Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways.

Research square Pub Date : 2024-06-05 DOI:10.21203/rs.3.rs-4480585/v1

Carlos Cruchaga, Joseph Bradley, Daniel Western, Ciyang Wang, Eder Lucio Da Fonseca, Achal Neupane, Jiji Kurup, NIcholas Ray, Melissa Jean-Francois, Priyanka Gorijala, Kristy Bergmann, John Budde, Eden Martin, Margaret Pericak-Vance, Michael Cuccaro, Brian Kunkle, John Morris, David Holtzman, Richard Perrin, Adam Naj, Jonathan Haines, Gerard Schellenberg, Victoria Fernandez, Christiane Reitz, Gary Beecham

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Abstract

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

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新型早老性痴呆相关基因通过谷氨酸、免疫激活和细胞内信号通路的失调影响发病风险。

阿尔茨海默病（AD）是一种高度多基因疾病，约有 5%的病例发病较早（≤70yo；EOAD）。其中约 90% 的 EOAD 病例仍无法用致病基因突变来解释。利用 EOAD 病例和对照组的数据，我们对非西班牙裔白人（NHW，NCase=6,282，NControl=13,386）、非裔美国人（AA NCase=782，NControl=3,663）和东亚人（NCase=375，NControl=838 CO）进行了全基因组关联研究（GWAS）和跨祖先荟萃分析。我们发现了 8 个新的重要基因位点：6 个在特定祖先分析中，2 个在跨祖先分析中。通过整合基于基因的分析、eQTL、pQTL 和功能注释，我们提名了四个参与小胶质细胞激活、谷氨酸生成和信号通路的新基因。这些结果表明，尽管EOAD与LOAD共享许多基因，但其中存在独特的基因和通路，可用于创建更好的预测模型或鉴定这种类型AD的靶点。

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