Citations 2
Fine‐mapping of the TMEM106B locus reveals four haplotypes that are differentially associated with risk for neurodegeneration
Salazar, Alex , Knoop, Lydian, Lee, Sven J van der, Wijesekera, Sanduni, Hiltunen, Mikko, Damme, Markus, Petrucelli, Leonard, Reinders, Marcel J.T., Smit, August B. , Hulsman, Marc , Holstege, Henne H. , Pijnenburg, Yolande A.L. , Křížová, Jana , Hiltunen, Mikko O. , Daμμe, Markus , Petrucelli, Leonard
Alzheimer's & Dementia | December 24, 2025 | Volume: 21 | Issue: S1 | Pages: No page available
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.
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Guen, Yann Le , Luo, Guo , Damotte, Vincent , Jansen, Iris E. , Nicolas, Aude , Rojas, Itziar de, Bellenguez, Céline , Lian, Michelle Mulan , Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier‐Boley, Benjamin , Naito, Tatsuhiko , Talyansky, Seth D., Yogeshwar, Selina , Sempere, Vicente Peris, Satake, Wataru , Álvarez, Victoria , Arosio, Beatrice , Boland, Anne , Daniele, Antonio , Darling, D.H., Dichgans, Martin , Dufouil, Carole , Düzel, Emrah , García‐Ribas, Guillermo, García‐Alberca, José María , García-González, Pablo, Giedraitis, Vilmantas , Graff, Caroline , Grünblatt, Edna , Hausner, Lucrezia , Jung, Yoo Jin , Deckert, Jürgen, Kern, Silke , Kuulasmaa, Teemu , Lee, Kun Ho , Lin, Ling , Masullo, Carlo , Mehrabian, Shima , Mendonça, Alexandre de , Boada, Merçé , Mir, Pablo , Moreno, Fermín , Nicolas, Gaël , Niida, Shumpei , Nordestgaard, Børge G. , Papenberg, Goran, Papma, Janne M., Pástor, Pau , Peters, Oliver , Popp, Julius , Molina‐Porcel, Laura , Puerta, Raquel , 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Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available
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.