Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Journal article

K. Farrell, Jack Humphrey, Timothy S. Chang, Yi Zhao, Y. Leung, Pavel P. Kuksa, Vishakha Patil, Wan-Ping Lee, A. Kuzma, O. Valladares, L. Cantwell, Hui Wang, Ashvin Ravi, Claudia De Sanctis, N. Han, Thomas D. Christie, Robina Afzal, Shrishtee Kandoi, Kristen Whitney, Margaret M. Krassner, Hadley W. Ressler, SoongHo Kim, Diana K. Dangoor, Megan A. Iida, A. Casella, Ruth H. Walker, Melissa J Nirenberg, A. Renton, Bergan Babrowicz, Giovanni Coppola, T. Raj, Günter U. Höglinger, Ulrich Müller, Lawrence I Golbe, Huw R. Morris, John Hardy, T. Révész, Tom T Warner, Z. Jaunmuktane, K. Mok, R. Rademakers, D. Dickson, Owen A. Ross, Li-San Wang, A. Goate, G. Schellenberg, D. Geschwind, J. Crary, A. Naj
Nature Communications, 2024

Semantic Scholar DOI PubMedCentral PubMed

Cite

APA Click to copy
Farrell, K., Humphrey, J., Chang, T. S., Zhao, Y., Leung, Y., Kuksa, P. P., … Naj, A. (2024). Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes. Nature Communications.

Chicago/Turabian Click to copy
Farrell, K., Jack Humphrey, Timothy S. Chang, Yi Zhao, Y. Leung, Pavel P. Kuksa, Vishakha Patil, et al. “Genetic, Transcriptomic, Histological, and Biochemical Analysis of Progressive Supranuclear Palsy Implicates Glial Activation and Novel Risk Genes.” Nature Communications (2024).

MLA Click to copy
Farrell, K., et al. “Genetic, Transcriptomic, Histological, and Biochemical Analysis of Progressive Supranuclear Palsy Implicates Glial Activation and Novel Risk Genes.” Nature Communications, 2024.

BibTeX Click to copy

@article{k2024a,
  title = {Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes},
  year = {2024},
  journal = {Nature Communications},
  author = {Farrell, K. and Humphrey, Jack and Chang, Timothy S. and Zhao, Yi and Leung, Y. and Kuksa, Pavel P. and Patil, Vishakha and Lee, Wan-Ping and Kuzma, A. and Valladares, O. and Cantwell, L. and Wang, Hui and Ravi, Ashvin and Sanctis, Claudia De and Han, N. and Christie, Thomas D. and Afzal, Robina and Kandoi, Shrishtee and Whitney, Kristen and Krassner, Margaret M. and Ressler, Hadley W. and Kim, SoongHo and Dangoor, Diana K. and Iida, Megan A. and Casella, A. and Walker, Ruth H. and Nirenberg, Melissa J and Renton, A. and Babrowicz, Bergan and Coppola, Giovanni and Raj, T. and Höglinger, Günter U. and Müller, Ulrich and Golbe, Lawrence I and Morris, Huw R. and Hardy, John and Révész, T. and Warner, Tom T and Jaunmuktane, Z. and Mok, K. and Rademakers, R. and Dickson, D. and Ross, Owen A. and Wang, Li-San and Goate, A. and Schellenberg, G. and Geschwind, D. and Crary, J. and Naj, A.}
}

Abstract

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10−8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson’s disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.