medRxiv-2024-PSP-GWAS-1

まだプレプリントだけど、驚いたので早めに書き留めておきます。

進行性核上性麻痺 (Progressive supranuclear palsy, PSP) 。

60-70歳くらいに多い、進行性の認知症、眼球運動障害、体幹部に強い筋強剛、強い姿勢反射障害などをきたし、発症から7-9年くらいで死に至る事が一般的です [1, 2] 。

病理学的には、一次性タウオパチーに分類され、4Rタウで構成される凝集体が、主に基底核や小脳歯状核などの神経細胞やアストロサイトに蓄積することが特徴で、アストロサイトのタウ病変はその形態からtufted astrocyteと呼ばれています [3, 4] 。

PSPが発症する原因は不明ですが、これまで、タウ蛋白をコードする遺伝子MAPTをカバーする、クロモソーム17q21.31のH1/H2ハプロタイプを持つと、PSPの発症率が5.6倍高くなる事が知られていました [5]。

また他にも、KANSL1, PLEKMHL1や [6]、中規模サイズのゲノムワイド関連解析（Genome Wide Association Study, GWAS）で、STX6, EIF2AK3, MOBP, SLCO1A2, DUSP10, RUNX2, LRRK2などの遺伝子変異がリスクとなる可能性も報告されてきました [7, 8, 9, 10]。

今回、1,718人のPSP症例を含む大規模GWAS解析で、既知の遺伝子の他、新たに6つのPSP関連新規遺伝子変異を同定しました [11]。

medRxiv-2024-PSP-GWAS-title

PSPのGWAS解析

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy
https://www.medrxiv.org/content/10.1101/2023.12.28.23300612v2
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 MAPT , MOBP , S TX6 , SLCO1A2 , DUSP10 , and SP1 , and further uncovered novel signals in APOE , FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1 . Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 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 IGH , PCMT1 , CYP2A13 , and SMCP . In the H1/H2 haplotype region, there is a burden of rare deletions and duplications ( P = 6.73×10-3) 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. ### Competing Interest Statement Laura Molina-Porcel received income from Biogen as a consultant in 2022. Gesine Respondek is now employed by Roche (Hoffmann-La Roche, Basel, Switzerland) since 2021. Her affiliation whilst completing her contribution to this manuscript was German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Thomas G Beach is a consultant for Aprinoia Therapeutics and a Scientific Advisor and stock option holder for Vivid Genomics. Huw Morris is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx; lecture fees/honoraria - BMJ, Kyowa Kirin, Movement Disorders Society. Huw Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). Giovanni Coppola is currently an employee of Regeneron Pharmaceuticals. Alison Goate serves on the SAB for Genentech and Muna Therapeutics. ### Funding Statement This work was supported by NIH 5UG3NS104095, the Rainwater Charitable Foundation, and CurePSP. HW and PLC are supported by RF1-AG074328, P30-AG072979, U54-AG052427 and U24-AG041689. TSC is supported by NIH K08AG065519 and the Larry L Hillblom Foundation 2021-A-005-SUP. KF was supported by CurePSP 685-2023-06-Pathway and K01 AG070326. MG is supported by P30 AG066511. BFG and KLN are supported by P30 AG072976 and R01 AG080001. TGB and GES are supported by P30AG072980. IR is supported by 2R01AG038791-06A, U01NS100610, R25NS098999, U19 AG063911-1 and 1R21NS114764-01A1. OR is support by U54 NS100693. DG is supported by P30AG062429. ALB is supported by U19AG063911, R01AG073482, R01AG038791, and R01AG071756. BLM is supported by P01 AG019724, R01 AG057234 and P0544014. VMV is supported by P01-AG-066597, P01-AG-017586. HRM is supported by CurePSP, PSPA, MRC, and Michael J Fox Foundation. RDS is supported by CurePSP, PSPA, and Reta Lila Weston Trust. JFC is supported by R01 AG054008, R01 NS095252, R01 AG060961, R01 NS086736, R01 AG062348, P30 AG066514, the Rainwater Charitable Foundation / Tau Consortium, Karen Strauss Cook Research, and Scholar Award, Stuart Katz & Dr. Jane Martin. AMG is supported by the Tau Consortium and U54-NS123746. YYL is supported by U54-AG052427; U24-AG041689. LSW is supported by U01AG032984, U54AG052427, and U24AG041689. DHG is supported by 3UH3NS104095, Tau Consortium. WPL is supported by RF1-AG074328; P30-AG072979; U54-AG052427; U24-AG041689. Cases from Banner Sun Health Research Institute were supported by the NIH (U24 NS072026, P30 AG19610 and P30AG072980), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research. The Mayo Clinic Brain Bank is supported through funding by NIA grants P50 AG016574, CurePSP Foundation, and support from Mayo Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data from the ADSP are available to qualified investigators via the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) (). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from the ADSP are available to qualified investigators via the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) ().

PSPの新規リスク遺伝子

彼らは、

  • PSP-NIH-CurePSP-Tau
  • PSP-CurePSP-Tau
  • PSP-UCLA
  • and AMPAD-MAYO

のコホートと、アルツハイマー病 (Alzheimer's disease, AD) のGWAS解析のコホート [12] のデータをもとに、

  • PSP症例 1,718例
    • 剖検確定症例 1,441例
    • 臨床診断 277例
  • 対照群 944例

の遺伝子を調べました。

結果、既知の遺伝子

  • MAPT
  • MOBP
  • STX6
  • SLCO1A2
  • DUSP10
  • SP1

の他、新規遺伝子

  • APOE
  • FCHO1/MAP1S
  • KIF13A
  • TRIM24
  • ELOVL1
  • TNXB

が同定されました。

medRxiv-2024-PSP-GWAS-1

APOE2はPSPのリスク

これらの新規遺伝子の中で、APOEは、ADのリスクとなる「APOE ε4」ではなく、保護的に働く「APOE ε2」を持っているとPSPになりやすい、という事がわかりました。

APOE ε2遺伝子をホモ接合体で持っている場合、PSPになるオッズ比は、なんと4.41倍 （APOE ε2 ハプロタイプのPSPリスク：P = 9.57 × 10-16, β = 0.87, MAF = 0.06）。

 

また、APOE ε2とは逆に、ADの最大のリスク多型APOE ε4は、逆にPSPには保護的に働くようです（P = 5.71 × 10-18, β = −0.60, MAF = 0.16）。

My View

今回、約1,700人のPSP患者さんを含むGWAS解析で、新たに6つのリスク遺伝子が同定されました。

とりあえずAPOE2に驚いたので、プレプリントの段階ですがまとめておきました。

ただ実は、かなり前に日本からAPOE2のPSPリスクについて報告されていたようです [13]。

また5年前にも、APOE2はPSPやCBDといったプライマリータウオパチーのリスクであると報告されていました [14]。

APOE2はADには保護的だけど、III型脂質異常症になりやすいし、PSP/CBDにはなりやすいし……なんでもうまくいくわけではないんですね。

References

  1. Lukic MJ, Respondek G, Kurz C, Compta Y, Gelpi E, Ferguson LW, Rajput A, Troakes C; MDS-endorsed PSP study group; van Swieten JC, Giese A, Roeber S, Herms J, Arzberger T, Höglinger G. Long-Duration Progressive Supranuclear Palsy: Clinical Course and Pathological Underpinnings. Ann Neurol. 2022 Oct;92(4):637-649. doi: 10.1002/ana.26455. Epub 2022 Aug 12. PMID: 35872640.
  2. Ali F, Martin PR, Botha H, Ahlskog JE, Bower JH, Masumoto JY, Maraganore D, Hassan A, Eggers S, Boeve BF, Knopman DS, Drubach D, Petersen RC, Dunkley ED, van Gerpen J, Uitti R, Whitwell JL, Dickson DW, Josephs KA. Sensitivity and Specificity of Diagnostic Criteria for Progressive Supranuclear Palsy. Mov Disord. 2019 Aug;34(8):1144-1153. doi: 10.1002/mds.27619. Epub 2019 Feb 6. PMID: 30726566; PMCID: PMC6688972.
  3. Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB, Coughlin D, Giese A, Grossman M, Kurz C, McMillan CT, Gelpi E, Compta Y, van Swieten JC, Laat LD, Troakes C, Al-Sarraj S, Robinson JL, Roeber S, Xie SX, Lee VM, Trojanowski JQ, Höglinger GU. Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. 2020 Aug;140(2):99-119. doi: 10.1007/s00401-020-02158-2. Epub 2020 May 7. PMID: 32383020; PMCID: PMC7360645.
  4. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994 Nov;44(11):2015-9. doi: 10.1212/wnl.44.11.2015. PMID: 7969952.
  5. Stamelou M, Respondek G, Giagkou N, Whitwell JL, Kovacs GG, Höglinger GU. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol. 2021 Oct;17(10):601-620. doi: 10.1038/s41582-021-00541-5. Epub 2021 Aug 23. PMID: 34426686.
  6. Wen Y, Zhou Y, Jiao B, Shen L. Genetics of Progressive Supranuclear Palsy: A Review. J Parkinsons Dis. 2021;11(1):93-105. doi: 10.3233/JPD-202302. PMID: 33104043; PMCID: PMC7990399.
  7. Cooper YA, Teyssier N, Dräger NM, Guo Q, Davis JE, Sattler SM, Yang Z, Patel A, Wu S, Kosuri S, Coppola G, Kampmann M, Geschwind DH. Functional regulatory variants implicate distinct transcriptional networks in dementia. Science. 2022 Aug 19;377(6608):eabi8654. doi: 10.1126/science.abi8654. Epub 2022 Aug 19. PMID: 35981026.
  8. Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P; PSP Genetics Study Group; Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011 Jun 19;43(7):699-705. doi: 10.1038/ng.859. PMID: 21685912; PMCID: PMC3125476.
  9. Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA, Caselli RJ, Uitti RJ, Wszolek ZK, Graff-Radford N, Petrucelli L, Wang LS, Schellenberg GD, Dickson DW, Rademakers R, Ross OA. Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener. 2018 Jul 9;13(1):37. doi: 10.1186/s13024-018-0267-3. PMID: 29986742; PMCID: PMC6038352.
  10. Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K, Yokoyama JS, Bensimon G, Leigh PN, Payan C, Shatunov A, Jones AR, Lewis CM, Deloukas P, Amouyel P, Tzourio C, Dartigues JF, Ludolph A, Boxer AL, Bronstein JM, Al-Chalabi A, Geschwind DH, Coppola G. Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener. 2018 Aug 8;13(1):41. doi: 10.1186/s13024-018-0270-8. PMID: 30089514; PMCID: PMC6083608.
  11. Jabbari E, Koga S, Valentino RR, Reynolds RH, Ferrari R, Tan MMX, Rowe JB, Dalgard CL, Scholz SW, Dickson DW, Warner TT, Revesz T, Höglinger GU, Ross OA, Ryten M, Hardy J, Shoai M, Morris HR; PSP Genetics Group. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol. 2021 Feb;20(2):107-116. doi: 10.1016/S1474-4422(20)30394-X. Epub 2020 Dec 17. PMID: 33341150; PMCID: PMC7116626.
  12. Hui Wang, Timothy S Chang, Beth A Dombroski, Po-Liang Cheng, Vishakha Patil, Leopoldo Valiente-Banuet, Kurt Farrell, Catriona Mclean, Laura Molina-Porcel, Alex Rajput, Peter Paul De Deyn, Nathalie Le Bastard, Marla Gearing, Laura Donker Kaat, John C Van Swieten, Elise Dopper, Bernardino F Ghetti, Kathy L Newell, Claire Troakes, Justo G de Yébenes, Alberto Rábano-Gutierrez, Tina Meller, Wolfgang H Oertel, Gesine Respondek, Maria Stamelou, Thomas Arzberger, Sigrun Roeber, Ulrich Müller, Franziska Hopfner, Pau Pastor, Alexis Brice, Alexandra Durr, Isabelle Le Ber, Thomas G Beach, Geidy E Serrano, Lili-Naz Hazrati, Irene Litvan, Rosa Rademakers, Owen A Ross, Douglas Galasko, Adam L Boxer, Bruce L Miller, Willian W Seeley, Vivanna M Van Deerlin, Edward B Lee, Charles L White III, Huw Morris, Rohan de Silva, John F Crary, Alison M Goate, Jeffrey S Friedman, Yuk Yee Leung, Giovanni Coppola, Adam C Naj, Li-San Wang, PSP genetics study group, Dennis W Dickson, Günter U Höglinger, Gerard D Schellenberg, Daniel H Geschwind, Wan-Ping Lee. Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy. medRxiv 2023.12.28.23300612; doi: https://doi.org/10.1101/2023.12.28.23300612
  13. Beecham GW, Bis JC, Martin ER, Choi SH, DeStefano AL, van Duijn CM, Fornage M, Gabriel SB, Koboldt DC, Larson DE, Naj AC, Psaty BM, Salerno W, Bush WS, Foroud TM, Wijsman E, Farrer LA, Goate A, Haines JL, Pericak-Vance MA, Boerwinkle E, Mayeux R, Seshadri S, Schellenberg G. The Alzheimer's Disease Sequencing Project: Study design and sample selection. Neurol Genet. 2017 Oct 13;3(5):e194. doi: 10.1212/NXG.0000000000000194. PMID: 29184913; PMCID: PMC5646177.
  14. Sawa A, Amano N, Yamada N, Kajio H, Yagishita S, Takahashi T, Oda M, Arai N, Ikeda K, Tadokoro M, Matsushita M. Apolipoprotein E in progressive supranuclear palsy in Japan. Mol Psychiatry. 1997 Jul;2(4):341-2. doi: 10.1038/sj.mp.4000285. PMID: 9246676.
  15. Zhao N, Liu CC, Van Ingelgom AJ, Linares C, Kurti A, Knight JA, Heckman MG, Diehl NN, Shinohara M, Martens YA, Attrebi ON, Petrucelli L, Fryer JD, Wszolek ZK, Graff-Radford NR, Caselli RJ, Sanchez-Contreras MY, Rademakers R, Murray ME, Koga S, Dickson DW, Ross OA, Bu G. APOE ε2 is associated with increased tau pathology in primary tauopathy. Nat Commun. 2018 Oct 22;9(1):4388. doi: 10.1038/s41467-018-06783-0. PMID: 30348994; PMCID: PMC6197187.
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