Year: 2015
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: To determine the independent association of the TMEM106B variants with transactive response DNA binding protein 43 (TDP-43) pathology in older persons without frontotemporal lobar degeneration (FTLD) and to explore functional pathways that link the risk variants to the pathology, including a GRN mRNA pathway. METHODS: Data came from 544 autopsied participants without FTLD in 2 community-based studies of aging. Participants underwent uniform neuropathologic evaluations, including TDP-43 cytoplasmic inclusions. We examined the association of TMEM106B variants with a semiquantitative measure of TDP-43 pathology in a series of regression analysis. We explored potential pathways by leveraging genetic, brain DNA methylation, miRNA, and transcriptomic data collected from this same group of participants. RESULTS: TDP-43 pathology was identified in 51.7% of the participants. The index single-nucleotide polymorphism (SNP), rs1990622(A), was associated with more advanced TDP-43 pathology. Top hits from fine mapping of the locus were in linkage disequilibrium of the index SNP. The association remained significant after adjustment for other neuropathologies including Alzheimer disease and hippocampal sclerosis (odds ratio = 1.351, 95% confidence interval = 1.068-1.709, p = 0.012). GRN expression was upregulated in rs1990622(AA/AG) carriers, and was associated with more advanced TDP-43 pathology. The TMEM106B variants were associated with lower level of DNA methylation in an active enhancer in GRN. CONCLUSIONS: Common variants in TMEM106B serve as a distinct risk factor for TDP-43 pathology in older persons without FTLD. The role of GRN expression and epigenetic mechanisms associating TMEM106B in the accumulation of TDP-43 in older persons require further study.
Source: Neurology
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Brain and Spinal Cord Microvascular Pathology in Late-Life Motor Impairment, Adult Neurological Phenotypes of Fragile X Gray Zone Expansion, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, G1184234779, G1282666458, Role of the Innate Immune System in Aging and Development of Alzheimer's Disease, G1827704456, G2200385677, Rush Center of Excellence on Disparties in HIV and Aging (CEDHA), Clinical Pathological Study of Cognitive Impairment in Essential Tremor, G249615658, Epidemiologic Study of TDP-43 Pathology in Aging and Dementia, G268727528, Targeted Proteomics of Resilient Cognition in Aging, Mechanisms linking insulin resistance to brain structure, pathology, and function, Exploring the Role of the Brain Transcriptome in Cognitive Decline, Neurobiology of Mild Cognitive Impairment in the Elderly, Pathway discovery, validation and compound identification for Alzheimer's disease, Alzheimer's Disease Core Center, TWO PRECLINICAL LATENT SCORES TO PREDICT OCCURRENCE OF DAT, Exploring the Role of the Brain Epigenome: Cognitive Decline and Life Experiences, Altered monocyte function in relation to the CD33 Alzheimers disease locus, Risk Factors, Pathology, and Clinical Expressions of AD, The Clinical Profile of Parkinson's Disease (PD) Pathology, Rush Alzheimer's Disease Core Center, Alzheimer's Disease Genetics Consortium, Epidemiology of Familial Late-Onset Alzheimer's Disease, Vascular Cognitive and Motor Decline: Impact of aPL, Influence of Dietary Fish and mercury Exposure on Brain health and Dementia, Role of impaired cognitive states & risk factors in conversion to mixed dementias, Risk Factors, Pathology, and Clinical Expressions of AD, G860030259, Exploring the Role of the Brain Epigenome: Cognitive Decline and Life Experiences, Development of Lewy Bodies Biofluid Signatures by Targeted Proteomics, Epidemiologic Study of Decision Making in Preclinical Alzheimer's Disease, Racial Differences in Late-Life Cognitive decline and risk of Alzheimer's Disease
OpenAlex ID: W1976537088