lee Kyoung A Viola, Tesdahl Corey, Aboobakar Inas F, Jain Ashish, Martinez Sanchez Mayra, 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.
Ophthalmol Sci. 2025 Jul 1;5(6):100873. doi: 10.1016/j.xops.2025.100873. eCollection 2025 Nov-Dec.
Despite significant evidence of a genetic contribution to strabismus, precise genetic mechanisms have not been identified. There are distinct population differences in the prevalence of strabismus and its subtypes. This study aimed to explore the genetic contributions to strabismus in different ancestral groups.
Case-control.
The Research Program includes genotypic and phenotypic data from a diverse population of adults (age ≥18 years at time of enrollment) across the United States. Among participants with whole-genome sequences available, strabismus cases were identified based on diagnosis codes from their electronic health record. Participants with conditions associated with acquired strabismus, such as trauma, thyroid eye disease, tumor, or stroke, were excluded from the case and control cohorts. The final cohort consisted of 1579 cases and 121 490 controls of European (EUR) ancestry, 235 cases and 40 602 controls of Admixed American (AMR) ancestry, and 365 cases and 53 577 controls of African American (AFR) ancestry. Individuals of other ancestral groups were not included due to small numbers of strabismus-affected participants.
Genome-wide association study of common variants (minor allele frequency >1%) and rare variant association study at the gene level for strabismus.
Individual single nucleotide polymorphisms (SNPs) significantly associated with strabismus and genes with significant burden of rare variants in strabismus.
Genome-wide association study identified one locus with 3 significant SNPs (rs2247113, rs2667037, and rs2715926) in intron 1 of in the AFR group, and 2 loci, one in intron (rs184071225) and one intergenic (rs191788703), in the AMR group. Rare variant association study revealed 33 genes with a statistically significant ( value < 5 x 10) increased burden of variants: 9 in the EUR cohort: , , , , , , , , and ; 14 in the AMR cohort: , , , , , , , , , , , , , and ; and 10 in the AFR cohort: , , , , , , , , , and .
Genetic associations with strabismus differed between ancestry groups, although genes in similar pathways, such as synaptic signaling and structural muscle proteins, were found in multiple groups. This highlights the importance of including diverse populations in studies of genetic associations and suggests that multiple pathways may lead to strabismus in different population groups.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
尽管有大量证据表明遗传因素与斜视有关，但尚未确定确切的遗传机制。斜视及其亚型的患病率存在明显的人群差异。本研究旨在探讨不同祖先群体中遗传因素对斜视的影响。
病例对照研究。
该研究项目包括来自美国不同成年人群体（入组时年龄≥18岁）的基因型和表型数据。在有全基因组序列的参与者中，根据其电子健康记录中的诊断代码确定斜视病例。患有与后天性斜视相关疾病（如创伤、甲状腺眼病、肿瘤或中风）的参与者被排除在病例组和对照组之外。最终队列包括1579例欧洲（EUR）血统的病例和121490例对照、235例混血美国（AMR）血统的病例和40602例对照，以及365例非裔美国（AFR）血统的病例和53577例对照。由于受斜视影响的参与者数量较少，未纳入其他祖先群体的个体。
对常见变异（次要等位基因频率>1%）进行全基因组关联研究，并在基因水平上对斜视进行罕见变异关联研究。
与斜视显著相关的个体单核苷酸多态性（SNP）以及斜视中罕见变异负担显著的基因。
全基因组关联研究在AFR组的内含子1中鉴定出一个位点，有三个显著的SNP（rs2247113、rs2667037和rs2715926），在AMR组中鉴定出两个位点，一个在内含子（rs184071225）中，另一个在基因间（rs191788703）。罕见变异关联研究揭示了33个基因的变异负担有统计学意义的增加（P值<5×10）：EUR队列中有9个：[具体基因名称1]、[具体基因名称2]、[具体基因名称3]、[具体基因名称4]、[具体基因名称5]、[具体基因名称6]、[具体基因名称7]、[具体基因名称8]和[具体基因名称9]；AMR队列中有14个：[具体基因名称10]、[具体基因名称11]、[具体基因名称12]、[具体基因名称13]、[具体基因名称14]、[具体基因名称15]、[具体基因名称16]、[具体基因名称17]、[具体基因名称18]、[具体基因名称19]、[具体基因名称20]、[具体基因名称21]、[具体基因名称22]和[具体基因名称23]；AFR队列中有10个：[具体基因名称24]、[具体基因名称25]、[具体基因名称26]、[具体基因名称27]、[具体基因名称28]、[具体基因名称29]、[具体基因名称30]、[具体基因名称31]、[具体基因名称32]和[具体基因名称33]。
不同祖先群体中与斜视的遗传关联有所不同，尽管在多个群体中发现了类似途径中的基因，如突触信号传导和结构肌肉蛋白相关基因。这突出了在遗传关联研究中纳入不同人群的重要性，并表明多种途径可能导致不同人群组中的斜视。
在本文末尾的脚注和披露中可能会找到专有或商业披露信息。
