Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease

Frontiers in Genetics

Genetics

Alexander Kulminski¹  Eric Stallard¹  Konstantin G. Arbeev¹  Svetlana Ukraintseva¹  Deqing Wu¹  Igor Akushevich¹  Olivia Bagley¹  Anatoliy I. Yashin¹  Hongzhe Duan¹  Kaare Christensen²  Jeffrey R. O’Connell³  Mary F. Feitosa⁴  Daniel Parker⁵  Heather Whitson⁶ 

[1] Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United States;Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark;Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, United States;Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States;Duke Center for the Study of Aging and Human Development, Duke University, Durham, NC, United States;Duke Center for the Study of Aging and Human Development, Duke University, Durham, NC, United States;Durham VA Geriatrics Research Education and Clinical Center, Durham, NC, United States;

关键词: aging;    Alzheimer’s disease;    physiological dysregulation;    resilience;    axon guidance;    synaptic function;    genetic interactions;    candidate genes;   

DOI  :  10.3389/fgene.2023.1236509

 received in 2023-06-07, accepted in 2023-08-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Dysregulation of physiological processes may contribute to Alzheimer’s disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.g., amyloid, tau, neurodegeneration) in the literature. Here, we tested the hypothesis that genes involved in PD and axon guidance/synapse function may jointly influence onset of AD. We assessed the impact of interactions between SNPs in such genes on AD onset in the Long Life Family Study and sought to replicate the findings in the Health and Retirement Study. We found significant interactions between SNPs in the UNC5C and CNTN6, and PLXNA4 and EPHB2 genes that influenced AD onset in both datasets. Associations with individual SNPs were not statistically significant. Our findings, thus, support a major role of genetic interactions in the heterogeneity of AD and suggest the joint contribution of genes involved in PD and axon guidance/synapse function (essential for the maintenance of complex neural networks) to AD development.

【 授权许可】

Unknown   
Copyright © 2023 Arbeev, Ukraintseva, Bagley, Duan, Wu, Akushevich, Stallard, Kulminski, Christensen, Feitosa, O’Connell, Parker, Whitson and Yashin.