A 39UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP

Augustine Chemparathy, Yann Le Guen, Yi Zeng, John Gorzynski, Tanner D. Jensen, Chengran Yang, Nandita Kasireddy, Lia Talozzi, Michael Belloy, Ilaria Stewart, Aaron D. Gitler, Anthony D. Wagner, Elizabeth Mormino, Victor W. Henderson, Tony Wyss-Coray, Euan Ashley, Carlos Cruchaga, Michael D. Greicius

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Objectives Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but the causal variant at this locus remains unclear. Here, we asked whether a novel structural variant on TMEM106B is the causal variant. Methods An exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on an Alu element insertion on the 39UTR of TMEM106B. This study included data from longitudinal aging and neurogenerative disease cohorts at Stanford University, case-control cohorts in the Alzheimer Disease Sequencing Project (ADSP), and expression and proteomics data from Washington University in St. Louis (WUSTL). Four hundred thirty-two individuals from 2 Stanford aging cohorts were whole-genome long-read and short-read sequenced. A total of 16,906 samples from ADSP were short-read sequenced. Genotypes, transcriptomics, and proteomics data were available in 1,979 participants from an aging and dementia cohort at WUSTL. Selection criteria were specific to each cohort. In primary analyses, the linkage disequilibrium between the TMEM106B locus variants in the FTLD-TDP GWAS and the 39UTR insertion was estimated. We then estimated linkage by ancestry in the ADSP and evaluated the effect of the TMEM106B lead variant on mRNA and protein levels. Results The primary analysis included 432 participants (52.5% female, age range 45–92 years). We identified a 316 bp Alu insertion overlapping the TMEM106B 39UTR tightly linked with top GWAS variants rs3173615(C) and rs1990622(A). In ADSP European ancestry participants, this insertion is in equivalent linkage with rs1990622(A) (R2 = 0.962, D’ = 0.998) and rs3173615(C) (R2 = 0.960, D’ = 0.996). In African ancestry participants, the insertion is in stronger linkage with rs1990622(A) (R2 = 0.992, D’ = 0.998) than with rs3173615(C) (R2 = 0.811, D’ = 0.994). In public data sets, rs1990622 was consistently associated with TMEM106B protein levels but not with mRNA expression. In the WUSTL data set, rs1990622 is associated with TMEM106B protein levels in plasma and CSF, but not with TMEM106B mRNA expression. Discussion We identified a novel Alu element insertion in the 39UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 39UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies.

Original languageEnglish
Article numbere200124
JournalNeurology: Genetics
Volume10
Issue number1
DOIs
StatePublished - Feb 5 2024

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