A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD).
A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD).
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DOI：
10.1007/s12017-015-8342-1
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发表时间：
2015-06
影响因子：
3.5
通讯作者：
Weber, Bernhard H. F.
中科院分区：
文献类型：
--
作者：
Grassmann, Felix;Friedrich, Ulrike;Fauser, Sascha;Schick, Tina;Milenkovic, Andrea;Schulz, Heidi L.;von Strachwitz, Claudia N.;Bettecken, Thomas;Lichtner, Peter;Meitinger, Thomas;Arend, Nicole;Wolf, Armin;Haritoglou, Christos;Rudolph, Guenther;Chakravarthy, Usha;Silvestri, Giuliana;McKay, Gareth J.;Freitag-Wolf, Sandra;Krawczak, Michael;Smith, R. Theodore;Merriam, John C.;Merriam, Joanna E.;Allikmets, Rando;Heid, Iris M.;Weber, Bernhard H. F.
关键词：
年龄相关性黄斑变性（AMD）是50岁以上白种人失明的主要原因，随着世界人口寿命的预期增加，患病率预计将显著增加。为了进一步扩大我们对该疾病遗传结构的了解，我们采用了一种候选基因方法，评估了25个基因和109个变体。其中，在对来自5项研究的3229例病例和2835例对照的联合分析中，发现位于死亡相关蛋白样1 （DAPL1）中的同属单核苷酸多态性（SNP） rs17810398与AMD相关[合并P ADJ = 1.15 × 10−6,OR 1.332(1.186 - 1.496)]。这种关联表现为极显著的性别差异（P diff = 0.0032），明显局限于女性，具有全基因组意义[P ADJ = 2.62 × 10−8,OR 1.541 (1.324-1.796)；男性：P ADJ = 0.382, OR 1.084(0.905-1.298)]。通过对DAPL1位点的风险和非风险相关单倍型进行靶向重测序，我们确定了额外的潜在功能风险变异，即常见的897 bp缺失和预测影响外显子剪接增强子的推定结合位点的SNP。我们发现风险单倍型与两种不常见的非规范DAPL1亚型的视网膜转录物水平降低相关。DAPL1在上皮细胞分化中发挥作用，并可能参与细胞凋亡过程，从而提示AMD发病机制可能的新途径。本文的在线版本（doi:10.1007/s12017-015-8342-1）含有补充资料，仅供授权用户使用。
Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10−6, OR 1.332 (1.187–1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10−8, OR 1.541 (1.324–1.796); males: P ADJ = 0.382, OR 1.084 (0.905–1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis. The online version of this article (doi:10.1007/s12017-015-8342-1) contains supplementary material, which is available to authorized users.
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SNPINFO：将GWA和候选基因信息整合到遗传关联研究的功能SNP中。
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