Genetic variation modifies risk for neurodegeneration based on biomarker status.
Genetic variation modifies risk for neurodegeneration based on biomarker status.
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DOI：
10.3389/fnagi.2014.00183
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发表时间：
2014
影响因子：
4.8
通讯作者：
Alzheimer's Neuroimaging Initiative
中科院分区：
文献类型：
--
作者：
Hohman TJ;Koran ME;Thornton-Wells TA;Alzheimer's Neuroimaging Initiative
背景资料：虽然大量的工作已经深入了解脑脊液（CSF）生物标志物，脑萎缩和疾病进展之间的关系，但很少有工作试图研究遗传变异如何改变这些关系。这项研究的目的是双重的。首先，我们试图根据CSF tau和Aβ负荷识别高风险与低风险个体，并描述这些个体在AD相关感兴趣区域的脑萎缩特征。接下来，我们试图确定改变生物标志物分类和神经退行性变之间关系的遗传变异。方法：根据生物标志物阳性的既定临界点对参与者进行分类。混合模型回归用于量化左下侧脑室的纵向变化。使用全基因组关联研究（GWAS）方法进行单核苷酸多态性（SNP）和生物标志物组状态之间的相互作用分析。使用Bonferroni程序进行多重比较校正。结果如下：一个基因间SNP（rs 4866650）和SPTLC 1基因内的一个SNP（rs7849530）改变了淀粉样蛋白阳性和神经变性之间的关联。WDR 11-AS 1基因的转录变体（rs 12261764）改变了tau蛋白阳性与神经变性之间的关联。这些效应在两个子数据集之间是一致的，并解释了心室扩张的约3%的方差。一个额外的SNP（rs6887649）改变了淀粉样蛋白阳性与基线心室容积之间的关联，但在子数据集中没有一致地观察到。结论：遗传变异改变了AD生物标志物和神经退行性变之间的关联。调节大脑对氧化应激的分子反应的基因可能与神经对淀粉样蛋白-β的损伤作用的脆弱性特别相关。
Background: While a great deal of work has gone into understanding the relationship between Cerebrospinal fluid (CSF) biomarkers, brain atrophy, and disease progression, less work has attempted to investigate how genetic variation modifies these relationships. The goal of this study was two-fold. First, we sought to identify high-risk vs. low-risk individuals based on their CSF tau and Aβ load and characterize these individuals with regard to brain atrophy in an AD-relevant region of interest. Next, we sought to identify genetic variants that modified the relationship between biomarker classification and neurodegeneration. Methods: Participants were categorized based on established cut-points for biomarker positivity. Mixed model regression was used to quantify longitudinal change in the left inferior lateral ventricle. Interaction analyses between single nucleotide polymorphisms (SNPs) and biomarker group status were performed using a genome wide association study (GWAS) approach. Correction for multiple comparisons was performed using the Bonferroni procedure. Results: One intergenic SNP (rs4866650) and one SNP within the SPTLC1 gene (rs7849530) modified the association between amyloid positivity and neurodegeneration. A transcript variant of WDR11-AS1 gene (rs12261764) modified the association between tau positivity and neurodegeneration. These effects were consistent across the two sub-datasets and explained approximately 3% of variance in ventricular dilation. One additional SNP (rs6887649) modified the association between amyloid positivity and baseline ventricular volume, but was not observed consistently across the sub-datasets. Conclusions: Genetic variation modifies the association between AD biomarkers and neurodegeneration. Genes that regulate the molecular response in the brain to oxidative stress may be particularly relevant to neural vulnerability to the damaging effects of amyloid-β.
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DOI：
10.3233/jad-2011-111202
发表时间：
2012
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Filippov V;Song MA;Zhang K;Vinters HV;Tung S;Kirsch WM;Yang J;Duerksen-Hughes PJ
通讯作者：
Duerksen-Hughes PJ
影响因子：
--
作者：
Kathiresan S;Manning AK;Demissie S;D'Agostino RB;Surti A;Guiducci C;Gianniny L;Burtt NP;Melander O;Orho-Melander M;Arnett DK;Peloso GM;Ordovas JM;Cupples LA
通讯作者：
Cupples LA
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：
Hohman TJ;Koran ME;Thornton-Wells T;Alzheimer's Neuroimaging Initiative
通讯作者：
Alzheimer's Neuroimaging Initiative
影响因子：
9.9
作者：
Mielke, Michelle M.;Bandaru, Veera Vankata Ratnam;Carlson, Michelle C.
通讯作者：
Carlson, Michelle C.