Perry Rodney T, Wiener Howard, Harrell Lindy E, Blacker Deborah, Tanzi Rudolph E, Bertram Lars, Bassett Susan S, Go Rodney C P
Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA.
Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):220-7. doi: 10.1002/ajmg.b.30433.
Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD.
除了位于19q13的载脂蛋白E（APOE）峰值外，在我们最初的基因组扫描中，9q22区域被确定为来自美国国立精神卫生研究所（NIMH）遗传学计划样本的晚发性阿尔茨海默病（AD）家系子集中多点对数优势分数（MLS）最高的候选区域（在101厘摩（cM）处MLS = 2.9）。我们现在已对该区域另外12个短串联重复序列（STR）进行了基因分型。多点分析表明，该区域仍然显著，峰值MLS从2.9增加到3.8，位于标记D9S1815附近的95 cM处，且1个LOD区间从21.5 cM缩小到11 cM。同源对数优势分数（HLOD）也提供了显著连锁的证据（α = 31%时为4.5），该区域进一步缩小到6.6 cM（92.2 - 98.8 cM）。据报道，位于83.3 cM的泛素连接酶1基因（UBQLN1）中的单核苷酸多态性（SNP）与AD显著相关，占原始连锁信号的很大一部分[伯特伦等人，2005年]。我们在此处生成的更高分辨率基因型数据的分析为9q22染色体上至少存在一个额外基因座提供了进一步支持。为了确定这个假定的AD易感基因，我们已开始分析这个缩小区域内及周围其他候选基因中的SNP，以测试与AD的其他关联。
