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PreprintCited by 5Cerebrovascular and genetic disordersMultiple Sclerosis Research StudiesNeurological Disease Mechanisms and Treatments

Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

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Debette, Stephanie, Caro, Ilana, Western, Daniel, Namba, Shinichi, Sun, Na, Kawaguchi, Shuji, He, Yunye, Fujita, Masashi +49 more·2024·Research Square
DOI 10.21203/rs.3.rs-4535534/v1PMC PMC11247936
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Abstract

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. We used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces). We describe a new biological fingerprint of 49 protein-cSVD associations, predominantly in the CSF. We implemented a multipronged follow-up, across fluids, platforms, and ancestries (Europeans and East-Asian), including testing associations of direct plasma protein measurements with MRI-cSVD. We highlight 16 proteins robustly associated in both CSF and plasma, with 24/4 proteins identified in CSF/plasma only. cSVD-proteins were enriched in extracellular matrix and immune response pathways, and in genes enriched in microglia and specific microglial states (integration with single-nucleus RNA sequencing). Immune-related proteins were associated with MRI-cSVD already at age twenty. Half of cSVD-proteins were associated with stroke, dementia, or both, and seven cSVD-proteins are targets for known drugs (used for other indications in directions compatible with beneficial therapeutic effects. This first cSVD proteogenomic signature opens new avenues for biomarker and therapeutic developments.

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  • The PILRA protein has been linked to Alzheimer's Disease (AD) in multiple MR studies using Olink pQTL instruments, but different directions of effect for PILRA on AD have been reported across studies using different platform's pQTL instruments.

    “The PILRA protein discussed above has been linked to Alzheimer’s Disease (AD) in multiple MR studies using Olink pQTL instruments27–29; however, different directions of effect for PILRA on AD have been reported across studies using different platform’s pQTL instruments.”

    From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [28]

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References 117 · Cited by 5

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  1. [1]Wardlaw J. M. ESO Guideline on covert cerebral small vessel disease. Eur. Stroke J. 6, CXI– CLXII (2021). 34414301 PMC8370079
  2. [2]Duering M. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol. 22, 602– 618 (2023). 37236211
  3. [3]Wardlaw J. M. Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities. Neurology 82, 1331– 1338 (2014). 24623838 PMC4001185
  4. [4]Rusina P. V. Genetic support for FDA-approved drugs over the past decade. Nat. Rev. Drug Discov. 22, 864 (2023). 37803084
  5. [5]Duperron M.-G. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease. Nat. Med. 29, 950– 962 (2023). 37069360 PMC10115645
  6. [6]Bordes C., Sargurupremraj M., Mishra A. & Debette S. Genetics of common cerebral small vessel disease. Nat. Rev. Neurol. 18, 84– 101 (2022). 34987231
  7. [7]Montaner J. Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke. Nat. Rev. Neurol. 16, 247– 264 (2020). 32322099
  8. [8]Walker K. A. Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nat. Aging 1, 473– 489 (2021). 37118015 PMC10154040
  9. [10]Chen L. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke. Nat. Commun. 13, 6143 (2022). 36253349 PMC9576777
  10. [11]Dammer E. B. Multi-platform proteomic analysis of Alzheimer’s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome. Alzheimers Res. Ther. 14, 174 (2022). 36384809 PMC9670630
  11. [13]Yang C. Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nat. Neurosci. 24, 1302– 1312 (2021). 34239129 PMC8521603
  12. [14]Kuipers S. A cluster of blood-based protein biomarkers reflecting coagulation relates to the burden of cerebral small vessel disease. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 42, 1282– 1293 (2022). PMC9207498 35086368
  13. [15]Wan S. Plasma inflammatory biomarkers in cerebral small vessel disease: A review. CNS Neurosci. Ther. 29, 498– 515 (2023). 36478511 PMC9873530
  14. [16]Fornage M. Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. Stroke 39, 1952– 1959 (2008). 18436879 PMC2888487
  15. [17]Satizabal C. L., Zhu Y. C., Mazoyer B., Dufouil C. & Tzourio C. Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study. Neurology 78, 720– 727 (2012). 22357713
  16. [18]Jiménez-Balado J. New candidate blood biomarkers potentially associated with white matter hyperintensities progression. Sci. Rep. 11, 14324 (2021). 34253757 PMC8275657
  17. [20]Sargurupremraj M. Cerebral small vessel disease genomics and its implications across the lifespan. Nat. Commun. 11, 6285 (2020). 33293549 PMC7722866
  18. [21]Cho B. P. H. Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke. JAMA Neurol. 79, 1303– 1311 (2022). 36300346 PMC9614680
  19. [22]Mishra A. Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. Brain J. Neurol. 142, 1009– 1023 (2019). PMC6439324 30859180
  20. [23]Mishra A. Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate. Brain J. Neurol. 145, 1992– 2007 (2022). PMC9255380 35511193
  21. [24]Consortium ReproGen An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236– 1241 (2015). 26414676 PMC4797329
  22. [25]Eldjarn G. H. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 622, 348– 358 (2023). 37794188 PMC10567571
  23. [26]Fujita M. Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain. Nat. Genet. 56, 605– 614 (2024). 38514782 PMC12288883
  24. [27]Garcia F. J. Single-cell dissection of the human brain vasculature. Nature 603, 893– 899 (2022). 35158371 PMC9680899
  25. [28]Sun N. Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease. Nat. Neurosci. 26, 970– 982 (2023). 37264161 PMC10464935
  26. [29]Sun N. Human microglial state dynamics in Alzheimer’s disease progression. Cell 186, 4386– 4403.e29 (2023). 37774678 PMC10644954
  27. [30]Pokhilko A. Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease. J. Cereb. Blood Flow Metab. 41, 2423– 2438 (2021). 33730931 PMC8392779
  28. [31]Joutel A., Haddad I., Ratelade J. & Nelson M. T. Perturbations of the cerebrovascular matrisome: A convergent mechanism in small vessel disease of the brain? J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 36, 143– 157 (2016). PMC4758555 25853907
  29. [32]Jiménez-Balado J. New candidate blood biomarkers potentially associated with white matter hyperintensities progression. Sci. Rep. 11, 14324 (2021). 34253757 PMC8275657
  30. [33]Gertje E. C. Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia. Neurology 100, e1812– e1824 (2023). 36882326 PMC10136007
  31. [34]Haffner C. Proteostasis in Cerebral Small Vessel Disease. Front. Neurosci. 13, 1142 (2019). 31798396 PMC6874119
  32. [35]Gaetani L. CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment. Trends Pharmacol. Sci. 41, 1023– 1037 (2020). 33127098
  33. [36]Luebke M., Parulekar M. & Thomas F. P. Fluid biomarkers for the diagnosis of neurodegenerative diseases. Biomark. Neuropsychiatry 8, 100062 (2023).
  34. [38]Park Y. H. Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease. Neurol. Genet. 6, e517 (2020). 33134515 PMC7577551
  35. [39]Fournier N. FDF03, a Novel Inhibitory Receptor of the Immunoglobulin Superfamily, Is Expressed by Human Dendritic and Myeloid Cells. J. Immunol. 165, 1197– 1209 (2000). 10903717
  36. [40]Charidimou A. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study. Lancet Neurol. 21, 714– 725 (2022). 35841910 PMC9389452
  37. [41]Greenberg S. M. Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways. Nat. Rev. Neurol. 16, 30– 42 (2020). 31827267 PMC7268202
  38. [42]Rathore N. Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease. PLOS Genet. 14, e1007427 (2018). 30388101 PMC6235402
  39. [43]Zhang X. Arylsulfatase B modulates neurite outgrowth via astrocyte chondroitin-4-sulfate: dysregulation by ethanol. Glia 62, 259– 271 (2014). 24311516 PMC4272875
  40. [45]He L. Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci. Data 5, 180160 (2018). 30129931 PMC6103262
  41. [46]Valayannopoulos V., Nicely H., Harmatz P. & Turbeville S. Mucopolysaccharidosis VI. Orphanet J. Rare Dis. 5, 5 (2010). 20385007 PMC2873242
  42. [47]Hook G. Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders. Pharmacol. Rev. 74, 600– 629 (2022). 35710131 PMC9553114
  43. [48]Hook G., Kindy M. & Hook V. Cathepsin B Deficiency Improves Memory Deficits and Reduces Amyloid-β in hAβPP Mouse Models Representing the Major Sporadic Alzheimer’s Disease Condition. J. Alzheimers Dis. 93, 33– 46 (2023). 36970896 PMC10185432
  44. [50]Mancuso M. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur. J. Neurol. 27, 909– 927 (2020). 32196841
  45. [51]Malik R. Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. Brain J. Neurol. 144, 2670– 2682 (2021). PMC8557338 34626176
  46. [52]Dichgans M. Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease. Res. Sq. rs. 3.rs-3523612 (2023) doi: 10.21203/rs.3.rs-3523612/v1. 39196222 · DOI
  47. [53]Low A., Mak E., Rowe J. B., Markus H. S. & O’Brien J. T. Inflammation and cerebral small vessel disease: A systematic review. Ageing Res. Rev. 53, 100916 (2019). 31181331
  48. [54]Low A. In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 92, 45– 52 (2021). PMC7803899 32917821
  49. [55]Evans L. E. Cardiovascular comorbidities, inflammation, and cerebral small vessel disease. Cardiovasc. Res. cvab284 (2021) doi: 10.1093/cvr/cvab284. 34499123 · DOI
  50. [56]Fu Y. & Yan Y. Emerging Role of Immunity in Cerebral Small Vessel Disease. Front. Immunol. 9, 67 (2018). 29422904 PMC5788893
  51. [57]Yang Y. Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. Brain 146, 492– 506 (2023). 35943854 PMC9924914
  52. [58]Solé-Guardia G. Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities. Acta Neuropathol. Commun. 11, 2 (2023). 36600303 PMC9811756
  53. [59]Gjoneska E. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365– 369 (2015). 25693568 PMC4530583
  54. [60]Mendiola A. S. Defining blood-induced microglia functions in neurodegeneration through multiomic profiling. Nat. Immunol. 24, 1173– 1187 (2023). 37291385 PMC10307624
  55. [61]Safaiyan S. White matter aging drives microglial diversity. Neuron 109, 1100– 1117.e10 (2021). 33606969
  56. [62]Leng F. & Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 17, 157– 172 (2021). 33318676
  57. [63]Kosciuk T. NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle. Nat. Commun. 11, 1067 (2020). 32103017 PMC7044312
  58. [64]Chen X., Lu W. & Wu D. Sirtuin 2 (SIRT2): Confusing Roles in the Pathophysiology of Neurological Disorders. Front. Neurosci. 15, 614107 (2021). 34108853 PMC8180884
  59. [65]Wu B. The role of SIRT2 in vascular-related and heart-related diseases: A review. J. Cell. Mol. Med. 25, 6470– 6478 (2021). 34028177 PMC8278089
  60. [66]Persyn E. Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants. Nat. Commun. 11, 2175 (2020). 32358547 PMC7195435
  61. [67]Pedrero-Prieto C. M. A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease. Clin. Proteomics 17, 21 (2020). 32518535 PMC7273668
  62. [68]Martínez-Estrada O. M. Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability. Eur. J. Neurosci. 18, 2538– 2544 (2003). 14622154
  63. [69]Zakharova E. T. Erythropoietin and Nrf2: key factors in the neuroprotection provided by apo-lactoferrin. BioMetals 31, 425– 443 (2018). 29748743
  64. [70]Spagnuolo P. A. & Hoffman-Goetz L. Dietary Lactoferrin Does Not Prevent Dextran Sulfate Sodium Induced Murine Intestinal Lymphocyte Death. Exp. Biol. Med. 233, 1099– 1108 (2008). 18535168
  65. [71]Van De Looij Y. Lactoferrin during lactation protects the immature hypoxic-ischemic rat brain. Ann. Clin. Transl. Neurol. 1, 955– 967 (2014). 25574471 PMC4284122
  66. [72]Mercier M. International approach to the assessment of chemical risks. Sci. Total Environ. 101, 1– 7 (1991). 2057757
  67. [73]Zhao X. Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: Pre-clinical experience. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 41, 53– 66 (2021). PMC7747168 32438861
  68. [74]Kittur F. S., Hung C.-Y., Li P. A., Sane D. C. & Xie J. Asialo-rhuEPO as a Potential Neuroprotectant for Ischemic Stroke Treatment. Pharm. Basel Switz. 16, 610 (2023). PMC10143832 37111367
  69. [75]Zhou B. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct. Target. Ther. 7, 95 (2022). 35332121 PMC8948217
  70. [77]Giugliano R. P. Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis. Stroke 51, 1546– 1554 (2020). 32312223
  71. [80]Mok V. Race-ethnicity and cerebral small vessel disease--comparison between Chinese and White populations. Int. J. Stroke Off. J. Int. Stroke Soc. 9 Suppl A100, 36– 42 (2014). 24661839
  72. [81]Chang C. C. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4, 7 (2015). 25722852 PMC4342193
  73. [82]Hemani G., Tilling K. & Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 13, e1007081 (2017). 29149188 PMC5711033
  74. [83]Burgess S., Butterworth A. & Thompson S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658– 665 (2013). 24114802 PMC4377079
  75. [84]Burgess S. & Thompson S. G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32, 377– 389 (2017). 28527048 PMC5506233
  76. [85]Burgess S. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 4, 186 (2019). 32760811 PMC7384151
  77. [86]Verbanck M., Chen C.-Y., Neale B. & Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693– 698 (2018). 29686387 PMC6083837
  78. [87]Bowden J., Davey Smith G. & Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512– 525 (2015). 26050253 PMC4469799
  79. [88]Giambartolomei C. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014). 24830394 PMC4022491
  80. [89]Cronjé H. T. Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study. BMC Med. 21, 158 (2023). 37101178 PMC10134514
  81. [90]Li J. & Ji L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95, 221– 227 (2005). 16077740
  82. [91]Godin O. White matter lesions as a predictor of depression in the elderly: the 3C-Dijon study. Biol. Psychiatry 63, 663– 669 (2008). 17977521
  83. [92]C Study Group. Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology 22, 316– 325 (2003). 14598854
  84. [93]Lind L. Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis. Atherosclerosis 242, 205– 210 (2015). 26204497
  85. [95]Zhu Y.-C. Frequency and location of dilated Virchow-Robin spaces in elderly people: a population-based 3D MR imaging study. AJNR Am. J. Neuroradiol. 32, 709– 713 (2011). 21349956 PMC7965873
  86. [96]Boutinaud P. 3D Segmentation of Perivascular Spaces on T1-Weighted 3 Tesla MR Images With a Convolutional Autoencoder and a U-Shaped Neural Network. Front. Neuroinformatics 15, 641600 (2021). PMC8273917 34262443
  87. [97]Duperron M.-G. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease. Nat. Med. 29, 950– 962 (2023). 37069360 PMC10115645
  88. [100]Funada S. Longitudinal Analysis of Bidirectional Relationships between Nocturia and Depressive Symptoms: The Nagahama Study. J. Urol. 203, 984– 990 (2020). 31750764
  89. [101]Jiang J. UBO Detector – A cluster-based, fully automated pipeline for extracting white matter hyperintensities. NeuroImage 174, 539– 549 (2018). 29578029
  90. [102]Montagni I., Guichard E. & Kurth T. Association of screen time with self-perceived attention problems and hyperactivity levels in French students: a cross-sectional study. BMJ Open 6, e009089 (2016). PMC4769424 26920440
  91. [103]Tsuchida A. Age-Related Variations in Regional White Matter Volumetry and Microstructure During the Post-adolescence Period: A Cross-Sectional Study of a Cohort of 1,713 University Students. Front. Syst. Neurosci. 15, 692152 (2021). 34413727 PMC8369154
  92. [104]Tsuchida A. The MRi-Share database: brain imaging in a cross-sectional cohort of 1870 university students. Brain Struct. Funct. 226, 2057– 2085 (2021). 34283296
  93. [105]Le Grand Q. Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 7, 616– 628 (2022). 34700051 PMC9395126
  94. [106]Tsuchida A. Early detection of white matter hyperintensities using SHIVA-WMH detector. Hum. Brain Mapp. (2023) doi: 10.1002/hbm.26548. PMC10789222 38050769 · DOI
  95. [108]Choi S. W., Mak T. S.-H. & O’Reilly P. F. Tutorial: a guide to performing polygenic risk score analyses. Nat. Protoc. 15, 2759– 2772 (2020). 32709988 PMC7612115
  96. [109]Choi S. W. & O’Reilly P. F. PRSice-2: Polygenic Risk Score software for biobank-scale data. GigaScience 8, giz082 (2019). 31307061 PMC6629542
  97. [110]Price A. L. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904– 909 (2006). 16862161
  98. [112]Mishra A. Stroke genetics informs drug discovery and risk prediction across ancestries. Nature 611, 115– 123 (2022). 36180795 PMC9524349
  99. [114]Jansen I. E. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404– 413 (2019). 30617256 PMC6836675
  100. [115]Nagai A. Overview of the BioBank Japan Project: Study design and profile. J. Epidemiol. 27, S2– S8 (2017). 28189464 PMC5350590
  101. [116]Koyama S. Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat. Genet. 52, 1169– 1177 (2020). 33020668
  102. [117]Liu X. Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing. Sci. Adv. 10, eadi8419 (2024). 38630824 PMC11023554
  103. [118]Willer C. J., Li Y. & Abecasis G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinforma. Oxf. Engl. 26, 2190– 2191 (2010). PMC2922887 20616382
  104. [119]He Y. East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease. Nat. Genet. 55, 2129– 2138 (2023). 38036781 PMC10703676
  105. [120]Terao C. Population-specific reference panel improves imputation quality and enhances locus discovery and fine-mapping. Preprint at 10.21203/rs.3.rs-3194976/v1 (2023). · DOI
  106. [121]Watanabe K., Taskesen E., van Bochoven A. & Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017). 29184056 PMC5705698

Authors
Debette, S., Caro, I., Western, D., Namba, S., Sun, N., Kawaguchi, S., He, Y., Fujita, M., Roshchupkin, G., D'Aoust, T., Duperron, M.-G., Sargurupremraj, M., Tsuchida, A., Koido, M., Ahmadi, M., Yang, C., Timsina, J., Ibanez, L., Matsuda, K., Suzuki, Y., Oda, Y., Kanai, A., Jandaghi, P., Munter, H. M., Auld, D., Astafeva, I., Puerta, R., Rotter, J., Psaty, B., Bis, J., Longstreth, W., Couffinhal, T., Garcia-Gonzalez, P., Pytel, V., Marquié, M., Cano, A., Boada, M., Joliot, M., Lathrop, M., Grand, Q. L., Launer, L., Wardlaw, J., Heiman, M., Ruiz, A., Matthews, P., Seshadri, S., Fornage, M., Adams, H., Mishra, A., Trégouët, D.-A., Okada, Y., Kellis, M., De Jager, P., Tzourio, C., Kamatani, Y., Matsuda, F., & Cruchaga, C.
Affiliations
  • University of Bordeaux
  • Université de Bordeaux (FR)
  • Washington University in St. Louis (US)
  • The University of Osaka (JP)
  • Broad Institute (US)
  • Kyoto University (JP)
  • The University of Tokyo (JP)
  • Columbia University Irving Medical Center (US)
  • Erasmus MC (NL)
  • Bordeaux Population Health, Inserm U1219, University of Bordeaux
  • University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, F-33000 Bordeaux, France; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases Unive
  • McGill University (CA)
  • Washington University in St. Louis
  • McGill University
  • Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University
  • Fundació ACE (ES)
  • The Lundquist Institute (US)
  • Cardiovascular Health Research Unit
  • University of Washington (US)
  • Ace Alzheimer Center Barcelona
  • Instituto de Salud Carlos III (ES)
  • Universitat Internacional de Catalunya
  • Centre National de la Recherche Scientifique (FR)
  • National Institute on Aging (US)
  • University of Edinburgh (GB)
  • Massachusetts Institute of Technology (US)
  • Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center; Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya;CIBERN
  • UK Dementia Research Institute (GB)
  • University of Texas Health Science Center
  • 1. Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center 2. Human Genetics Center, Department of Epidemiology, School of Public Health
  • Adolfo Ibáñez University (CL)
  • Inserm (FR)
  • RIKEN (JP)
  • Columbia University Irving Medical Center
ORCID
Venue
Research Square
Publisher
Springer Science and Business Media LLC
Published
2024-07-02
DOI
10.21203/rs.3.rs-4535534/v1
PMC
PMC11247936
OpenAlex
W4400226826
Cited by
5
References
117
Citations by year
2026: 3 · 2025: 2
Type
posted content
Language
en
Open access
Licence
Locations
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • HAL (submittedVersion)
Funders
  • U.S. Department of Defense (W81XWH2010849)
  • Alzheimer's Association (ZEN-22-848604)
  • Yale University
  • Japan Agency for Medical Research and Development (JP23zf0127008, 21gm4010006h0002, JPMJMS2021, 22ek0410075h0003, JPMJMS2024, JP 223fa627002, JP223fa627010, JP22km0405211, JP233fa627011, JP22ek0109594, JP22km0405217)
  • UK Research and Innovation
  • Hope Center for Neurological Disorders
  • National Institute for Health and Care Research
  • Imperial College London
  • Imperial College Healthcare NHS Trust
  • Agence Nationale de la Recherche (ANR-18-RHUS-0002)
  • Eisai
  • UK Dementia Research Institute
  • National Institutes of Health (n01hc085082-026, n01hc085081-021, n01hc085079-024, 1r01hl120393-01a1, n01hc085083-027, n01hc085080-026, n01hc085086-022, n01hc55222-0-0-0, AG066515)
  • Medical Research Council
  • Japan Society for the Promotion of Science (JPMJMS2024, JPMJMS2021, 22H00476)
  • National Institute on Aging (RF1AG053303, R01AG044546, P01AG003991, R01AG023629, R00AG062723, RF1AG074007, U01AG058922, RF1AG058501, P30AG066444, P30AG066515, P01AG026276)
  • National Heart, Lung, and Blood Institute (R01HL087652, R01HL103612, U01HL130114, R01HL105756, U01HL080295)
  • National Cancer Institute
  • Moonshot Research and Development Program (JPMJMS2024, JPMJMS2021)
Topics
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
cerebral small vessel disease, cerebrospinal fluid proteomics, plasma proteomics, proteogenomics, white matter hyperintensities, perivascular spaces, MRI markers, Mendelian randomization, protein quantitative trait loci, microglia, extracellular matrix, immune response, stroke, dementia, biomarkers, therapeutic target, single-nucleus RNA sequencing, East Asian ancestry

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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