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The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion
- Source :
- Acta Neuropathol
- Publication Year :
- 2019
-
Abstract
- Apart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the TMEM106B gene region as significantly associated with neuronal proportion (p value = 6.40 × 10−07) and replicated this finding in an independent dataset (p value = 7.41 × 10−04) surpassing the genome-wide threshold in the meta-analysis (p value = 9.42 × 10−09). This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r2 = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the TMEM106B gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that TMEM106B could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits.
- Subjects :
- 0301 basic medicine
Male
Aging
Genome-wide association study
Nerve Tissue Proteins
Disease
Biology
Polymorphism, Single Nucleotide
Article
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
medicine
Humans
Genetic Predisposition to Disease
Genetic association
Aged
Aged, 80 and over
Neurons
Neurodegeneration
Brain
Membrane Proteins
Neurodegenerative Diseases
Frontotemporal lobar degeneration
medicine.disease
Cortex (botany)
030104 developmental biology
medicine.anatomical_structure
Cerebral cortex
Schizophrenia
Immunology
Female
Neurology (clinical)
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathol
- Accession number :
- edsair.doi.dedup.....df0e49939a81d11a6dfd5aa9ca0a1017