Fine mapping of the α-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees
Fine mapping of the α-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees
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DOI：
10.1093/hmg/ddg343
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发表时间：
2003-12-01
影响因子：
3.5
通讯作者：
Younkin, S
中科院分区：
文献类型：
--
作者：
Ertekin-Taner, N;Ronald, J;Younkin, S
使用血浆淀粉样β蛋白（A β 42）水平作为迟发性阿尔茨海默病（LOAD）的中间定量表型，我们先前获得了10号染色体上类似于80 cM的显著连锁。在受影响的LOAD同胞对的研究中独立获得了与同一区域的连锁。总之，这两项研究为10号染色体上的一个新的LOAD位点提供了强有力的证据，该位点可以增加Abeta 42。VR 22是一个位于80 cM的大基因（1.7 Mb），编码α-T连环蛋白，α-T连环蛋白是β连环蛋白的结合伴侣。这使得VR 22成为一个有吸引力的候选基因，因为β连环蛋白与早老素1相互作用，早老素1具有许多突变，这些突变升高了A β 42并导致早发性家族性AD。我们在10个扩展LOAD家族中鉴定了两个内含子VR 22 SNPs（4360和4783），它们在强连锁不平衡（LD）中显示出与血浆Abeta 42的高度显著关联（P=0.0001和0.0006）。这种关联显然有助于在相似于80 cM的连锁，因为当以VR 22关联为条件进行连锁分析时，lod评分降低。这种关联在另一组独立的12个LOAD系列中复制（4783的P=0.04，4360的P=0.08）。使用多个SNP的关联区域的边界显示VR 22是关联区域内唯一确认的基因。这些发现表明，VR 22具有影响A β 42的变体，并有助于先前报告的LOAD家族中血浆A β 42的关联。
Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at similar to80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at similar to80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.