Work

Fine‐mapping of the TMEM106B locus reveals four haplotypes that are differentially associated with risk for neurodegeneration

Year: 2025

Type: article

Abstract: BACKGROUND: Genome-wide association studies (GWAS) linked TMEM106B variants to susceptibility for neurodegenerative diseases, but the causal genetic elements remain unclear. METHOD: We used genotyping data from 5,792 Alzheimer disease cases and controls, and applied COJO to identify haplotypes in the TMEM106B locus that independently associated with AD. Then, we used long-read sequencing data from 513 individuals to annotate these haplotypes with structural variations that map into them. RESULTS: Analysis of the genotyping data revealed that the TMEM106B locus consists of four major haplotypes: HA/Ha (covering the coding region), and HB/Hb (covering the upstream regulatory region). These combine into four combinations with varying population-frequencies: HAB (57%), HaB (34%), Hab (9%), and HAb (<1%). Long-read sequencing of 513 individuals showed that HA haplotypes (marked by 185-Threonine) carry unique methylated CpG sites and an AluYb8-retrotransposon in the 3' UTR, while the Ha haplotypes are marked by the 185-Serine allele. Hb haplotypes carry several structural variants (SVs) in nearby distal enhancers, including a 19 Kbp rearrangement, absent in all other haplotypes. Joint association models revealed that the HAB combination (AluYb8+185-Threonine) is risk-increasing, while Hab (SVs+185-Serine) confers the protective effect. HaB (185-Serine only) is neutral, while HAb was too rare to assess. Relative to middle-aged non-demented controls, cognitively healthy centenarians were more enriched with Hab (OR=1.49, padj=2.18×10-2) than with HaB (OR=1.23, padj=5.06×10-2). Proteomic analysis of temporal cortex tissues (n = 182) indicated that relative to the neutral HaB combination, the protective Hab is associated with 1.1-fold lower TMEM106B C-terminal peptide abundance, while the risk-increasing HAB is associated with 1.16-fold higher abundance. CONCLUSION: Our data indicates that the genetic structure underlying the association of the TMEM106B locus with neurodegenerative diseases is driven by the effect of multiple haplotypes.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70855_104407