Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort.
Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort.
复制标题
DOI：
10.1016/j.neuroimage.2010.01.042
复制
发表时间：
2010-11-15
期刊：
影响因子：
5.7
通讯作者：
Saykin, Andrew J.
中科院分区：
文献类型：
--
作者：
Shen, Li;Kim, Sungeun;Risacher, Shannon L.;Nho, Kwangsik;Swaminathan, Shanker;West, John D.;Foroud, Tatiana;Pankratz, Nathan;Moore, Jason H.;Sloan, Chantel D.;Huentelman, Matthew J.;Craig, David W.;DeChairo, Bryan M.;Potkin, Steven G.;Jack, Clifford R., Jr.;Weiner, Michael W.;Saykin, Andrew J.
描述了一种全基因组、全脑方法来研究遗传对神经影像表型的影响，以识别数量性状位点。使用基于体素的形态测量 (VBM) 和 FreeSurfer 分区对阿尔茨海默病神经影像计划 1.5 T MRI 和遗传数据集进行研究，然后进行全基因组关联研究 (GWAS)。从基线扫描中提取了一百四十二个灰质（GM）密度、体积和皮质厚度的测量值。使用 PLINK 对每种表型进行了 GWAS，使用质量控制的基因型和扫描数据，包括 620,903 个单核苷酸多态性 (SNP) 中的 530,992 个，以及 818 名参与者中的 733 名（175 名 AD、354 名遗忘性轻度认知障碍、MCI 和 204 名健康对照，HC）。层次聚类和热图用于分析 GWAS 结果，并在两个显着性阈值（p<10−7 和 p<10−6）下报告关联性。正如预期的那样，APOE 和 TOMM40 基因中的 SNP 被确认为与多个大脑区域密切相关的标记。其他顶级 SNP 接近 EPHA4、TP63 和 NXPH1 基因。 rs6463843（侧翼 NXPH1）的详细图像分析显示，相对于 GG 纯合子，TT 诊断组的整体和区域 GM 密度降低。交互作用分析表明，T 等位基因纯合的 AD 患者对右侧海马 GM 密度损失表现出不同的脆弱性。 NXPH1 编码一种与促进树突和轴突之间粘附有关的蛋白质，这是突触完整性的关键因素，突触完整性的丧失是 AD 的一个标志。全基因组、全脑搜索策略有可能揭示新的候选基因和基因座，值得进一步研究和复制。
A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimer's Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10−7 and p<10−6). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication.
登录
查看更多内容
影响因子：
5.7
作者：
Fischl, B;Sereno, MI;Dale, AM
通讯作者：
Dale, AM
影响因子：
3.7
作者：
Bearden, Carrie E.;van Erp, Theo G. M.;Thompson, Paul M.
通讯作者：
Thompson, Paul M.
影响因子：
5.7
作者：
Dale, AM;Fischl, B;Sereno, MI
通讯作者：
Sereno, MI
影响因子：
2.5
作者：
Lind, J;Larsson, A;Nyberg, L
通讯作者：
Nyberg, L
影响因子：
25
作者：
Kriegeskorte, Nikolaus;Simmons, W. Kyle;Bellgowan, Patrick S. F.;Baker, Chris I.
通讯作者：
Baker, Chris I.