Data_Sheet_1_Discovery of Novel Genetic Risk Loci for Acute Central Serous Chorioretinopathy and Genetic Pleiotropic Effect With Age-Related Macular Degeneration.docx

BackgroundCentral serous chorioretinopathy (CSC) is a severe and heterogeneous chorioretinal disorder. Shared clinical manifestations between CSC and age-related macular degeneration (AMD) and the confirmation of CFH as genetic risk locus for both CSC and AMD suggest possible common pathophysiologic mechanisms between two diseases.
MethodsTo advance the understanding of genetic susceptibility of CSC and further investigate genetic pleiotropy between CSC and AMD, we performed genetic association analysis of 38 AMD-associated single nucleotide polymorphisms (SNPs) in a Chinese CSC cohort, consisting of 464 patients and 548 matched healthy controls.
ResultsTwelve SNPs were found to be associated with CSC at nominal significance (p < 0.05), and four SNPs on chromosomes 1, 4, and 15 showed strong associations whose evidences surpassed Bonferroni (BF)-corrected significance [rs1410996, odds ratios (OR) = 1.47, p = 2.37 × 10–5; rs1329428, OR = 1.40, p = 3.32 × 10–4; rs4698775, OR = 1.45, p = 2.20 × 10–4; and rs2043085, OR = 1.44, p = 1.91 × 10–4]. While the genetic risk effects of rs1410996 and rs1329428 (within the well-established locus CFH) are correlated (due to high LD), rs4698775 on chromosome 4 and rs2043085 on chromosome 15 are novel risk loci for CSC. Polygenetic risk score (PRS) constructed by using three independent SNPs (rs1410996, rs4698775, and rs2043085) showed highly significant association with CSC (p = 2.10 × 10–7), with the top 10% of subjects with high PRS showing 6.39 times higher risk than the bottom 10% of subjects with lowest PRS. Three SNPs were also found to be associated with clinic manifestations of CSC patients. In addition, by comparing the genetic effects (ORs) of these 38 SNPs between CSC and AMD, our study revealed significant, but complex genetic pleiotropic effect between the two diseases.
ConclusionBy discovering two novel genetic risk loci and revealing significant genetic pleiotropic effect between CSC and AMD, the current study has provided novel insights into the role of genetic composition in the pathogenesis of CSC.

背景 中心性浆液性脉络膜视网膜病变（Central serous chorioretinopathy，CSC）是一种严重且具有异质性的脉络膜视网膜疾病。CSC与年龄相关性黄斑变性（age-related macular degeneration，AMD）存在共有的临床表现，且补体因子H（CFH）被证实为两者共同的遗传风险位点，这提示两种疾病可能存在共同的病理生理机制。
方法 为深化对CSC遗传易感性的认识，并进一步探究CSC与AMD之间的遗传多效性，我们针对一个中国CSC队列开展了38个AMD相关单核苷酸多态性（single nucleotide polymorphisms，SNPs）的遗传关联分析，该队列共纳入464例CSC患者与548例匹配健康对照个体。
结果 经名义显著性检验（p < 0.05），共有12个SNPs与CSC存在显著关联；其中位于1号、4号及15号染色体上的4个SNPs达到了经Bonferroni（BF）校正后的显著性标准，具体如下：rs1410996（比值比（odds ratios，OR）=1.47，p=2.37×10–5）、rs1329428（OR=1.40，p=3.32×10–4）、rs4698775（OR=1.45，p=2.20×10–4）以及rs2043085（OR=1.44，p=1.91×10–4）。由于rs1410996与rs1329428（位于已明确的CFH位点内）存在高度连锁不平衡（linkage disequilibrium，LD），二者的遗传风险效应具有相关性；而位于4号染色体的rs4698775与15号染色体的rs2043085则为CSC全新的遗传风险位点。我们利用rs1410996、rs4698775及rs2043085这3个独立SNPs构建的多基因风险评分（polygenic risk score，PRS）与CSC呈现出极强的关联性（p=2.10×10–7），其中PRS最高的前10%受试者的患病风险是PRS最低的后10%受试者的6.39倍。此外，另有3个SNPs与CSC患者的临床表型存在关联。通过对比这38个SNPs在CSC与AMD中的遗传效应（OR值），本研究还揭示了两种疾病之间存在显著且复杂的遗传多效性效应。
结论 本研究发现了两个全新的CSC遗传风险位点，并阐明了CSC与AMD之间存在显著的遗传多效性，为解析遗传构成在CSC发病机制中的作用提供了全新的视角。