LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry

Abstract Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse...

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Published in:Journal of neuropathology and experimental neurology Vol. 82; no. 9; pp. 760 - 768
Main Authors: Katsumata, Yuriko, Fardo, David W, Shade, Lincoln M P, Nelson, Peter T
Format: Journal Article
Language:English
Published: England Oxford University Press 01.09.2023
Subjects:
African Americans
Aging - pathology
Alleles
Allelomorphism
Alzheimer Disease - genetics
Alzheimer Disease - pathology
Cognition disorders
Degeneration
Dementia
Genetic aspects
Genetic variation
Genomics
Health aspects
Health risk assessment
Humans
Membrane Proteins - genetics
Nerve Tissue Proteins - genetics
Nervous system
Neurological research
Neuropathology
Original
Polymorphism, Single Nucleotide - genetics
Progranulins - genetics
Risk factors
Sulfonylurea Receptors - genetics
TDP-43 Proteinopathies - pathology
United States
KATP
Genome-Wide Association Studies (GWAS)
Epidemiology
Diversity
FTLD
Dementia
KCNMB2
ISSN:0022-3069, 1554-6578, 1554-6578
Online Access:Get full text
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Summary:Abstract Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes—TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer’s Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer’s Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.
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ISSN:0022-3069
1554-6578
1554-6578
DOI:10.1093/jnen/nlad059