A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated with Increased Risk for FTLD-TDP.
medRxiv
; 2023 Nov 17.
Article
en En
| MEDLINE
| ID: mdl-37461476
ABSTRACT
Background and Objectives:
Single nucleotide variants near TMEM106B associate with risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer's disease (AD) in genome-wide association studies (GWAS), 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 3'UTR of TMEM106B. This study included data from longitudinal aging and neurogenerative disease cohorts at Stanford University, case-control cohorts in the Alzheimer's Disease Sequencing Project (ADSP), and expression and proteomics data from Washington University in St. Louis (WUSTL). 432 individuals from two Stanford aging cohorts were whole-genome long-read and short-read sequenced. 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 3'UTR 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% females, age range 45-92 years old). We identified a 316 bp Alu insertion overlapping the TMEM106B 3'UTR 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 datasets, rs1990622 was consistently associated with TMEM106B protein levels but not with mRNA expression. In the WUSTL dataset, rs1990622 is associated with TMEM106B protein levels in plasma and cerebrospinal fluid, but not with TMEM106B mRNA expression.Discussion:
We identified a novel Alu element insertion in the 3'UTR 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 3'UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Idioma:
En
Revista:
MedRxiv
Año:
2023
Tipo del documento:
Article
País de afiliación:
Canadá