2023
DOI: 10.1101/2023.07.06.23292312
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A 3’UTR Insertion Is a Candidate Causal Variant at theTMEM106BLocus Associated with Increased Risk for FTLD-TDP

Abstract: Single nucleotide variants (SNVs) near TMEM106B have been associated with risk of frontotemporal lobar dementia with TDP pathology (FTLD-TDP) but the causal variant at this locus has not yet been isolated. The initial leading FTLD-TDP genome-wide association study (GWAS) hit at this locus, rs1990622, is intergenic and is in linkage disequilibrium (LD) with a TMEM106B coding SNV, rs3173615. We developed a long-read sequencing (LRS) dataset of 407 individuals in order to identify structural variants associated w… Show more

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Cited by 8 publications
(7 citation statements)
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“…Recent (functional) studies support the above mechanisms. First, (brain) tissue-specific eQTL and pQTL databases highlight that the risk haplotype of TMEM106B leads to lower gene expression and protein abundance than the protective haplotype 27 . Furthermore, in vitro TDP-43 knockdown experiments in cell lines with the TMEM106B risk haplotype lead to significant decrease of TMEM106B expression levels compared to cell lines with the protective TMEM106B haplotype 71,72 .…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Recent (functional) studies support the above mechanisms. First, (brain) tissue-specific eQTL and pQTL databases highlight that the risk haplotype of TMEM106B leads to lower gene expression and protein abundance than the protective haplotype 27 . Furthermore, in vitro TDP-43 knockdown experiments in cell lines with the TMEM106B risk haplotype lead to significant decrease of TMEM106B expression levels compared to cell lines with the protective TMEM106B haplotype 71,72 .…”
Section: Discussionmentioning
confidence: 99%
“…Thus far, studies have exclusively focused on single nucleotide variants from GWAS and/or short-read whole-genome sequencing data. Here, we explored whether a 317 bp insertion, previously reported to be in linkage with the risk haplotype of TMEM106B 27 , may be the driver of the genetic association with altered disease risk.…”
Section: Introductionmentioning
confidence: 99%
“…For LRS SV this is a major challenge as existing short-read references such as gnomAD, CCDG, and 1000G, show low ascertainment of SVs discovered from LRS data (Figure S1f) [29][30][31]. To address this issue, we used a technology-matched population reference of nanopore genomes generated from Stanford's Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) (n=571) [32]. ADRC + SAMS nanopore genomes were processed with the same SV calling workflow and were merged using Jasmine-SV with the UDN callset; allele frequencies were estimated based on merged allele counts in the combined set.…”
Section: Long-read Population References Enable Frequency Estimates F...mentioning
confidence: 99%
“…Using the combined population of over 600 genomes of our UDN and ADRC + SAMS cohort [32], we dramatically improved our ability to filter LRS SVs for rare disease diagnosis. We detected a median of 716 rare SVs (>50bp) per genome, whereas using a short-read references (i.e.…”
Section: Long-read Population References Enable Frequency Estimates F...mentioning
confidence: 99%
“…TMEM106B APA might impact dimer levels by influencing the subcellular localization of TMEM106B mRNA and its ability as a scaffold for protein-protein interactions, as has been shown for other APA events 17 . Recent studies discovered an Alu element insertion in the TMEM106B 3' UTR, in perfect linkage with the top FTLD-TDP risk allele at this locus [56][57][58] . Given the proximity of these variants to TMEM106B's distal polyA site, future work will explore if and how these disease-associated genetic variants impact APA.…”
mentioning
confidence: 99%