Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease
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 ass...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1236509/full |
| _version_ | 1827855335714455552 |
|---|---|
| author | Konstantin G. Arbeev Svetlana Ukraintseva Olivia Bagley Hongzhe Duan Deqing Wu Igor Akushevich Eric Stallard Alexander Kulminski Kaare Christensen Mary F. Feitosa Jeffrey R. O’Connell Daniel Parker Heather Whitson Heather Whitson Anatoliy I. Yashin |
| author_facet | Konstantin G. Arbeev Svetlana Ukraintseva Olivia Bagley Hongzhe Duan Deqing Wu Igor Akushevich Eric Stallard Alexander Kulminski Kaare Christensen Mary F. Feitosa Jeffrey R. O’Connell Daniel Parker Heather Whitson Heather Whitson Anatoliy I. Yashin |
| author_sort | Konstantin G. Arbeev |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:49:40Z |
| format | Article |
| id | doaj.art-6441fe0893bb4ec6a432b8001284a234 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-03-12T11:49:40Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-6441fe0893bb4ec6a432b8001284a2342023-08-31T10:38:56ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-08-011410.3389/fgene.2023.12365091236509Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s diseaseKonstantin G. Arbeev0Svetlana Ukraintseva1Olivia Bagley2Hongzhe Duan3Deqing Wu4Igor Akushevich5Eric Stallard6Alexander Kulminski7Kaare Christensen8Mary F. Feitosa9Jeffrey R. O’Connell10Daniel Parker11Heather Whitson12Heather Whitson13Anatoliy I. Yashin14Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesDanish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, DenmarkDivision of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United StatesDivision of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, United StatesDuke Center for the Study of Aging and Human Development, Duke University, Durham, NC, United StatesDuke Center for the Study of Aging and Human Development, Duke University, Durham, NC, United StatesDurham VA Geriatrics Research Education and Clinical Center, Durham, NC, United StatesBiodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United StatesDysregulation 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.https://www.frontiersin.org/articles/10.3389/fgene.2023.1236509/fullagingAlzheimer’s diseasephysiological dysregulationresilienceaxon guidancesynaptic function |
| spellingShingle | Konstantin G. Arbeev Svetlana Ukraintseva Olivia Bagley Hongzhe Duan Deqing Wu Igor Akushevich Eric Stallard Alexander Kulminski Kaare Christensen Mary F. Feitosa Jeffrey R. O’Connell Daniel Parker Heather Whitson Heather Whitson Anatoliy I. Yashin Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease Frontiers in Genetics aging Alzheimer’s disease physiological dysregulation resilience axon guidance synaptic function |
| title | Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease |
| title_full | Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease |
| title_fullStr | Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease |
| title_full_unstemmed | Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease |
| title_short | Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer’s disease |
| title_sort | interactions between genes involved in physiological dysregulation and axon guidance role in alzheimer s disease |
| topic | aging Alzheimer’s disease physiological dysregulation resilience axon guidance synaptic function |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1236509/full |
| work_keys_str_mv | AT konstantingarbeev interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT svetlanaukraintseva interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT oliviabagley interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT hongzheduan interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT deqingwu interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT igorakushevich interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT ericstallard interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT alexanderkulminski interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT kaarechristensen interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT maryffeitosa interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT jeffreyroconnell interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT danielparker interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT heatherwhitson interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT heatherwhitson interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease AT anatoliyiyashin interactionsbetweengenesinvolvedinphysiologicaldysregulationandaxonguidanceroleinalzheimersdisease |