Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
Por:
Duperron, MG, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Tregouet, DA, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bulow, R, Carrera, C, Chen, CSP, Cheng, CY, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, JY, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Maniega, SM, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Hernandez, MCV, Vernooij, MW, Volker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, JY, Zhao, WT, Zhu, YC, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, Debette, S
Publicada:
17 abr 2023
Ahead of Print:
1 abr 2023
Resumen:
Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 +/- 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 +/- 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 +/- 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.
Filiaciones:
Duperron, MG:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Bordeaux Univ Hosp, Inst Neurodegenerat Dis, Dept Neurol, Bordeaux, France
Knol, MJ:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Le Grand, Q:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Evans, TE:
Erasmus MC Univ, Dept Clin Genet, Med Ctr, Rotterdam, Netherlands
Erasmus MC Univ, Dept Radiol & Nucl Med, Med Ctr, Rotterdam, Netherlands
Mishra, A:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Tsuchida, A:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Univ Bordeaux, CEA, CNRS, UMR 5293,GIN,IMN, Bordeaux, France
Roshchupkin, G:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Erasmus MC Univ, Dept Radiol & Nucl Med, Med Ctr, Rotterdam, Netherlands
Konuma, T:
Osaka Univ, Grad Sch Med, Dept Stat Genet, Suita, Osaka, Japan
Tregouet, DA:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Romero, JR:
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Frenzel, S:
Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany
Luciano, M:
Univ Edinburgh, Sch Psychol, Edinburgh, Midlothian, Scotland
Hofer, E:
Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria
Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria
Bourgey, M:
McGill Univ, Dept Human Genet, Montreal, PQ, Canada
McGill Univ, Victor Phillip Dahdaleh Inst Genom Med, Montreal, PQ, Canada
McGill Univ, Canadian Ctr Computat Genom, Montreal, PQ, Canada
Dueker, ND:
Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA
Delgado, P:
Univ Autonoma Barcelona, Inst Recerca Vall dhebron, Neurovasc Res Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Univ Vall dhebron, Neurol Dept, Barcelona, Spain
Hilal, S:
Natl Univ Hlth Syst, Memory Aging & Cognit Ctr, Singapore, Singapore
Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore
Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore
Natl Univ Hlth Syst, Singapore, Singapore
Tankard, RM:
Curtin Univ, Dept Math & Stat, Perth, WA, Australia
Dubost, F:
Erasmus MC Univ, Dept Radiol & Nucl Med, Med Ctr, Rotterdam, Netherlands
Erasmus MC Univ, Dept Med Informat, Med Ctr, Rotterdam, Netherlands
Shin, J:
Univ Toronto, Hosp Sick Children, Toronto, ON, Canada
Univ Toronto, Dept Physiol, Toronto, ON, Canada
Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada
Saba, Y:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Med Univ Graz, Inst Mol Biol & Biochem, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Graz, Austria
Armstrong, NJ:
Curtin Univ, Dept Math & Stat, Perth, WA, Australia
Bordes, C:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Bastin, ME:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Beiser, A:
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Brodaty, H:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
UNSW, Dementia Collaborat Res Ctr Assessment & Better C, Sydney, NSW, Australia
Bulow, R:
Univ Med Greifswald, Inst Radiol & Neuroradiol, Greifswald, Germany
Carrera, C:
Biomed Res Inst St Pau IIB St Pau, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Chen, CSP:
Natl Univ Hlth Syst, Memory Aging & Cognit Ctr, Singapore, Singapore
Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore
Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Psychol Med, Singapore, Singapore
Cheng, CY:
Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore
Natl Univ Singapore, Ctr Innovat & Precis Eye Hlth, Yong Loo Lin Sch Med, Singapore, Singapore
Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore
Duke NUS Med Sch, Ophthalmol & Visual Sci Acad Clin Program, Singapore, Singapore
Deary, IJ:
Univ Edinburgh, Sch Psychol, Edinburgh, Midlothian, Scotland
Gampawar, PG:
Med Univ Graz, Inst Mol Biol & Biochem, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Graz, Austria
Himali, JJ:
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
UT Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX USA
Jiang, JY:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
Kawaguchi, T:
Kyoto Univ, Ctr Genom Med, Grad Sch Med, Kyoto, Japan
Li, S:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Macalli, M:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Marquis, P:
McGill Univ, Dept Human Genet, Montreal, PQ, Canada
McGill Univ, Victor Phillip Dahdaleh Inst Genom Med, Montreal, PQ, Canada
McGill Univ, Canadian Ctr Computat Genom, Montreal, PQ, Canada
Morris, Z:
Royal Infirm Edinburgh NHS Trust, Dept Clin Neurosci, Neuroimaging, Edinburgh, Midlothian, Scotland
Maniega, SM:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Univ Edinburgh, UK Dementia Res Inst Ctr, Edinburgh, Midlothian, Scotland
Miyamoto, S:
Kyoto Univ Hosp, Kyoto, Japan
Okawa, M:
Kyoto Univ, Grad Sch Med, Dept Neurosurg, Kyoto, Japan
Paradise, M:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
Parva, P:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Med, Radiol Dept, Boston, MA 02118 USA
Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA
Rundek, T:
Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA
Univ Miami, Evelyn F McKnight Brain Inst, Dept Neurol, Miami, FL USA
Sargurupremraj, M:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Schilling, S:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Setoh, K:
Kyoto Univ, Ctr Genom Med, Grad Sch Med, Kyoto, Japan
Shizuoka Grad Univ Publ Hlth, Grad Sch Publ Hlth, Shizuoka, Japan
Soukarieh, O:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Tabara, Y:
Kyoto Univ, Ctr Genom Med, Grad Sch Med, Kyoto, Japan
Shizuoka Grad Univ Publ Hlth, Grad Sch Publ Hlth, Shizuoka, Japan
Teumer, A:
Univ Med Greifswald, Inst Community Med, Greifswald, Germany
Thalamuthu, A:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
Trollor, JN:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
UNSW, Dept Dev Disabil Neuropsychiat, Sydney, NSW, Australia
Hernandez, MCV:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Univ Edinburgh, Row Fogo Ctr Res Ageing & Brain, Edinburgh, Midlothian, Scotland
Vernooij, MW:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Erasmus MC Univ, Dept Radiol & Nucl Med, Med Ctr, Rotterdam, Netherlands
Volker, U:
Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany
Wittfeld, K:
Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany
German Ctr Neurodegenerat Dis DZNE, Site Rostock Greifswald, Greifswald, Germany
Wong, TY:
Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore
Tsinghua Univ, Tsinghua Med, Beijing, Peoples R China
Wright, MJ:
Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia
Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia
Zhang, JY:
Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia
Zhao, WT:
Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore
Duke NUS Med Sch, Ctr Quantitat Med, Singapore, Singapore
Zhu, YC:
Peking Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China
Schmidt, H:
Med Univ Graz, Inst Mol Biol & Biochem, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Graz, Austria
Sachdev, PS:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia
Wen, W:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
Yoshida, K:
Kyoto Univ, Grad Sch Med, Dept Neurosurg, Kyoto, Japan
Joutel, A:
Univ Paris Cite, Inst Psychiat & Neurosci Paris, INSERM, Paris, France
Satizabal, CL:
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
UT Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX USA
Sacco, RL:
Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA
Univ Miami, Evelyn F McKnight Brain Inst, Dept Neurol, Miami, FL USA
Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA
Univ Miami, Miller Sch Med, Dept Human Genom, Miami, FL 33136 USA
Univ Miami, Miller Sch Med, Dept Neurosurg, Miami, FL 33136 USA
Bourque, G:
McGill Univ, Dept Human Genet, Montreal, PQ, Canada
McGill Univ, Victor Phillip Dahdaleh Inst Genom Med, Montreal, PQ, Canada
McGill Univ, Canadian Ctr Computat Genom, Montreal, PQ, Canada
Lathrop, M:
McGill Univ, Dept Human Genet, Montreal, PQ, Canada
McGill Univ, Victor Phillip Dahdaleh Inst Genom Med, Montreal, PQ, Canada
Paus, T:
Univ Montreal, Fac Med, Dept Psychiat, Montreal, PQ, Canada
Univ Montreal, Fac Med, Dept Neurosci, Montreal, PQ, Canada
Univ Toronto, Dept Psychol, Toronto, ON, Canada
Ctr Hosp Univ St Justine, Montreal, PQ, Canada
Univ Toronto, Dept Psychiat, Toronto, ON, Canada
Fernandez-Cadenas, I:
Biomed Res Inst St Pau IIB St Pau, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Fundacio Docencia & Recerca Mutua Terrassa, Stroke Pharmacogen & Genet Grp, Terrassa, Spain
Yang, Q:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Mazoyer, B:
Univ Bordeaux, CEA, CNRS, UMR 5293,GIN,IMN, Bordeaux, France
Bordeaux Univ Hosp, Bordeaux, France
Boutinaud, P:
Fealinx, Lyon, France
Okada, Y:
Osaka Univ, Grad Sch Med, Dept Stat Genet, Suita, Osaka, Japan
Osaka Univ, Immunol Frontier Res Ctr WPI IFReC, Lab Stat Immunol, Suita, Osaka, Japan
Osaka Univ, Inst Open & Transdisciplinary Res Initiat, Integrated Frontier Res Med Sci Div, Suita, Osaka, Japan
Osaka Univ, Ctr Infect Dis Educ & Res CiDER, Suita, Osaka, Japan
Univ Tokyo, Grad Sch Med, Dept Genome Informat, Tokyo, Japan
Grabe, HJ:
Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany
German Ctr Neurodegenerat Dis DZNE, Site Rostock Greifswald, Greifswald, Germany
Mather, KA:
Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Discipline Psychiat & Mental Hlth, Sydney, NSW, Australia
Neurosci Res Australia, Sydney, NSW, Australia
Schmidt, R:
Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria
Joliot, M:
Univ Bordeaux, CEA, CNRS, UMR 5293,GIN,IMN, Bordeaux, France
Ikram, MA:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Matsuda, F:
Kyoto Univ, Ctr Genom Med, Grad Sch Med, Kyoto, Japan
Tzourio, C:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Bordeaux Univ Hosp, Dept Med Informat, Bordeaux, France
Wardlaw, JM:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Univ Edinburgh, UK Dementia Res Inst Ctr, Edinburgh, Midlothian, Scotland
Univ Edinburgh, Row Fogo Ctr Res Ageing & Brain, Edinburgh, Midlothian, Scotland
Seshadri, S:
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
UT Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX USA
Adams, HHH:
Erasmus MC Univ, Dept Clin Genet, Med Ctr, Rotterdam, Netherlands
Erasmus MC Univ, Dept Radiol & Nucl Med, Med Ctr, Rotterdam, Netherlands
Univ Adolfo Ibanez, Latin Amer Brain Hlth BrainLat, Santiago, Chile
Debette, S:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Bordeaux Univ Hosp, Inst Neurodegenerat Dis, Dept Neurol, Bordeaux, France
Green Published, Green Accepted, Green Submitted, hybrid, All Open Access, Hybrid Gold, Green
|