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全基因组荟萃分析阿尔茨海默病脑脊液生物标志物。

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.

机构信息

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.

Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.

出版信息

Acta Neuropathol. 2022 Nov;144(5):821-842. doi: 10.1007/s00401-022-02454-z. Epub 2022 Sep 6.

DOI:10.1007/s00401-022-02454-z
PMID:36066633
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9547780/
Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

摘要

脑脊液（CSF）中的淀粉样蛋白β 42（Aβ42）和磷酸化 tau（pTau）水平比临床诊断更能直接反映阿尔茨海默病（AD）发病机制的核心特征。该研究由欧洲阿尔茨海默病和痴呆症生物银行（EADB）发起，建立了迄今为止最大的 CSF 生物标志物遗传基础合作研究，包括 31 个队列，共 13116 人（发现队列 n=8074；复制队列 n=5042 人）。除了 APOE 基因座外，还观察到与另外两个已确立的 AD 风险基因座的新关联；CR1 被证明是 Aβ42 的基因座，BIN1 是 pTau 的基因座。进一步确定 GMNC 和 C16orf95 为 pTau 的基因座，后者是新发现的。探索所有已知 AD 风险基因座对 CSF 蛋白水平影响的聚类方法揭示了 4 个生物学类别，表明 AD 病因中涉及多个与 Aβ42 和 pTau 相关的生物学途径。在功能后续分析中，GMNC 和 C16orf95 均与侧脑室容积相关，表明 tau 水平和脑室内容积的遗传病因存在重叠。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/5544e5986e76/401_2022_2454_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/b48eaa60add5/401_2022_2454_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/0f0cf563a1af/401_2022_2454_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/5544e5986e76/401_2022_2454_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/b48eaa60add5/401_2022_2454_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/0f0cf563a1af/401_2022_2454_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/9547780/5544e5986e76/401_2022_2454_Fig3_HTML.jpg

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