Hulsman, Marc

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.

ABSTRACT Genetic variation at the TMEM106B locus has been associated with Alzheimer’s disease (AD) and related neurodegenerative phenotypes, yet its haplotypic architecture remains incompletely resolved. We refined the genetic landscape of TMEM106B by integrating AD-GWAS summary statistics (∼978K individuals) with haplotype analyses in 5,873 Dutch genomes including AD-cases, age-matched controls, and cognitively healthy centenarians. In addition to the known linkage disequilibrium (LD) block defining risk and protective haplotypes characterized by the amino acid substitution at residue 185 (Threonine/Serine), we identify a second conditionally independent LD block. Together these form four haplotypes (T1-T4), with T3 strongly enriched in centenarians. Long-read whole-genome sequencing in 493 individuals reveals haplotype-linked structural variation and methylation patterns, including a ∼19 Kbp genomic rearrangement carried by T3. These findings indicate that the TMEM106B locus comprises multiple haplotypes defined by methylation patterns and structural variants, offering insights into GWAS associations with AD risk and preserved cognition at extreme age.

AbstractBackgroundThe TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome‐wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD‐TDP). However, the causal variant that drives the association has thus far remained elusive.MethodsWe generated long‐read whole‐genome sequencing data of 256 individuals, primarily from Dutch descent. We characterized SNPs and larger structural variants in the TMEM106B locus using de novo genome assembly.ResultsWe identified an insertion of an AluYb8 retrotransposon in the 3’ UTR of TMEM106B gene, that was in complete linkage with the TMEM106B risk‐SNP. AluYb8 retrotransposons have the propensity to propagate through our genomes by utilising a ‘copy‐paste’ mechanism, and once integrated can disrupt transcription and translation of nearby genes. However, propagation of retrotransposons can be suppressed by methylation of the insert and its surrounding regions. Indeed, we observed that the risk haplotype with the AluYb8 insertion, but not the protective haplotype, accumulated CpG islands over evolutionary time. Notably, we observed similar retrotransposon insertions in the 3’ UTR of TMEM106B orthologs in non‐primate species. This suggests a survival advantage, which may be explained by recent findings that TMEM106B is an entry‐receptor for specific viruses in lung‐tissue, such that SINE‐mediated downregulation of TMEM106B may limit viral infection‐load across species.ConclusionsWe speculate that AluYb8‐mediated downregulation of TMEM106B may be protective at younger ages in lung tissues, but that at advanced ages its downregulation in the brain may contribute to increased risk of neurodegenerative diseases. Furthermore, next to the supression of AluYb8 activation by DNA methylation, it may also be suppressed by TDP‐43, in its role in post‐translational RNA‐processing. This leads us to further speculate that age‐related demethylation and age‐related dysregulation of TDP‐43 may result in a negative feedback loop that ultimately reduces the endolysosomal activity in cells. We argue that such a mechanism would explain why increased age is among the strongest risk factors of neurodegenerative diseases.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.