Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.
Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.
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DOI：
10.1371/journal.pone.0076001
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
中科院分区：
文献类型：
--
作者：
Honea RA;Cruchaga C;Perea RD;Saykin AJ;Burns JM;Weinberger DR;Goate AM;Alzheimer’s Disease Neuroimaging Initiative (ADNI)
越来越多的证据表明，神经营养因子，如脑源性神经营养因子（BDNF），可能会影响衰老和阿尔茨海默病。然而，传统的遗传关联研究尚未发现BDNF与AD之间的明确关系。我们的目标是测试BDNF单核苷酸多态性（SNPs）是否影响阿尔茨海默病相关的脑成像和疾病的认知标志物。我们对645名阿尔茨海默病神经影像学倡议参与者（ND=175，MCI=316，AD=154）完成了一项成像遗传学研究，这些参与者在基线时有认知，脑成像和遗传学数据，并且在两年时有脑成像数据。使用Illumina Human 610-Quad BeadChip对样品进行基因分型。在质量控制措施之后，在数据集中鉴定了BDNF的13个SNP（rs6265（Val66Met），rs12273363，rs11030094，rs925946，rs1050187，rs2203877，rs11030104，rs11030108，rs10835211，rs7934165，rs908867，rs1491850，rs1157459）。我们分析了一个亚组的8个SNPs是在低连锁不平衡。ADNI研究人员可以进行自动脑形态测量，我们分析了基线认知评分、海马和全脑体积、海马和全脑萎缩率以及一年和两年内ADAS-Cog的变化率。分析的8个BDNF SNPs中有3个与认知能力下降显著相关（rs 1157659，rs 11030094，rs 11030108）。没有SNPs与基线脑容量测量值显著相关，但6个SNPs与海马和/或全脑萎缩在两年内显著相关（rs 908867，rs 11030094，rs6265，rs 10501087，rs 1157659，rs 1491850）。我们还发现了BDNF Val 66 Met SNP和年龄与全脑体积之间的相互作用。我们在一个大型数据集中的成像遗传学分析表明，虽然BDNF遗传变异与AD的诊断没有特异性相关，但它似乎在AD相关的脑神经退行性变中发挥作用。
There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer’s Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer’s Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer’s Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154) who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met), rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459). We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108). No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850). We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD-related brain neurodegeneration.
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