Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC University of Pittsburgh, Pittsburgh, PA 15224, USA.
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Hum Mol Genet. 2018 Mar 1;27(5):929-940. doi: 10.1093/hmg/ddy002.
Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.
家族和人群遗传研究已经成功鉴定出多个与年龄相关性黄斑变性（AMD）相关的疾病易感性位点，AMD 是全基因组关联研究最早和最成功的范例之一。然而，迄今为止，大多数遗传研究都集中在晚期 AMD（脉络膜新生血管或地理萎缩）的病例对照研究上。遗传对疾病进展的影响在很大程度上尚未得到探索。我们汇集了独特的资源，对 2721 名来自大型多中心随机临床试验——年龄相关性眼病研究的白种人进行了全基因组双变量生存时间分析，以测试与晚期 AMD 相关的时间与约 900 万个变体之间的关联。据我们所知，这是 AMD 遗传研究中首次对疾病进展（双变量生存结局）进行全基因组关联研究，从而为 AMD 遗传学提供了新的见解。我们使用稳健的 Cox 比例风险模型，在分析每个参与者双眼的进展时间时，适当考虑到眼间相关性。我们确定了四个先前报道的与 AMD 进展具有全基因组显著关联的易感位点：ARMS2-HTRA1（P=8.1×10-43）、CFH（P=3.5×10-37）、C2-CFB-SKIV2L（P=8.1×10-10）和 C3（P=1.2×10-9）。此外，我们还检测到 rs58978565 附近的 TNR（P=2.3×10-8）、rs28368872 附近的 ATF7IP2（P=2.9×10-8）和 rs142450006 附近的 MMP9（P=0.0006）与脉络膜新生血管进展有关，但与地理萎缩无关。对仅限于 34 个报道的风险变异的二次分析表明，LIPC 和 CTRB2-CTRB1 也与 AMD 进展相关（P<0.0015）。我们的全基因组分析因此扩展了 AMD 发生和进展的遗传学，并应有助于早期识别高危个体。
