Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

  1. Wang, Hui
  2. Chang, Timothy S.
  3. Dombroski, Beth A.
  4. Cheng, Po-Liang
  5. Patil, Vishakha
  6. Valiente-Banuet, Leopoldo
  7. Farrell, Kurt
  8. Mclean, Catriona
  9. Molina-Porcel, Laura
  10. Rajput, Alex
  11. De Deyn, Peter Paul
  12. Le Bastard, Nathalie
  13. Gearing, Marla
  14. Kaat, Laura Donker
  15. Van Swieten, John C.
  16. Dopper, Elise
  17. Ghetti, Bernardino F.
  18. Newell, Kathy L.
  19. Troakes, Claire
  20. de Yébenes, Justo G.
  21. Rábano-Gutierrez, Alberto
  22. Meller, Tina
  23. Oertel, Wolfgang H.
  24. Respondek, Gesine
  25. Stamelou, Maria
  26. Arzberger, Thomas
  27. Roeber, Sigrun
  28. Müller, Ulrich
  29. Hopfner, Franziska
  30. Pastor, Pau
  31. Brice, Alexis
  32. Durr, Alexandra
  33. Le Ber, Isabelle
  34. Beach, Thomas G.
  35. Serrano, Geidy E.
  36. Hazrati, Lili-Naz
  37. Litvan, Irene
  38. Rademakers, Rosa
  39. Ross, Owen A.
  40. Galasko, Douglas
  41. Boxer, Adam L.
  42. Miller, Bruce L.
  43. Seeley, Willian W.
  44. Van Deerlin, Vivanna M.
  45. Lee, Edward B.
  46. White, Charles L.
  47. Morris, Huw
  48. de Silva, Rohan
  49. Crary, John F.
  50. Goate, Alison M.
  51. Friedman, Jeffrey S.
  52. Leung, Yuk Yee
  53. Coppola, Giovanni
  54. Naj, Adam C.
  55. Wang, Li-San
  56. P. S. P. genetics study group
  57. Dalgard, Clifton
  58. Dickson, Dennis W.
  59. Höglinger, Günter U.
  60. Schellenberg, Gerard D.
  61. Geschwind, Daniel H.
  62. Lee, Wan-Ping ORCID logo

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1000 Titel
  • Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
1000 Autor/in
  1. Wang, Hui |
  2. Chang, Timothy S. |
  3. Dombroski, Beth A. |
  4. Cheng, Po-Liang |
  5. Patil, Vishakha |
  6. Valiente-Banuet, Leopoldo |
  7. Farrell, Kurt |
  8. Mclean, Catriona |
  9. Molina-Porcel, Laura |
  10. Rajput, Alex |
  11. De Deyn, Peter Paul |
  12. Le Bastard, Nathalie |
  13. Gearing, Marla |
  14. Kaat, Laura Donker |
  15. Van Swieten, John C. |
  16. Dopper, Elise |
  17. Ghetti, Bernardino F. |
  18. Newell, Kathy L. |
  19. Troakes, Claire |
  20. de Yébenes, Justo G. |
  21. Rábano-Gutierrez, Alberto |
  22. Meller, Tina |
  23. Oertel, Wolfgang H. |
  24. Respondek, Gesine |
  25. Stamelou, Maria |
  26. Arzberger, Thomas |
  27. Roeber, Sigrun |
  28. Müller, Ulrich |
  29. Hopfner, Franziska |
  30. Pastor, Pau |
  31. Brice, Alexis |
  32. Durr, Alexandra |
  33. Le Ber, Isabelle |
  34. Beach, Thomas G. |
  35. Serrano, Geidy E. |
  36. Hazrati, Lili-Naz |
  37. Litvan, Irene |
  38. Rademakers, Rosa |
  39. Ross, Owen A. |
  40. Galasko, Douglas |
  41. Boxer, Adam L. |
  42. Miller, Bruce L. |
  43. Seeley, Willian W. |
  44. Van Deerlin, Vivanna M. |
  45. Lee, Edward B. |
  46. White, Charles L. |
  47. Morris, Huw |
  48. de Silva, Rohan |
  49. Crary, John F. |
  50. Goate, Alison M. |
  51. Friedman, Jeffrey S. |
  52. Leung, Yuk Yee |
  53. Coppola, Giovanni |
  54. Naj, Adam C. |
  55. Wang, Li-San |
  56. P. S. P. genetics study group |
  57. Dalgard, Clifton |
  58. Dickson, Dennis W. |
  59. Höglinger, Günter U. |
  60. Schellenberg, Gerard D. |
  61. Geschwind, Daniel H. |
  62. Lee, Wan-Ping |
1000 Verlag BioMed Central
1000 Erscheinungsjahr 2024
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2024-08-16
1000 Erschienen in
1000 Quellenangabe
  • 19(1):61
1000 Copyrightjahr
  • 2024
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1186/s13024-024-00747-3 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330058/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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).</jats:p> </jats:sec><jats:sec> <jats:title>Method</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Our analysis of common SNVs and indels confirmed known genetic loci at <jats:italic>MAPT</jats:italic>, <jats:italic>MOBP</jats:italic>, S<jats:italic>TX6</jats:italic>, <jats:italic>SLCO1A2</jats:italic>, <jats:italic>DUSP10</jats:italic>, and <jats:italic>SP1</jats:italic>, and further uncovered novel signals in <jats:italic>APOE</jats:italic>, <jats:italic>FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1</jats:italic>. Notably, in contrast to Alzheimer’s disease (AD), we observed the <jats:italic>APOE</jats:italic> ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in <jats:italic>ZNF592</jats:italic> 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 <jats:italic>IGH</jats:italic>, <jats:italic>PCMT1</jats:italic>, <jats:italic>CYP2A13</jats:italic>, and <jats:italic>SMCP</jats:italic>. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (<jats:italic>P</jats:italic> = 6.73 × 10<jats:sup>–3</jats:sup>) in PSP.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.</jats:p> </jats:sec>
1000 Sacherschließung
lokal Whole-Genome Sequencing (WGS)
lokal Female [MeSH]
lokal Structural Variants (SVs)
lokal Aged, 80 and over [MeSH]
lokal Whole Genome Sequencing [MeSH]
lokal Aged [MeSH]
lokal Humans [MeSH]
lokal Apolipoprotein E (APOE)
lokal Middle Aged [MeSH]
lokal Polymorphism, Single Nucleotide/genetics [MeSH]
lokal Genome-Wide Association Study [MeSH]
lokal Genome-Wide Association Study (GWAS)
lokal Male [MeSH]
lokal Supranuclear Palsy, Progressive/genetics [MeSH]
lokal Research Article
lokal Genetic Predisposition to Disease/genetics [MeSH]
lokal Progressive Supranuclear Palsy (PSP)
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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