King Rebecca, Li Ying, Wang Jiaxing, Struebing Felix L, Geisert Eldon E
Department of Ophthalmology, Emory University, Atlanta, Georgia 30322.
Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China.
G3 (Bethesda). 2018 May 4;8(5):1571-1578. doi: 10.1534/g3.118.200190.
Intraocular pressure (IOP) is the primary risk factor for developing glaucoma, yet little is known about the contribution of genomic background to IOP regulation. The present study leverages an array of systems genetics tools to study genomic factors modulating normal IOP in the mouse. The BXD recombinant inbred (RI) strain set was used to identify genomic loci modulating IOP. We measured the IOP in a total of 506 eyes from 38 different strains. Strain averages were subjected to conventional quantitative trait analysis by means of composite interval mapping. Candidate genes were defined, and immunohistochemistry and quantitative PCR (qPCR) were used for validation. Of the 38 BXD strains examined the mean IOP ranged from a low of 13.2mmHg to a high of 17.1mmHg. The means for each strain were used to calculate a genome wide interval map. One significant quantitative trait locus (QTL) was found on Chr.8 (96 to 103 Mb). Within this 7 Mb region only 4 annotated genes were found: , , and Only two genes ( and ) were candidates for modulating IOP based on the presence of non-synonymous SNPs. Further examination using SIFT (Sorting Intolerant From Tolerant) analysis revealed that the SNPs in (Cadherin 8) were predicted to not change protein function; while the SNPs in (Cadherin 11) would not be tolerated, affecting protein function. Furthermore, immunohistochemistry demonstrated that CDH11 is expressed in the trabecular meshwork of the mouse. We have examined the genomic regulation of IOP in the BXD RI strain set and found one significant QTL on Chr. 8. Within this QTL, there is one good candidate gene, .
眼压（IOP）是青光眼发病的主要危险因素，但关于基因组背景对眼压调节的作用知之甚少。本研究利用一系列系统遗传学工具来研究调节小鼠正常眼压的基因组因素。使用BXD重组近交（RI）系来鉴定调节眼压的基因组位点。我们测量了来自38个不同品系的总共506只眼睛的眼压。通过复合区间作图对品系平均值进行常规数量性状分析。定义了候选基因，并使用免疫组织化学和定量PCR（qPCR）进行验证。在所检查的38个BXD品系中，平均眼压范围从低至13.2mmHg到高至17.1mmHg。每个品系的平均值用于计算全基因组区间图。在8号染色体（96至103 Mb）上发现了一个显著的数量性状位点（QTL）。在这个7 Mb区域内仅发现4个注释基因： 、 、 和 。基于非同义单核苷酸多态性（SNP）的存在，只有两个基因（ 和 ）是调节眼压的候选基因。使用SIFT（从耐受中筛选不耐受）分析进一步检查发现， （钙黏蛋白8）中的SNP预计不会改变蛋白质功能；而 （钙黏蛋白11）中的SNP将不被耐受，会影响蛋白质功能。此外，免疫组织化学表明CDH11在小鼠小梁网中表达。我们已经研究了BXD RI系中眼压的基因组调节，并在8号染色体上发现了一个显著的QTL。在这个QTL内，有一个很好的候选基因， 。
