近日，美国圣路易斯华盛顿大学Carlos Cruchaga研究组发现，人类脑脊液的蛋白质组学分析识别出神经学相关的调控，并揭示阿尔茨海默病的致病蛋白。相关论文于2024年11月11日在线发表在《自然—遗传学》杂志上。

研究人员表示，将定量性状基因座（QTL）与疾病全基因组关联研究（GWAS）相结合，已被证明在优先筛选疾病相关基因方面取得了成功。QTL绘图主要集中在多组织表达QTL或血浆蛋白QTL（pQTL）上。

研究人员通过测量3506个样本中的6361种蛋白质，生成了脑脊液（CSF）pQTL图谱。研究人员识别了1883种蛋白质的3885个关联，包括2885个新的pQTL，展示了CSF中的独特基因调控。研究人员还在第3号染色体（chr3q28）靠近OSTN和第19号染色体（chr19q13.32）靠近APOE处识别出脑脊液富集的多效性区域，这些区域在神经元特异性和神经发育中富集。

通过蛋白质组全基因组关联研究（PWAS）、共定位和孟德尔随机化，研究人员将这些关联与阿尔茨海默病（AD）结合，识别出38个假定的致病蛋白，其中15个已有药物可用。最后，研究人员开发了一种基于蛋白质组学的AD预测模型，该模型优于基于遗传学的模型。这些发现对于进一步理解生物学机制并识别脑部和神经系统特征的致病及可成药蛋白质具有重要意义。

附：英文原文

Title: Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease

Author: Western, Daniel, Timsina, Jigyasha, Wang, Lihua, Wang, Ciyang, Yang, Chengran, Phillips, Bridget, Wang, Yueyao, Liu, Menghan, Ali, Muhammad, Beric, Aleksandra, Gorijala, Priyanka, Kohlfeld, Pat, Budde, John, Levey, Allan I., Morris, John C., Perrin, Richard J., Ruiz, Agustin, Marqui, Marta, Boada, Merc, de Rojas, Itziar, Rutledge, Jarod, Oh, Hamilton, Wilson, Edward N., Le Guen, Yann, Reus, Lianne M., Tijms, Betty, Visser, Pieter Jelle, van der Lee, Sven J., Pijnenburg, Yolande A. L., Teunissen, Charlotte E., del Campo Milan, Marta, Alvarez, Ignacio, Aguilar, Miquel, Greicius, Michael D., Pastor, Pau, Pulford, David J., Ibanez, Laura, Wyss-Coray, Tony, Sung, Yun Ju, Cruchaga, Carlos

Issue&Volume: 2024-11-11

Abstract: The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

DOI: 10.1038/s41588-024-01972-8

Source: https://www.nature.com/articles/s41588-024-01972-8