Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways-Reference-Cited by-同舟云学术

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

Published:2024-06-05 Issue: Volume: Page:
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Author:

Cruchaga Carlos¹^ORCID,Bradley Joseph²^ORCID,Western Daniel³^ORCID,Wang Ciyang⁴^ORCID,Fonseca Eder Lucio Da⁵,Neupane Achal²,Kurup Jiji⁶^ORCID,Ray NIcholas⁶,Jean-Francois Melissa⁵,Gorijala Priyanka⁴,Bergmann Kristy⁷,Budde John^ORCID,Martin Eden⁵,Pericak-Vance Margaret⁵^ORCID,Cuccaro Michael⁸,Kunkle Brian⁹,Morris John¹⁰,Holtzman David⁴^ORCID,Perrin Richard²^ORCID,Naj Adam¹¹^ORCID,Haines Jonathan¹²^ORCID,Schellenberg Gerard¹¹,Fernandez Victoria²,Reitz Christiane⁶^ORCID,Beecham Gary⁵,Consortium Alzheimer's Disease Genetics¹³,ADRC Charles F. and Joanne Knight Alzheimer's disease research ce¹⁴

Affiliation:

1. Washington University, School of Medicine

2. Washington University in St. Louis

3. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

4. Washington University School of Medicine

5. University of Miami

6. Columbia University

7. Washington University School of Medicine, St. Louis

8. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida

9. University of Miami School of Medicine

10. Knight Alzheimer Disease Research Center

11. University of Pennsylvania

12. Case Western Reserve University

13. University of Pennsylvania School of Medicine

14. Charles F. and Joanne Knight Alzheimer's disease research center

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

Publisher

Research Square Platform LLC

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