Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood
Abstract
An increased risk of developing Alzheimer's disease (AD) has previously been found to be associated with variants at the MS4A6A locus. We sought to identify which genes and transcripts in this region have altered expression in AD and mild cognitive impairment (MCI) and are influenced by the AD risk variant(s), as a first step to understanding the molecular basis of AD susceptibility at this locus. Common variants located within highly expressed MS4A6A transcripts were significantly associated with AD and MS4A6A expression levels in blood from MCI and AD subjects (p < 0.05, rs610932, rs7232, rs583791). More copies of the protective (minor) allele were associated with lower MS4A6A expression of each transcript (e.g., p = 0.019; rs610932-total MS4A6A). Furthermore, in heterozygous AD subjects, relative expression of the protective allele of V4-MS4A6A transcripts was lower (p < 0.008). Irrespective of genotype, MS4A6A transcripts were increased in blood from people with AD (p < 0.003), whereas lower expression of full length V1-MS4A6A (p = 0.002) and higher expression of V4-MS4A6A (p = 1.8 × 10(-4)) were observed in MCI, relative to elderly controls. The association between genotype and expression was less consistent in brain, although BA9 did have a similar genotype association with V4-MS4A6A transcripts as in blood. MS4A6A transcripts were widely expressed in tissues and cells, with the exception of V4-MS4A6A, which was not expressed in neuronal cells. Together these results su…
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Pathway analyses identified immune-related pathways that may be relevant for the mechanisms of microglial aging, including STAT-3 and IL-6 signaling, and LXR/RXR activation.
“Our pathway analyses identified immune-related pathways that may be of relevance for the mechanisms of microglial aging, including STAT-3 and IL-6 signaling, as well as LXR/RXR activation, which has emerged as a key player in regulating cholesterol homeostasis and inflammation in the brain with a potential role in neurodegenerative disorders65–67.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [67]
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Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
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Functional characterization of Alzheimer’s disease genetic variants in microglia
Yang, X., Wen, J., Yang, H., Jones, I. R., Zhu, X., Liu, W., Li, B., Clelland, C. D., Luo, W., Wong, M. Y., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01506-8 · Cited by 71 · see citing works
- Authors
- Proitsi, P., Lee, S. H., Lunnon, K., Keohane, A., Powell, J., Troakes, C., Al-Sarraj, S., Furney, S., Soininen, H., Kłoszewska, I., Mecocci, P., Tsolaki, M., Vellas, B., Lovestone, S., & Hodges, A.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 35
- Issue
- 2
- Pages
- 279-290
- ISSN
- 0197-4580
- Cited by
- 55
- References
- 5
- Language
- en
- Funders
- InnoMed
- European Union of the Sixth Framework program
- Alzheimer's Research UK
- The John and Lucille van Geest Foundation
- Rosetrees Trust
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