Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama City 700-8558, Japan.
Department of Ophthalmology, Okayama University Hospital, Okayama City 700-8558, Japan.
Int J Mol Sci. 2024 Jun 26;25(13):6986. doi: 10.3390/ijms25136986.
Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed and , respectively, as candidate genes at a significant level of < 5 × 10, while the idiopathic superior oblique muscle palsy group showed as a candidate gene which is involved in neuronal migration. was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of < 1 × 10. In comparison with BBJ (180K), (retinoic acid receptor-β) was detected as a candidate at a significant level of < 5 × 10 in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus.
共同性斜视中的内斜视和外斜视是具有遗传和环境背景的多因素疾病。特发性上斜肌麻痹作为非共同性（麻痹性）斜视的主要类型，也具有遗传背景，表现为不同程度的肌肉发育不良。对 711 例日本内斜视（n=253）、外斜视（n=356）和特发性上斜肌麻痹（n=102）患者进行了全基因组关联研究（GWAS）。通过 Infinium Asian Screening Array 确定单核苷酸多态性（SNP）的基因型。使用来自日本人群的三个对照队列：两个来自 BioBank Japan（BBJ）的队列和长滨队列。BBJ（180K）通过不同的阵列（Illumina Infinium OmniExpressExome 或 HumanOmniExpress）进行基因分型，而 BBJ（ASA）和长滨队列通过相同的亚洲阵列进行基因分型。在对 SNP 和个体进行质量控制后，在不同阵列基因分型的条件下选择病例队列和对照队列之间的常见 SNP，同时使用相同阵列基因分型的所有 SNP 进行 SNP 推断。使用 R-square 值≥0.3 的 SNP 进行比较，将每个实体的病例队列或合并实体与对照队列进行比较。与 BBJ（180K）相比，内斜视组和外斜视组分别显示和为候选基因，达到 5×10-8的显著水平，而特发性上斜肌麻痹组显示为候选基因，参与神经元迁移。与 BBJ（ASA）和长滨队列相比，在较弱的显著水平（<1×10）下，也检测到为候选基因。与 BBJ（180K）相比，在共同的内斜视、外斜视和特发性上斜肌麻痹组中，在显著水平（<5×10）下检测到候选基因（视黄酸受体-β）。综上所述，使用三个不同对照队列的一系列 GWAS 是一种有效的方法，可用于搜索斜视等多因素疾病的候选基因。
