A 3’UTR Insertion Is a Candidate Causal Variant at theTMEM106BLocus Associated with Increased Risk for FTLD-TDP

Abstract

AbstractBackground and ObjectivesSingle nucleotide variants nearTMEM106Bassociate 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 onTMEM106Bis the causal variant.MethodsAn exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on anAluelement insertion on the 3’UTR ofTMEM106B. 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 theTMEM106Blocus 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 theTMEM106Blead variant on mRNA and protein levels.ResultsThe primary analysis included 432 participants (52.5% females, age range 45-92 years old). We identified a 316 bpAluinsertion overlapping theTMEM106B3’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 withTMEM106BmRNA expression.DiscussionWe identified a novelAluelement insertion in the 3’UTR ofTMEM106Bin 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.