美国肯塔基大学David W. Fardo研究组在研究中取得进展。他们通过检测具有多种神经病理学内表型的全基因组关联研究（GWAS），发现了新的风险基因位点，有助于深入了解痴呆的遗传机制。2024年10月8日出版的《自然—遗传学》杂志发表了这项成果。

据介绍，GWAS鉴定了超过80个ADRD的潜在风险基因位点。然而，大多数之前研究中使用的临床结果，掩盖了潜在神经病理学的复杂基因位点。

研究人员对11种与阿尔茨海默病及相关痴呆症（ADRD）的神经病理学内表型进行了GWAS分析，参与者有以下三个来源：美国国家阿尔茨海默氏症协调中心、宗教秩序研究和拉什记忆与衰老项目以及成人思维变化研究（n=7804名尸检患者）。

研究发现了八个独立的明显相关基因位点，其中四个是新的基因位点（COL4A1、PIK3R5、LZTS1和APOC2）。在对已知的ADRD基因位点进行单独检测后，有19个基因位点与至少一种神经病理学有明显相关性。遗传共定位分析确定了多效应和数量性状位点。大脑皮层APOC2附近两个位点的甲基化与脑淀粉样血管病相关。对神经病理学内表型的研究是了解遗传性ADRD风险机制的重要一步。

附：英文原文

Title: GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia

Author: Shade, Lincoln M. P., Katsumata, Yuriko, Abner, Erin L., Aung, Khine Zin, Claas, Steven A., Qiao, Qi, Heberle, Bernardo Aguzzoli, Brandon, J. Anthony, Page, Madeline L., Hohman, Timothy J., Mukherjee, Shubhabrata, Mayeux, Richard P., Farrer, Lindsay A., Schellenberg, Gerard D., Haines, Jonathan L., Kukull, Walter A., Nho, Kwangsik, Saykin, Andrew J., Bennett, David A., Schneider, Julie A., Ebbert, Mark T. W., Nelson, Peter T., Fardo, David W.

Issue&Volume: 2024-10-08

Abstract: Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n=7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.

DOI: 10.1038/s41588-024-01939-9

Source: https://www.nature.com/articles/s41588-024-01939-9