Department of Ophthalmology, David Geffen School of Medicine, UC, Los Angeles, CA, USA.
Mol Aspects Med. 2012 Aug;33(4):467-86. doi: 10.1016/j.mam.2012.04.004. Epub 2012 Apr 27.
Age-related macular degeneration (AMD) is a common condition among the elderly population that leads to the progressive central vision loss and serious compromise of quality of life for its sufferers. It is also one of the few disorders for whom the investigation of its genetics has yielded rich insights into its diversity and causality and holds the promise of enabling clinicians to provide better risk assessments for individuals as well as to develop and selectively deploy new therapeutics to either prevent or slow the development of disease and lessen the threat of vision loss. The genetics of AMD began initially with the appreciation of familial aggregation and increase risk and expanded with the initial association of APOE variants with the disease. The first major breakthroughs came with family-based linkage studies of affected (and discordant) sibs, which identified a number of genetic loci and led to the targeted search of the 1q31 and 10q26 loci for associated variants. Three of the initial four reports for the CFH variant, Y402H, were based on regional candidate searches, as were the two initial reports of the ARMS2/HTRA1 locus variants. Case-control association studies initially also played a role in discovering the major genetic variants for AMD, and the success of those early studies have been used to fuel enthusiasm for the methodology for a number of diseases. Until 2010, all of the subsequent genetic variants associated with AMD came from candidate gene testing based on the complement factor pathway. In 2010, several large-scale genome-wide association studies (GWAS) identified genes that had not been previously identified. Much of this historical information is available in a number of recent reviews (Chen et al., 2010b; Deangelis et al., 2011; Fafowora and Gorin, 2012b; Francis and Klein, 2011; Kokotas et al., 2011). Large meta analysis of AMD GWAS has added new loci and variants to this collection (Chen et al., 2010a; Kopplin et al., 2010; Yu et al., 2011). This paper will focus on the ongoing controversies that are confronting AMD genetics at this time, rather than attempting to summarize this field, which has exploded in the past 5 years.
年龄相关性黄斑变性（AMD）是老年人中常见的疾病，可导致中心视力进行性丧失，并严重影响患者的生活质量。AMD 也是少数几种通过遗传学研究能深入了解其多样性和病因的疾病之一，有望使临床医生能够更好地为个体进行风险评估，并开发和有选择地应用新的治疗方法来预防或减缓疾病的发展，减少视力丧失的威胁。AMD 的遗传学研究最初始于对家族聚集和增加风险的认识，并随着 APOE 变体与疾病的最初关联而扩展。第一个重大突破来自受影响（和不一致）同胞的基于家族的连锁研究，该研究确定了一些遗传位点，并导致针对 1q31 和 10q26 位点相关变体的靶向搜索。最初四个关于 CFH 变体 Y402H 的报告中有三个，两个关于 ARMS2/HTRA1 位点变体的最初报告都是基于区域候选搜索。病例对照关联研究最初也在发现 AMD 的主要遗传变体方面发挥了作用，这些早期研究的成功为许多疾病的方法学提供了动力。直到 2010 年，与 AMD 相关的所有后续遗传变体都来自基于补体因子途径的候选基因测试。2010 年，几项大规模全基因组关联研究（GWAS）确定了以前未发现的基因。大量的历史信息可在最近的一些综述中获得（Chen 等人，2010b；Deangelis 等人，2011；Fafowora 和 Gorin，2012b；Francis 和 Klein，2011；Kokotas 等人，2011）。对 AMD GWAS 的大型荟萃分析增加了新的位点和变体（Chen 等人，2010a；Kopplin 等人，2010；Yu 等人，2011）。本文将重点讨论 AMD 遗传学目前面临的持续争议，而不是试图总结过去 5 年中爆发的这一领域。
