SIBLING STUDY OF AGE-RELATED MACULAR DEGENERATION

描述（由申请人提供）：我们建议招募一对兄弟姐妹进行分子遗传学研究，寻找在新生血管性年龄相关性黄斑变性（AMD）发展中起作用的基因。两种类型的兄弟姐妹将被招募，极端不和谐的兄弟姐妹和极端和谐的兄弟姐妹。极度不一致的兄弟姐妹将由一个成员组成，即指数兄弟姐妹，患有新生血管性AMD，而第二个成员在指数兄弟姐妹发生新生血管性AMD的年龄很少或没有黄斑的衰老迹象。极其一致的兄弟姐妹将由两个患有新生血管性AMD的兄弟姐妹组成。白细胞DNA将从这些兄弟姐妹的血样中纯化。这些兄弟姐妹将构成全基因组连锁研究的基础，以寻找染色体区域，在这些区域中，极度不一致的兄弟姐妹平均共享的等位基因比预期的少，而在这些区域中，极度一致的兄弟姐妹平均共享的等位基因比预期的多。具有这些特性的染色体区域可能含有AMD基因。此外，ABCA4和apoE等可能与AMD易感性相关的候选基因将通过评估这些基因的DNA序列变化并寻找任何等位基因与新生血管性AMD之间的相关性来进行分析。据我们所知，基于极端不一致和极端一致的兄弟姐妹的分子遗传学方法来寻找新生血管性AMD的基因，以前没有任何其他研究小组进行过。如果成功，我们的工作将为确定新血管性AMD的遗传原因提供实质性进展，这是老年人法定失明的主要原因之一。

DESCRIPTION (provided by applicant): We propose to recruit pairs of siblings for a molecular genetic search for genes having a role in the development of neovascular age-related macular degeneration (AMD). Two types of sibling pairs will be recruited, extremely discordant sibpairs and extremely concordant sibpairs. Extremely discordant sibpairs will be composed of one member, the index sib, with neovascular AMD, and the second member with few or no aging signs of the macula at the age at which the index sibling developed neovascular AMD. Extremely concordant sibpairs will be composed of two siblings with neovascular AMD. Leukocyte DNA will be purified from blood samples collected from these siblings. The sibpairs will form the basis for a genome-wide linkage study to search for chromosomal regions where the extremely discordant pairs, on average, share fewer alleles than expected by chance alone, and where the extremely concordant sibpairs, on average, share more alleles than expected. Chromosomal regions having these properties are likely to harbor AMD genes. In addition, candidate genes that may have a role in susceptibility to AMD, such as ABCA4 and apoE, will be analyzed by evaluating DNA sequence variations in those genes and looking for a correlation between any alleles and neovascular AMD. To our knowledge, a molecular genetics approach to finding genes for neovascular AMD based on extremely discordant and extremely concordant sibpairs has not been previously carried out by any other group of investigators. If successful, our work should provide substantial progress toward identifying the genetic causes of neovascular AMD, one of the leading causes of legal blindness among the elderly.