PDF(Pubmed)
Abstract：
Late-onset Alzheimer\'s disease (LOAD) is a complex and multifactorial disease. So far ten loci have been identified for LOAD, including APOE, PICALM, CLU, BIN1, CD2AP, CR1, CD33, EPHA1, ABCA7, and MS4A4A/MS4A6E, but they explain about 50% of the genetic risk and thus additional risk genes need to be identified. Amyloid beta (Aβ) plaques develop in the brains of LOAD patients and are considered to be a pathological hallmark of this disease. Recently 12 new Aβ toxicity modifier genes (ADSSL1, PICALM, SH3KBP1, XRN1, SNX8, PPP2R5C, FBXL2, MAP2K4, SYNJ1, RABGEF1, POMT2, and XPO1) have been identified that potentially play a role in LOAD risk. In this study, we have examined the association of 222 SNPs in these 12 candidate genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. Single site and haplotype analyses were performed using PLINK. Following adjustment for APOE genotype, age, sex, and principal components, we found single nucleotide polymorphisms (SNPs) in PPP2R5C, PICALM, SH3KBP1, XRN1, and SNX8 that showed significant association with risk of LOAD. The top SNP was located in intron 3 of PPP2R5C (P=0.009017), followed by an intron 19 SNP in PICALM (P=0.0102). Haplotype analysis revealed significant associations in ADSSL1, PICALM, PPP2R5C, SNX8, and SH3KBP1 genes. Our data indicate that genetic variation in these new candidate genes affects the risk of LOAD. Further investigation of these genes, including additional replication in other case-control samples and functional studies to elucidate the pathways by which they affect Aβ, are necessary to determine the degree of involvement these genes have for LOAD risk.
摘要：
迟发性阿尔茨海默病(LOAD)是一种复杂的多因素疾病。到目前为止，已经确定了10个LOAD基因座，包括APOE,Picalm,CLU,BIN1,CD2AP,CR1、CD33、EPHA1、ABCA7和MS4A4A/MS4A6E，但是它们解释了大约50％的遗传风险，因此需要识别其他风险基因。淀粉样β（Aβ）斑块在LOAD患者的大脑中形成，被认为是该疾病的病理标志。最近12个新的Aβ毒性修饰基因（ADSSL1，PICALM，SH3KBP1,XRN1,SNX8,PPP2R5C,FBXL2，MAP2K4，SYNJ1，RABGEF1，POMT2和XPO1）已被确定可能在LOAD风险中起作用。在这项研究中,在1291例LOAD病例和958例认知正常对照中,我们研究了这12个候选基因中222个SNP与LOAD风险的相关性.使用PLINK进行单位点和单倍型分析。在调整APOE基因型后，年龄,性别,和主要成分，我们在PPP2R5C中发现了单核苷酸多态性（SNPs），Picalm,SH3KBP1、XRN1和SNX8与LOAD风险显著相关。顶部SNP位于PPP2R5C的内含子3（P=0.009017），随后是PICALM中的内含子19SNP(P=0.0102)。单倍型分析显示ADSSL1、PICALM、PPP2R5C,SNX8和SH3KBP1基因。我们的数据表明，这些新候选基因的遗传变异会影响LOAD的风险。进一步研究这些基因,包括在其他病例对照样品中的额外复制和功能研究，以阐明它们影响Aβ的途径，有必要确定这些基因参与LOAD风险的程度。
