Maller Julian, George Sarah, Purcell Shaun, Fagerness Jes, Altshuler David, Daly Mark J, Seddon Johanna M
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St., Boston, Massachusetts 02114, USA.
Nat Genet. 2006 Sep;38(9):1055-9. doi: 10.1038/ng1873. Epub 2006 Aug 27.
Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based analysis has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the associations of four other previously reported common alleles in three genes (P values ranging from 10(-6) to 10(-70)). Despite excellent power to detect epistasis, we observed purely additive accumulation of risk from alleles at these genes. We found no differences in association of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.
年龄相关性黄斑变性（AMD）是一种常见的迟发性疾病，具有看似典型的复杂性：患病个体的兄弟姐妹的复发率比普通人群高3至6倍，基于家族的分析仅得出了适度显著的连锁证据。在一项基于美国欧洲裔人群的病例对照研究中，我们在编码补体因子H的基因CFH中发现了一个先前未被识别的常见非编码变体，该变体显著增加了该基因座对AMD的影响，并且我们在三个基因中强烈重复了其他四个先前报道的常见等位基因的关联（P值范围从10^(-6)到10^(-70)）。尽管有很强的能力检测上位性，但我们观察到这些基因的等位基因的风险纯粹是累加的。我们发现这些基因座与晚期AMD的主要表型类别之间的关联没有差异。这五个常见单核苷酸多态性（SNP）的基因型定义了个体间疾病风险的广泛范围，并解释了我们研究人群中约一半的AMD经典兄弟姐妹风险。
