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脑脊液中蛋白质表达的遗传调控。

The genetic regulation of protein expression in cerebrospinal fluid.

机构信息

Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.

Memory Clinic, Skåne University Hospital, Lund University, Lund, Sweden.

出版信息

EMBO Mol Med. 2023 Jan 11;15(1):e16359. doi: 10.15252/emmm.202216359. Epub 2022 Dec 12.

DOI:10.15252/emmm.202216359
PMID:36504281
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9832827/
Abstract

Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10 , 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.

摘要

对脑脊液（CSF）蛋白的遗传调控研究可能揭示治疗神经疾病的途径。在 BioFINDER 研究中，对 1591 名参与者的 CSF 中的 398 种蛋白质进行了测量。蛋白质数量性状基因座（pQTL）被定义为遗传变异与蛋白质之间的关联，有 176 个 CSF 蛋白质的 pQTL（P < 1.25×10 ，117 个顺式 pQTL 和 59 个反式 pQTL）。脑室体积（通过脑磁共振成像测量）是几个 pQTL 的混杂因素。CSF 和血浆蛋白的 pQTL 总体上是相关的，但也观察到了 CSF 特异性的 pQTL。孟德尔随机化分析表明，几种蛋白质（例如，载脂蛋白 E、CD33 和 GRN 在阿尔茨海默病中，MMP-10 在阿尔茨海默病前临床阶段，SIGLEC9 在肌萎缩侧索硬化症中，CD38、GPNMB 和 ADAM15 在帕金森病中）起因果作用。GRN、MMP-10 和 GPNMB 的 CSF 水平在阿尔茨海默病、阿尔茨海默病前临床阶段和帕金森病中分别发生改变。这些发现为探索新疗法的途径指明了方向。脑室体积混杂 pQTL 的新发现对未来 CSF 蛋白质组遗传调控研究的设计具有重要意义。

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