AI Article Synopsis

  • Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease linked to tau protein accumulation, and previous studies using genotype arrays overlooked important genetic variations like rare variants and structural changes.* -
  • This study utilized whole genome sequencing (WGS) involving 1,718 PSP patients and 2,944 controls, confirming known genetic markers and discovering new associations, including the unique role of the ε2 allele as a risk factor.* -
  • The findings from this research advance the understanding of PSP genetics, highlighting potential new targets for disease mechanisms and treatment strategies.*

Article Abstract

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).

Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.

Results: Our analysis of common SNVs and indels confirmed known genetic loci at , , S, , , and , and further uncovered novel signals in , . Notably, in contrast to Alzheimer's disease (AD), we observed the ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including , , , and . In the H1/H2 haplotype region, there is a burden of rare deletions and duplications ( = 6.73×10) in PSP.

Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10793533PMC
http://dx.doi.org/10.1101/2023.12.28.23300612DOI Listing

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