小柯机器人

美国埃默里大学医学院Thomas S. Wingo和Aliza P. Wingo合作取得最新进展。他们将人脑蛋白质组与全基因组关联数据整合在一起，揭示新蛋白与阿尔茨海默氏病（AD）的发病机理有关。这一研究成果发表在2021年1月28日出版的国际学术期刊《自然-遗传学》杂志上。

他们旨在确定通过其对脑蛋白丰度的影响而赋予AD风险的基因座，从而为AD发病机理提供新见解。为此，他们将AD GWAS结果与人脑蛋白质组相结合，以进行AD的蛋白质组范围关联研究（PWAS），然后进行孟德尔随机化和共定位分析。

他们通过其顺式调节的脑蛋白丰度确定了11个与在AD中具有因果关系的基因。在确认的PWAS中复制了9个，其中8个代表AD GWAS之前未发现的新的AD风险基因。此外，他们证明了结果独立于APOE e4。总之，他们的发现为AD发病机制提供了新见解，并为进一步的机理和治疗研究提供了有希望的靶标。

据了解，全基因组关联研究（GWAS）已经确定了许多AD的风险基因座，但是这些基因座如何赋予AD风险尚不清楚。

附：英文原文

Title: Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis

Author: Aliza P. Wingo, Yue Liu, Ekaterina S. Gerasimov, Jake Gockley, Benjamin A. Logsdon, Duc M. Duong, Eric B. Dammer, Chloe Robins, Thomas G. Beach, Eric M. Reiman, Michael P. Epstein, Philip L. De Jager, James J. Lah, David A. Bennett, Nicholas T. Seyfried, Allan I. Levey, Thomas S. Wingo

Issue&Volume: 2021-01-28

Abstract: Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer’s disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.

DOI: 10.1038/s41588-020-00773-z

Source: https://www.nature.com/articles/s41588-020-00773-z

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex