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.

View details for DOI 10.1101/2023.07.06.23292312

View details for PubMedID 37461476

View details for PubMedCentralID PMC10350161