Fine-mapping of the TMEM106B locus identifies four haplotypes with differential associations to neurodegeneration

Salazar, A., Tesi, N., Knoop, L., van Schoor, N. M., Tijms, B., Vijverberg, E., van der Lee, S. J., Wijesekera, S., Krizova, J., Hiltunen, M., Damme, M., Petrucelli, L., Reinders, M., Smit, A. B., Dijkstra, A. A., Hulsman, M., ADGC, , Bonn, , CHARGE, , EADB, , EADI, , FinnGen, , GERAD, , GR@ACE/DEGESCO, , PGC-ALZ, , Holstege, H.

Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlan · medrxiv

Paper

Abstract

Genetic variation at the TMEM106B locus has been associated with Alzheimers disease (AD) and related neurodegenerative phenotypes, yet the underlying 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-specific structural variants, including a ~19 Kbp rearrangement carried by T3. We also observe haplotype-specific DNA methylation patterns. These findings indicate that TMEM106B haplotypes represent coordinated structural and epigenetic states refining GWAS signals associated with AD risk and cognitive longevity.

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Research summary

The paper identifies four haplotypes at the TMEM106B locus that are associated with neurodegeneration and cognitive longevity. The research explores genetic factors that may contribute to longevity and cognitive resilience, which aligns with the broader goals of understanding aging mechanisms.

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