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 with neurodegenerative disorders. We identified a prevalent 322 base pair deletion on the TMEM106B 3 ′untranslated region (UTR) that was in perfect linkage with rs1990622 and near-perfect linkage with rs3173615 (genotype discordance in two of 274 individuals who had LRS and short-read next-generation sequencing). In Alzheimer's Disease Sequencing Project (ADSP) participants, this deletion was in greater LD with rs1990622 (R2=0.920916, D′=0.963472) than with rs3173615 (R2=0.883776, D′=0.963575). rs1990622 and rs3173615 are less closely linked (R2=0.7403, D′=0.9915) in African populations. Among African ancestry individuals in the ADSP, the deletion is in even greater LD with rs1990622 (R2=0.936841, D′=0.976782) than with rs3173615 (R2=0.764242, D′=0.974406). Querying publicly available genetic datasets with associated mRNA expression and protein levels, we confirmed that rs1990622 is consistently a protein quantitative trait locus but not an expression quantitative trait locus, consistent with a causal variant present on the TMEM106B 3′UTR. In summary, the TMEM106B 3′ UTR deletion is a large genetic variant on the TMEM106B transcript that is in higher LD with the leading GWAS hit rs1990622 than rs3173615 and may mediate the protective effect of this locus in neurodegenerative disease.

An AluYb8 retrotransposon characterises a risk haplotype of TMEM106B associated in neurodegeneration

“…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 .…”

“…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.…”

Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease

“…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.…”

“…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.…”

TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

“…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.…”