@article {8634,
	title = {{Cerebral small vessel disease genomics and its implications across the lifespan},
	journal = {Nat Commun},
	volume = {11},
	year = {2020},
	month = {12},
	pages = {6285},
	abstract = {White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5{\~A}{\textemdash}10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.},
	author = {Sargurupremraj, M. and Suzuki, H. and Jian, X. and Sarnowski, C. and Evans, T. E. and Bis, J. C. and Eiriksdottir, G. and Sakaue, S. and Terzikhan, N. and Habes, M. and Zhao, W. and Armstrong, N. J. and Hofer, E. and Yanek, L. R. and Hagenaars, S. P. and Kumar, R. B. and van den Akker, E. B. and McWhirter, R. E. and Trompet, S. and Mishra, A. and Saba, Y. and Satizabal, C. L. and Beaudet, G. and Petit, L. and Tsuchida, A. and Zago, L. and Schilling, S. and Sigurdsson, S. and Gottesman, R. F. and Lewis, C. E. and Aggarwal, N. T. and Lopez, O. L. and Smith, J. A. and Vald?s Hern?ndez, M. C. and van der Grond, J. and Wright, M. J. and Knol, M. J. and D?rr, M. and Thomson, R. J. and Bordes, C. and Le Grand, Q. and Duperron, M. G. and Smith, A. V. and Knopman, D. S. and Schreiner, P. J. and Evans, D. A. and Rotter, J. I. and Beiser, A. S. and Maniega, S. M. and Beekman, M. and Trollor, J. and Stott, D. J. and Vernooij, M. W. and Wittfeld, K. and Niessen, W. J. and Soumar?, A. and Boerwinkle, E. and Sidney, S. and Turner, S. T. and Davies, G. and Thalamuthu, A. and V?lker, U. and van Buchem, M. A. and Bryan, R. N. and Dupuis, J. and Bastin, M. E. and Ames, D. and Teumer, A. and Amouyel, P. and Kwok, J. B. and B?low, R. and Deary, I. J. and Schofield, P. R. and Brodaty, H. and Jiang, J. and Tabara, Y. and Setoh, K. and Miyamoto, S. and Yoshida, K. and Nagata, M. and Kamatani, Y. and Matsuda, F. and Psaty, B. M. and Bennett, D. A. and De Jager, P. L. and Mosley, T. H. and Sachdev, P. S. and Schmidt, R. and Warren, H. R. and Evangelou, E. and Tr?gou?t, D. A. and Ikram, M. A. and Wen, W. and DeCarli, C. and Srikanth, V. K. and Jukema, J. W. and Slagboom, E. P. and Kardia, S. L. R. and Okada, Y. and Mazoyer, B. and Wardlaw, J. M. and Nyquist, P. A. and Mather, K. A. and Grabe, H. J. and Schmidt, H. and van Duijn, C. M. and Gudnason, V. and Longstreth, W. T. and Launer, L. J. and Lathrop, M. and Seshadri, S. and Tzourio, C. and Adams, H. H. and Matthews, P. M. and Fornage, M. and Debette, S. and Amouyel, P. and de Andrade, M. and Basu, S. and Berr, C. and Brody, J. A. and Chasman, D. I. and Dartigues, J. F. and Folsom, A. R. and Germain, M. and de Haan, H. and Heit, J. and Houwing-Duitermaat, J. and Kabrhel, C. and Kraft, P. and Legal, G. and Lindstr?m, S. and Monajemi, R. and Morange, P. E. and Psaty, B. M. and Reitsma, P. H. and Ridker, P. M. and Rose, L. M. and Rosendaal, F. R. and Saut, N. and Slagboom, E. and Smadja, D. and Smith, N. L. and Suchon, P. and Tang, W. and Taylor, K. D. and Tr?gou?t, D. A. and Tzourio, C. and de Visser, M. C. H. and van Hylckama Vlieg, A. and Weng, L. C. and Wiggins, K. L. and Gormley, P. and Anttila, V. and Winsvold, B. S. and Palta, P. and Esko, T. and Pers, T. H. and Farh, K. H. and Cuenca-Leon, E. and Muona, M. and Furlotte, N. A. and Kurth, T. and Ingason, A. and McMahon, G. and Ligthart, L. and Terwindt, G. M. and Kallela, M. and Freilinger, T. M. and Ran, C. and Gordon, S. G. and Stam, A. H. and Steinberg, S. and Borck, G. and Koiranen, M. and Quaye, L. and Adams, H. H. H. and Lehtim?ki, T. and Sarin, A. P. and Wedenoja, J. and Hinds, D. A. and Buring, J. E. and Sch?rks, M. and Ridker, P. M. and Gudlaug Hrafnsdottir, M. and Stefansson, H. and Ring, S. M. and Hottenga, J. J. and Penninx, B. W. J. H. and F?rkkil?, M. and Artto, V. and Kaunisto, M. and Veps?l?inen, S. and Malik, R. and Heath, A. C. and Madden, P. A. F. and Martin, N. G. and Montgomery, G. W. and Kurki, M. and Kals, M. and M?gi, R. and P?rn, K. and H?m?l?inen, E. and Huang, H. and Byrnes, A. E. and Franke, L. and Huang, J. and Stergiakouli, E. and Lee, P. H. and Sandor, C. and Webber, C. and Cader, Z. and Muller-Myhsok, B. and Schreiber, S. and Meitinger, T. and Eriksson, J. G. and Salomaa, V. and Heikkil?, K. and Loehrer, E. and Uitterlinden, A. G. and Hofman, A. and van Duijn, C. M. and Cherkas, L. and Pedersen, L. M. and Stubhaug, A. and Nielsen, C. S. and M?nnikk?, M. and Mihailov, E. and Milani, L. and G?bel, H. and Esserlind, A. L. and Francke Christensen, A. and Folkmann Hansen, T. and Werge, T. and Kaprio, J. and Aromaa, A. J. and Raitakari, O. and Ikram, M. A. and Spector, T. and J?rvelin, M. R. and Metspalu, A. and Kubisch, C. and Strachan, D. P. and Ferrari, M. D. and Belin, A. C. and Dichgans, M. and Wessman, M. and van den Maagdenberg, A. M. J. M. and Zwart, J. A. and Boomsma, D. I. and Davey Smith, G. and Stefansson, K. and Eriksson, N. and Daly, M. J. and Neale, B. M. and Olesen, J. and Chasman, D. I. and Nyholt, D. R. and Palotie, A.}
}
@article {9106,
	title = {{Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate},
	journal = {Brain},
	volume = {145},
	year = {2022},
	month = {Jun},
	pages = {1992{\textendash}2007},
	abstract = {Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5{\textquoteright} UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer{\textquoteright}s disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.},
	author = {Mishra, A. and Dupla{\`a}, C. and Vojinovic, D. and Suzuki, H. and Sargurupremraj, M. and Zilhao, N. R. and Li, S. and Bartz, T. M. and Jian, X. and Zhao, W. and Hofer, E. and Wittfeld, K. and Harris, S. E. and van der Auwera-Palitschka, S. and Luciano, M. and Bis, J. C. and Adams, H. H. H. and Satizabal, C. L. and Gottesman, R. F. and Gampawar, P. G. and B{\"u}low, R. and Weiss, S. and Yu, M. and Bastin, M. E. and Lopez, O. L. and Vernooij, M. W. and Beiser, A. S. and V{\"o}lker, U. and Kacprowski, T. and Soumare, A. and Smith, J. A. and Knopman, D. S. and Morris, Z. and Zhu, Y. and Rotter, J. I. and Dufouil, C. and Vald{\'e}s Hern{\'a}ndez, M. and Mu{\~n}oz Maniega, S. and Lathrop, M. and Boerwinkle, E. and Schmidt, R. and Ihara, M. and Mazoyer, B. and Yang, Q. and Joutel, A. and Tournier-Lasserve, E. and Launer, L. J. and Deary, I. J. and Mosley, T. H. and Amouyel, P. and DeCarli, C. S. and Psaty, B. M. and Tzourio, C. and Kardia, S. L. R. and Grabe, H. J. and Teumer, A. and van Duijn, C. M. and Schmidt, H. and Wardlaw, J. M. and Ikram, M. A. and Fornage, M. and Gudnason, V. and Seshadri, S. and Matthews, P. M. and Longstreth, W. T. and Couffinhal, T. and Debette, S.}
}
