SIBLING STUDY OF AGE-RELATED MACULAR DEGENERATION

描述（由申请人提供）：我们建议招募成对的兄弟姐妹进行分子遗传学搜索，以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。将招募两种类型的同胞对，极端不一致的同胞对和极端一致的同胞对。极不一致的同胞将由一个成员（患有新生血管性AMD的指数同胞）和第二个成员组成，第二个成员在指数同胞发展新生血管性AMD的年龄时具有很少或没有黄斑老化迹象。非常一致的同胞将由患有新生血管性AMD的两个同胞组成。将从这些兄弟姐妹采集的血液样本中纯化白细胞DNA。这些同胞对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，平均而言，极端不一致的对共享的等位基因比预期的少，而平均而言，极端一致的同胞对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，将通过评估这些基因中的DNA序列变异并寻找任何等位基因与新生血管性AMD之间的相关性来分析可能在AMD易感性中起作用的候选基因，如ABCA 4和apoE。据我们所知，分子遗传学方法来寻找基因的新生血管性AMD的基础上，非常不一致和非常一致的同胞以前没有进行任何其他组的调查。如果成功的话，我们的工作将为确定新生血管性AMD的遗传原因提供实质性的进展，新生血管性AMD是老年人法律的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.