Abstract
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer’s Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer’s pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer’s-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.
Document Type
Article
Publication Date
9-15-2021
Digital Object Identifier (DOI)
https://doi.org/10.1186/s40478-021-01250-2
Funding Information
This work was supported by the National Institutes of Health [R56-AG057191, R01-AG057187, P30-AG028383, R01-AG059716, K01-AG049164].
Related Content
NACC data are available upon request via NACC’s website (https://naccdata.org/). ROSMAP data are available online at the Rush Alzheimer’s Disease Center Resource Sharing Hub (https://www.radc.rush.edu/), as well as on the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) Knowledge Portal (syn3219045). ADGC data are available upon request via the NIAGADS website (https://www.niagads.org/user/login?destination=data/request/new_request/).
Repository Citation
Dugan, Adam J.; Nelson, Peter T.; Katsumata, Yuriko; Shade, Lincoln M. P.; Boehme, Kevin L.; Teylan, Merilee A.; Cykowski, Matthew D.; Mukherjee, Shubhabrata; Kauwe, John S. K.; Hohman, Timothy J.; Schneider, Julie A.; Alzheimer’s Disease Genetics Consortium; and Fardo, David W., "Analysis of Genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) Implicated in Risk for LATE-NC and Hippocampal Sclerosis Provides Pathogenetic Insights: A Retrospective Genetic Association Study" (2021). Biostatistics Faculty Publications. 57.
https://uknowledge.uky.edu/biostatistics_facpub/57
Additional file 1: Supplemental Table 1 for a summary of the rare conditions excluded from the NACC sample; these conditions are extremely rare among ROSMAP participants. ROSMAP participants included in the Nelson et al. 2014 hippocampal sclerosis (HS) genome wise association study (GWAS) were explicitly excluded from the current study; NACC participants were only included in the current study if version 10 NACC neuropathology (NP) data were available, which were not collected until after 2014. LATE-NC = limbic-predominant age-related TDP-43 encephalopathy neuropathological change; HS = hippocampal sclerosis; NACC = National Alzheimer's Coordinating Center; ROSMAP = Religious Orders Study and Rush Memory and Aging Project; GWAS = genome wide association study.
Included in
Biostatistics Commons, Epidemiology Commons, Geriatrics Commons, Neurology Commons, Pathology Commons
Notes/Citation Information
Published in Acta Neuropathologica Communications, v. 9, issue 1, article no. 152.
© 2021 The Author(s)
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