Rare Complement Factor H Variant Associated With Age-Related Macular Degeneration in the Amish
Rare Complement Factor H Variant Associated With Age-Related Macular Degeneration in the Amish
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DOI：
10.1167/iovs.13-13684
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发表时间：
2014-07-01
影响因子：
4.4
通讯作者：
Haines, Jonathan L.
中科院分区：
文献类型：
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作者：
Hoffman, Joshua D.;Bailey, Jessica N. Cooke;Haines, Jonathan L.
目的。年龄相关性黄斑变性是发达国家成年人失明的主要原因。为了进一步了解这种疾病，我们研究了俄亥俄州和印第安纳州基因隔离的阿米什人。累积遗传风险评分使用19个已知的等位基因关联来计算。对患有AMD的Amish小家族的3名成员进行了外显子组测序，他们缺乏补体因子H （CFH）和ARMS2/HTRA1的共同风险等位基因。对973名阿米什人进行了随访基因分型和关联分析，其中95名阿米什人自我报告患有amd。累积遗传风险评分分析得出Amish对照组的平均遗传风险评分为1.12(95%可信区间[CI]: 1.10, 1.13)， Amish病例的平均遗传风险评分为1.18（95%可信区间[CI]: 1.13, 1.22）。遗传风险评分的平均差异有统计学意义（P = 0.0042）。外显子组测序鉴定出CFH中一种罕见的变异（P503A）。对其余阿米什样本的关联分析显示，P503A变异与AMD显著相关（P = 9.27 X 10(-13)）。在791名非阿米什老年人对照和1456名非阿米什病例的队列中，不存在变异P503A。来自累积遗传风险评分分析的数据表明，与非阿米什高加索人群相比，AMDGene联盟报告的变异在阿米什人中造成的疾病遗传负担较小。利用外显子组测序数据，我们发现了一种新的错义突变，这种突变在一个受严重影响的阿米什核家族中共享，位于一个先前与AMD风险有关的基因中。
PURPOSE. Age-related macular degeneration is the leading cause of blindness among the adult population in the developed world. To further the understanding of this disease, we have studied the genetically isolated Amish population of Ohio and Indiana.METHODS. Cumulative genetic risk scores were calculated using the 19 known allelic associations. Exome sequencing was performed in three members of a small Amish family with AMD who lacked the common risk alleles in complement factor H (CFH) and ARMS2/HTRA1. Follow-up genotyping and association analysis was performed in a cohort of 973 Amish individuals, including 95 with self-reported AMD.RESULTS. The cumulative genetic risk score analysis generated a mean genetic risk score of 1.12 (95% confidence interval [CI]: 1.10, 1.13) in the Amish controls and 1.18 (95% CI: 1.13, 1.22) in the Amish cases. This mean difference in genetic risk scores is statistically significant (P = 0.0042). Exome sequencing identified a rare variant (P503A) in CFH. Association analysis in the remainder of the Amish sample revealed that the P503A variant is significantly associated with AMD (P = 9.27 X 10(-13)). Variant P503A was absent when evaluated in a cohort of 791 elderly non-Amish controls, and 1456 non-Amish cases.CONCLUSIONS. Data from the cumulative genetic risk score analysis suggests that the variants reported by the AMDGene consortium account for a smaller genetic burden of disease in the Amish compared with the non-Amish Caucasian population. Using exome sequencing data, we identified a novel missense mutation that is shared among a densely affected nuclear Amish family and located in a gene that has been previously implicated in AMD risk.