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1. Stroke genetics informs drug discovery and risk prediction across ancestries

Author: Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, Gravel, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, and Gravel, S
Abstract: Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Published: 2022

2. Diffusion tensor imaging of the hippocampus predicts the risk of dementia; the RUN DMC study

Author: van Uden, I. W.M., Tuladhar, A. M., van der Holst, H. M., van Leijsen, E. M.C., van Norden, A. G.W., de Laat, K. F., Rutten-Jacobs, L. C.A., Norris, D. G., Claassen, J. A.H.R, van Dijk, E. J., Kessels, R. P.C., and de Leeuw, F-E
Published: 2016
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3. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Author: Traylor, M, Persyn, E, Tomppo, L, Klasson, S, Abedi, V, Bakker, MK, Torres, N, Li, LX, Bell, S, Rutten-Jacobs, L, Tozer, DJ, Griessenauer, CJ, Zhang, YF, Pedersen, A, Sharma, P, Jimenez-Conde, J, Rundek, T, Grewal, RP, Lindgren, A, Meschia, JF, Salomaa, V, Havulinna, A, Kourkoulis, C, Crawford, K, Marini, S, Mitchell, BD, Kittner, SJ, Rosand, J, Dichgans, M, Jern, C, Strbian, D, Fernandez-Cadenas, I, Zand, R, Ruigrok, Y, Rost, N, Lemmens, R, Rothwell, PM, Anderson, CD, Wardlaw, J, Lewis, CM, Markus, HS, Helsinki Stroke Study, Dutch Parelsnoer Inst Cerebrovasc, Natl Inst Neurological Disorders, UK DNA Lacunar Stroke Study, Int Stroke Genetics Consortium, University of St Andrews. School of Biology, Bell, Steven [0000-0001-6774-3149], Tozer, Daniel [0000-0002-0404-3214], Markus, Hugh [0000-0002-9794-5996], Apollo - University of Cambridge Repository, HUS Neurocenter, Helsinki University Hospital Area, Neurologian yksikkö, Medicum, Institute for Molecular Medicine Finland, and University of Helsinki
Subjects: Oncology, PATHOGENESIS, LOCI, Genome-wide association study, Disease, VARIANTS, 3124 Neurology and psychiatry, SUBTYPES, 0302 clinical medicine, SMALL VESSEL DISEASE, Stroke, RISK, 0303 health sciences, Magnetic Resonance Imaging, 3. Good health, Europe, ISCHEMIC-STROKE, Meta-analysis, Medical genetics, Life Sciences & Biomedicine, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, medicine.medical_specialty, Lacunar stroke, Clinical Neurology, QH426 Genetics, CLASSIFICATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, QH426, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, business.industry, 3112 Neurosciences, Australia, DAS, medicine.disease, Hyperintensity, United States, ONSET, Stroke, Lacunar, RC0321, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Funding: This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate
Published: 2021
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4. Risk Prediction Using Polygenic Risk Scores for Prevention of Stroke and Other Cardiovascular Diseases

Author: Abraham, G, Rutten-Jacobs, L, Inouye, M, Abraham, G, Rutten-Jacobs, L, and Inouye, M
Abstract: Early prediction of risk of cardiovascular disease (CVD), including stroke, is a cornerstone of disease prevention. Clinical risk scores have been widely used for predicting CVD risk from known risk factors. Most CVDs have a substantial genetic component, which also has been confirmed for stroke in recent gene discovery efforts. However, the role of genetics in prediction of risk of CVD, including stroke, has been limited to testing for highly penetrant monogenic disorders. In contrast, the importance of polygenic variation, the aggregated effect of many common genetic variants across the genome with individually small effects, has become more apparent in the last 5 to 10 years, and powerful polygenic risk scores for CVD have been developed. Here we review the current state of the field of polygenic risk scores for CVD including stroke, and their potential to improve CVD risk prediction. We present findings and lessons from diseases such as coronary artery disease as these will likely be useful to inform future research in stroke polygenic risk prediction.
Published: 2021

5. Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study

Author: Barlas, Yesilot N., Putaala, J., Waje-Andreassen, U., Vassilopoulou, S., Nardi, K., Odier, C., Hofgart, G., Engelter, S., Burow, A., Mihalka, L., Kloss, M., Ferrari, J., Lemmens, R., Coban, O., Haapaniemi, E., Maaijwee, N., Rutten-Jacobs, L., Bersano, A., Cereda, C., Baron, P., Borellini, L., Valcarenghi, C., Thomassen, L., Grau, A. J., Palm, F., Urbanek, C., Tuncay, R., Tolvanen, Durukan A., van Dijk, E. J., de Leeuw, F.-E., Thijs, V., Greisenegger, S., Vemmos, K., Lichy, C., Bereczki, D., Csiba, L., Michel, P., Leys, D., Spengos, K., Naess, H., Tatlisumak, T., and Bahar, S. Z.
Published: 2013
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6. 7 TO 29 YEAR FOLLOW-UP STUDY OF COGNITIVE OUTCOME AFTER YOUNG STROKE. THE FUTURE STUDY: 21

Author: Maaijwee, N. A.M., Rutten-Jacobs, L. C.A., Schaapsmeerders, P., Kessels, R. P.C., van Dijk, E. J., and de Leeuw, F. E.
Published: 2011

7. PND60 Prevalence and Incidence of Huntington's Disease in the UK (2000–2018): A UK-Based Primary Care Study

Author: Furby, H., primary, Siadimas, T., additional, Rutten–Jacobs, L., additional, Dillon, A., additional, Oliveri, D., additional, and Wild, E.J., additional
Published: 2020
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8. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (vol 50, pg 524, 2018)

Author: Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, A-K, Van der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, W-M, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, DeStefano, AL, Den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, F-C, Hyacinth, IH, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jimenez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, J-M, Lemmens, R, Leys, D, Lewis, CM, Lin, W-Y, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmae, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Rotter, JI, Rundek, T, Sacco, RL, Sakaue, S, Sale, MM, Salomaa, V, Sapkota, BR, Schmidt, R, Schmidt, CO, Schminke, U, Sharma, P, Slowik, A, Sudlow, CLM, Tanislav, C, Tatlisumak, T, Taylor, KD, Thijs, VNS, Thorleifsson, G, Thorsteinsdottir, U, Tiedt, S, Trompet, S, Tzourio, C, Van Duijn, CM, Walters, M, Wareham, NJ, Wassertheil-Smoller, S, Wilson, JG, Wiggins, KL, Yang, Q, Yusuf, S, Bis, JC, Pastinen, T, Ruusalepp, A, Schadt, EE, Koplev, S, Bjorkegren, JLM, Codoni, V, Civelek, M, Smith, NL, Tregouet, DA, Christophersen, IE, Roselli, C, Lubitz, SA, Ellinor, PT, Tai, ES, Kooner, JS, Kato, N, He, J, Van der Harst, P, Elliott, P, Chambers, JC, Takeuchi, F, Johnson, AD, Sanghera, DK, Melander, O, Jern, C, Strbian, D, Fernandez-Cadenas, I, Longstreth, WT, Rolfs, A, Hata, J, Woo, D, Rosand, J, Pare, G, Hopewell, JC, Saleheen, D, Stefansson, K, Worrall, BB, Kittner, SJ, Seshadri, S, Fornage, M, Markus, HS, Howson, JMM, Kamatani, Y, Debette, S, and Dichgans, M
Subjects: Genetics & Heredity, International Genomics of Blood Pressure (iGEN-BP) Consortium, COMPASS Consortium, MEGASTROKE Consortium, Science & Technology, UK Young Lacunar DNA Study, AFGen Consortium, INVENT Consortium, STARNET, 06 Biological Sciences, METASTROKE Consortium, EPIC-CVD Consortium, BioBank Japan Cooperative Hospital Group, International Stroke Genetics Consortium (ISGC), NINDS Stroke Genetics Network (SiGN), Neurology Working Group of the CHARGE Consortium, EPIC-InterAct Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Developmental Biology
Published: 2019

9. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author: Chauhan, G., Adams, H., Satizabal, C., Bis, J., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A., Jian, X., Malik, R., Traylor, M., Pulit, S., Amouyel, P., Mazoyer, B., Zhu, Y., Kaffashian, S., Schilling, S., Beecham, G., Montine, T., Schellenberg, G., Kjartansson, O., Guethnason, V., Knopman, D., Griswold, M., Windham, B., Gottesman, R., Mosley, T., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K., Aggarwal, N., De Jager, P., Evans, D., Psaty, B., Rotter, J., Rice, K., Lopez, O., Liao, J., Chen, C., Cheng, C., Wong, T., Ikram, M., van der Lee, S., Amin, N., Chouraki, V., DeStefano, A., Aparicio, H., Romero, J., Maillard, P., DeCarli, C., Wardlaw, J., Hernandez, M., Luciano, M., Liewald, D., Deary, I., Starr, J., Bastin, M., Munoz Maniega, S., Slagboom, P., Beekman, M., Deelen, J., Uh, H., Lemmens, R., Brodaty, H., Wright, M., Ames, D., Boncoraglio, G., Hopewell, J., Beecham, A., Blanton, S., Wright, C., Sacco, R., Wen, W., Thalamuthu, A., Armstrong, N., Chong, E., Schofield, P., Kwok, J., van der Grond, J., Stott, D., Ford, I., Jukema, J., Vernooij, M., Hofman, A., Uitterlinden, A., van der Lugt, A., Wittfeld, K., Grabe, H., Hosten, N., von Sarnowski, B., Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C., Rosand, J., Woo, D., Cole, J., Meschia, J., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R., Rundek, T., Rexrode, K., Rothwell, P., Arnett, D., Jern, C., Johnson, J., Benavente, O., Wasssertheil-Smoller, S., Lee, J., Wong, Q., Mitchell, B., Rich, S., McArdle, P., Geerlings, M., van der Graaf, Y., de Bakker, P., Asselbergs, F., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L., Bevan, S., Tzourio, C., Mather, K., Sachdev, P., van Duijn, C., Worrall, B., Dichgans, M., Kittner, S., Markus, H., Fornage, M., Launer, L., Seshadri, S., Longstreth, W., Debette, S., Stroke Genetics Network, t., the Neurology Working Group of the Cohorts for, H., and Aging Research in Genomic Epidemiology, C.
Abstract: OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 x 10(-25); p [SSBI] = 5.23 x 10(-14) for hypertension), smoking (p [BI] = 4.4 x 10(-10); p [SSBI] = 1.2 x 10(-4)), diabetes (p [BI] = 1.7 x 10(-8); p [SSBI] = 2.8 x 10(-3)), previous cardiovascular disease (p [BI] = 1.0 x 10(-18); p [SSBI] = 2.3 x 10(-7)), stroke (p [BI] = 3.9 x 10(-69); p [SSBI] = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 x 10(-157); p [SSBI] = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p
Published: 2019

10. Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226)

Author: Traylor, M, Tozer, D, Croall, I, Lisiecka-Ford, D, Olorunda, A, Boncoraglio, G, Dichgans, M, Lemmens, R, Rosand, J, Rost, N, Rothwell, P, Sudlow, C, Thijs, V, Rutten-Jacobs, L, Markus, H, Consortium, International Stroke Genetics, Thijs, Vincent [0000-0002-6614-8417], Rutten-Jacobs, Loes [0000-0003-3223-885X], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, genetics [Stroke, Lacunar], genetics [Rho Guanine Nucleotide Exchange Factors], genetics [Brain Ischemia], Polymorphism, Single Nucleotide, PLEKHG1 protein, human, diagnostic imaging [White Matter], Brain Ischemia, diagnostic imaging [Stroke], Humans, ddc:610, diagnostic imaging [Stroke, Lacunar], Aged, Middle Aged, White Matter, Stroke, diagnostic imaging [Brain Ischemia], Cerebral Small Vessel Diseases, Stroke, Lacunar, genetics [Stroke], genetics [Cerebral Small Vessel Diseases], Female, diagnostic imaging [Cerebral Small Vessel Diseases], Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract: Objective To identify novel genetic associations with white matter hyperintensities (WMH). Methods We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. Results We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10−8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10−9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03–1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00–1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10−11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10−12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. Conclusions Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.
Published: 2019
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11. Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study

Author: Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, and Rothwell, PM
Subjects: Stroke, Neurology & Neurosurgery, Intracranial Embolism, Humans, Calcium, Magnesium, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Brain Ischemia
Abstract: © 2019 American Academy of Neurology. ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2018

12. Publisher correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes(Nature Genetics, (2018) 50, 4, (524-537), 10.1038/s41588-018-0058-3)

Author: Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, van der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, de Bakker, PIW, Destefano, AL, Den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Arfan Ikram, M, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Wouter Jukema, J, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O’donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Rotter, JI, Rundek, T, Sacco, RL, Sakaue, S, and Sale, MM
Subjects: Developmental Biology
Abstract: © 2019, Nature Publishing Group. All rights reserved. In the HTML version of this article initially published, the author groups ‘AFGen Consortium’, ‘Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium’, ‘International Genomics of Blood Pressure (iGEN-BP) Consortium’, ‘INVENT Consortium’, ‘STARNET’, ‘BioBank Japan Cooperative Hospital Group’, ‘COMPASS Consortium’, ‘EPIC-CVD Consortium’, ‘EPIC-InterAct Consortium’, ‘International Stroke Genetics Consortium (ISGC)’, ‘METASTROKE Consortium’, ‘Neurology Working Group of the CHARGE Consortium’, ‘NINDS Stroke Genetics Network (SiGN)’, ‘UK Young Lacunar DNA Study’ and ‘MEGASTROKE Consortium’ appeared at the end of the author list but should have appeared earlier in the list. In addition, the author group ‘MEGASTROKE Consortium’ was duplicated, and its members were not displayed in the ‘Author information’ section. The errors have been corrected in the HTML version of the article.
Published: 2018

13. Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study

Author: Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, and Rothwell, PM
Abstract: © 2019 American Academy of Neurology. ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019

14. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), Morris, R.W. (Richard), Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), and Morris, R.W. (Richard)
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018
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15. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author: Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Rotter, JI, Rundek, T, Sacco, RL, Sakaue, S, Sale, MM, Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Rotter, JI, Rundek, T, Sacco, RL, Sakaue, S, and Sale, MM
Abstract: © 2018 The Author(s). Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
Published: 2018

16. Long-term depressive symptoms and anxiety after transient ischaemic attack or ischaemic stroke in young adults

Author: Maaijwee, N. A. M. M., primary, Tendolkar, I., additional, Rutten-Jacobs, L. C. A., additional, Arntz, R. M., additional, Schaapsmeerders, P., additional, Dorresteijn, L. D., additional, Schoonderwaldt, H. C., additional, van Dijk, E. J., additional, and de Leeuw, F.-E., additional
Published: 2016
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17. Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study

Author: Barlas, N. Yesilot Putaala, J. Waje-Andreassen, U. and Vassilopoulou, S. Nardi, K. Odier, C. Hofgart, G. and Engelter, S. Burow, A. Mihalka, L. Kloss, M. Ferrari, J. and Lemmens, R. Coban, O. Haapaniemi, E. Maaijwee, N. and Rutten-Jacobs, L. Bersano, A. Cereda, C. Baron, P. and Borellini, L. Valcarenghi, C. Thomassen, L. Grau, A. J. and Palm, F. Urbanek, C. Tuncay, R. Durukan Tolvanen, A. van Dijk, E. J. de Leeuw, F. -E. Thijs, V. Greisenegger, S. and Vemmos, K. Lichy, C. Bereczki, D. Csiba, L. Michel, P. and Leys, D. Spengos, K. Naess, H. Tatlisumak, T. Bahar, S. Z.
Abstract: Background and purposeRisk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers. MethodsStroke etiology was reported in detail for 3331 patients aged 15-49years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity. ResultsEtiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe. ConclusionsThe etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria. Click here for the corresponding questions to this CME article.
Published: 2013

18. Epilepsy after TIA or stroke in young patients impairs long-term functional outcome: The FUTURE Study

Author: Arntz, R. M., primary, Maaijwee, N. A. M., additional, Rutten-Jacobs, L. C. A., additional, Schoonderwaldt, H. C., additional, Dorresteijn, L. D., additional, van Dijk, E. J., additional, and de Leeuw, F.-E., additional
Published: 2013
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19. Etiology of first‐ever ischaemic stroke in European young adults: the 15 cities young stroke study

Author: Yesilot Barlas, N., primary, Putaala, J., additional, Waje‐Andreassen, U., additional, Vassilopoulou, S., additional, Nardi, K., additional, Odier, C., additional, Hofgart, G., additional, Engelter, S., additional, Burow, A., additional, Mihalka, L., additional, Kloss, M., additional, Ferrari, J., additional, Lemmens, R., additional, Coban, O., additional, Haapaniemi, E., additional, Maaijwee, N., additional, Rutten‐Jacobs, L., additional, Bersano, A., additional, Cereda, C., additional, Baron, P., additional, Borellini, L., additional, Valcarenghi, C., additional, Thomassen, L., additional, Grau, A. J., additional, Palm, F., additional, Urbanek, C., additional, Tuncay, R., additional, Durukan Tolvanen, A., additional, van Dijk, E. J., additional, de Leeuw, F.‐E., additional, Thijs, V., additional, Greisenegger, S., additional, Vemmos, K., additional, Lichy, C., additional, Bereczki, D., additional, Csiba, L., additional, Michel, P., additional, Leys, D., additional, Spengos, K., additional, Naess, H., additional, Tatlisumak, T., additional, and Bahar, S. Z., additional
Published: 2013
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20. Demographic and geographic vascular risk factor differences in European young adults with ischemic stroke: the 15 cities young stroke study.

Author: Putaala J, Yesilot N, Waje-Andreassen U, Pitkäniemi J, Vassilopoulou S, Nardi K, Odier C, Hofgart G, Engelter S, Burow A, Mihalka L, Kloss M, Ferrari J, Lemmens R, Coban O, Haapaniemi E, Maaijwee N, Rutten-Jacobs L, Bersano A, and Cereda C
Published: 2012
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21. Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (Nature Genetics, (2018), 50, 4, (524-537), 10.1038/s41588-018-0058-3)

Author: Malik, R., Chauhan, G., Traylor, M., Sargurupremraj, M., Okada, Y., Mishra, A., Rutten-Jacobs, L., Giese, A. -K, Laan, S. W., Gretarsdottir, S., Anderson, C. D., Chong, M., Adams, H. H. H., Ago, T., Almgren, P., Amouyel, P., Ay, H., Bartz, T. M., Benavente, O. R., Bevan, S., Boncoraglio, G. B., Brown, R. D., Butterworth, A. S., Carrera, C., Carty, C. L., Chasman, D. I., Chen, W. -M, Cole, J. W., Correa, A., Cotlarciuc, I., Cruchaga, C., Danesh, J., Bakker, P. I. W., Destefano, A. L., Den Hoed, M., Duan, Q., Engelter, S. T., Falcone, G. J., Gottesman, R. F., Grewal, R. P., Gudnason, V., Gustafsson, S., Haessler, J., Harris, T. B., Hassan, A., Havulinna, A. S., Heckbert, S. R., Holliday, E. G., Howard, G., Hsu, F. -C, Hyacinth, H. I., Ikram, M. A., Ingelsson, E., Irvin, M. R., Jian, X., Jiménez-Conde, J., Johnson, J. A., Jukema, J. W., Kanai, M., Keene, K. L., Kissela, B. M., Kleindorfer, D. O., Kooperberg, C., Kubo, M., Lange, L. A., Langefeld, C. D., Langenberg, C., Launer, L. J., Lee, J. -M, Lemmens, R., Leys, D., Lewis, C. M., Lin, W. -Y, Lindgren, A. G., Lorentzen, E., Magnusson, P. K., Maguire, J., Manichaikul, A., Mcardle, P. F., Meschia, J. F., Mitchell, B. D., Mosley, T. H., Nalls, M. A., Ninomiya, T., O’donnell, M. J., Psaty, B. M., Pulit, S. L., Rannikmäe, K., Reiner, A. P., Rexrode, K. M., Rice, K., Rich, S. S., Ridker, P. M., Rost, N. S., Rothwell, P. M., Rotter, J. I., Rundek, T., Sacco, R. L., Sakaue, S., Sale, M. M., Salomaa, V., Sapkota, B. R., Schmidt, R., Schmidt, C. O., Schminke, U., Sharma, P., Slowik, A., Sudlow, C. L. M., Tanislav, C., Tatlisumak, T., Taylor, K. D., Thijs, V. N. S., Thorleifsson, G., Thorsteinsdottir, U., Tiedt, S., Trompet, S., Tzourio, C., Duijn, C. M., Walters, M., Wareham, N. J., Wassertheil-Smoller, S., Wilson, J. G., Wiggins, K. L., Yang, Q., Yusuf, S., Bis, J. C., Pastinen, T., Ruusalepp, A., Schadt, E. E., Koplev, S., Björkegren, J. L. M., Codoni, V., Civelek, M., Smith, N. L., Trégouët, D. A., Christophersen, I. E., Roselli, C., Lubitz, S. A., Ellinor, P. T., Tai, E. S., Kooner, J. S., Kato, N., He, J., Harst, P., Elliott, P., Chambers, J. C., Takeuchi, F., Johnson, A. D., Amin, N., Aparicio, H. S., Arnett, D. K., Attia, J., Beiser, A. S., Berr, C., Buring, J. E., Bustamante, M., Caso, V., Cheng, Y. -C, Choi, S. H., Chowhan, A., Cullell, N., Dartigues, J. -F, Delavaran, H., Delgado, P., Dörr, M., Engström, G., Ford, I., Gurpreet, W. S., Hamsten, A., Heitsch, L., Hozawa, A., Ibanez, L., Ilinca, A., Ingelsson, M., Iwasaki, M., Jackson, R. D., Jood, K., Jousilahti, P., Kaffashian, S., Kalra, L., Kamouchi, M., Kitazono, T., Kjartansson, O., Kloss, M., Koudstaal, P. J., Krupinski, J., Labovitz, D. L., Laurie, C. C., Levi, C. R., Li, L., Lind, L., Lindgren, C. M., Lioutas, V., Liu, Y. M., Lopez, O. L., Makoto, H., Martinez-Majander, N., Matsuda, K., Minegishi, N., Montaner, J., Morris, A. P., Muiño, E., Müller-Nurasyid, M., Norrving, B., Ogishima, S., Parati, E. A., Peddareddygari, L. R., Pedersen, N. L., Pera, J., Perola, M., Pezzini, A., Pileggi, S., Rabionet, R., Riba-Llena, I., Ribasés, M., Romero, J. R., Roquer, J., Rudd, A. G., Sarin, A. -P, Sarju, R., Sarnowski, C., Sasaki, M., Satizabal, C. L., Satoh, M., Sattar, N., Sawada, N., Sibolt, G., Sigurdsson, Á, Smith, A., Sobue, K., Soriano-Tárraga, C., Stanne, T., Stine, O. C., Stott, D. J., Strauch, K., Takai, T., Tanaka, H., Tanno, K., Teumer, A., Tomppo, L., Nuria P Torres-Aguila, Touze, E., Tsugane, S., Uitterlinden, A. G., Valdimarsson, E. M., Lee, S. J., Völzke, H., Wakai, K., Weir, D., Williams, S. R., Wolfe, C. D. A., Wong, Q., Xu, H., Yamaji, T., Sanghera, D. K., Melander, O., Jern, C., Strbian, D., Fernandez-Cadenas, I., Longstreth, W. T., Rolfs, A., Hata, J., Woo, D., Rosand, J., Pare, G., Hopewell, J. C., Saleheen, D., Stefansson, K., Worrall, B. B., Kittner, S. J., Seshadri, S., Fornage, M., Markus, H. S., Howson, J. M. M., Kamatani, Y., Debette, S., and Dichgans, M.

22. Risk factors and prognosis of young stroke. The FUTURE study: A prospective cohort study. Study rationale and protocol

Author: Zwiers Marcel P, Kessels Roy PC, van Heerde Waander L, Janssen Mirian C, Drost Gea, Overeem Sebastiaan, Dorresteijn Lucille DA, Schoonderwaldt Henny C, Schaapsmeerders Pauline, Van Alebeek Mayte E, Arntz Renate M, Maaijwee Noortje AM, Rutten-Jacobs Loes CA, Norris David G, van der Vlugt Maureen J, van Dijk Ewoud J, and de Leeuw Frank-Erik
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Young stroke can have devastating consequences with respect to quality of life, the ability to work, plan or run a family, and participate in social life. Better insight into risk factors and the long-term prognosis is extremely important, especially in young stroke patients with a life expectancy of decades. To date, detailed information on risk factors and the long-term prognosis in young stroke patients, and more specific risk of mortality or recurrent vascular events, remains scarce. Methods/Design The FUTURE study is a prospective cohort study on risk factors and prognosis of young ischemic and hemorrhagic stroke among 1006 patients, aged 18-50 years, included in our study database between 1-1-1980 and 1-11-2010. Follow-up visits at our research centre take place from the end of 2009 until the end of 2011. Control subjects will be recruited among the patients' spouses, relatives or social environment. Information on mortality and incident vascular events will be retrieved via structured questionnaires. In addition, participants are invited to the research centre to undergo an extensive sub study including MRI. Discussion The FUTURE study has the potential to make an important contribution to increase the knowledge on risk factors and long-term prognosis in young stroke patients. Our study differs from previous studies by having a maximal follow-up of more than 30 years, including not only TIA and ischemic stroke but also hemorrhagic stroke, the addition of healthy controls and prospectively collect data during an extensive follow-up visit. Completion of the FUTURE study may provide better information for treating physicians and patients with respect to the prognosis of young stroke.
Published: 2011
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23. Serum magnesium and calcium levels in relation to ischemic stroke Mendelian randomization study

Author: Susanna C. Larsson, Matthew Traylor, Stephen Burgess, Giorgio B. Boncoraglio, Christina Jern, Karl Michaëlsson, Hugh S. Markus, Rainer Malik, Ganesh Chauhan, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, raci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, Berr, Claudine, Unit of Cardiovascular and Nutritional Epidemiology [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Institute of Environmental Medicine [Stockholm, Sweden], Stroke Research Group [London, UK] (Department of Brain Repair and Rehabilitation), University of London - UCL [London, UK], MRC Biostatistics Unit [Cambridge, UK], University of Cambridge [UK] (CAM), Department of Public Health and Primary Care [Cambridge, UK] (Institute of Public Health), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Section of Clinical Immunology [Uppsala, Sweden] (Department of Immunology, Genetics and Pathology), Uppsala University, Department of Surgical Sciences [Uppsala, Sweden], This work was supported by the Swedish Research Council for Health, Working Life and Welfare (Forte) and the Swedish Research Council. Hugh Markus is supported by an NIHR Senior Investigator award. His and Matthew Traylor’s work is supported by infrastructural support from the Cambridge University Hospitals Trust NIHR Biomedical Research Centre., MEGASTROKE project of the International Stroke Genetics Consortium : Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HH, Ago T, Almgren P, Amouyel P, Ay H, Bartz RM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PI, DeStefano AL, Hoed MD, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CL, Tanislav C, Tatlisumak T, Taylor KD, Thijs VN, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Amin N, Aparicio HS, Arnett DK, Attia J, Beiser AS, Berr C, Buring JE, Bustamante M, Caso V, Cheng YC, Choi SH, Chowhan A, Cullell N, Dartigues JF, Delavaran H, Delgado P, Dörr M, Engström G, Ford I, Gurpreet WS, Hamsten A, Heitsch L, Hozawa A, Ibanez L, Ilinca A, Ingelsson M, Iwasaki M, Jackson RD, Jood K, Jousilahti P, Kaffashian S, Kalra L, Kamouchi M, Kitazono T, Kjartansson O, Kloss M, Koudstaal PJ, Krupinski J, Labovitz DL, Laurie CC, Levi CR, Li L, Lind L, Lindgren CM, Lioutas V, Liu YM, Lopez OL, Makoto H, Martinez-Majander N, Matsuda K, Minegishi N, Montaner J, Morris AP, Muiño E, Müller-Nurasyid M, Norrving B, Ogishima S, Parati EA, Peddareddygari LR, Pedersen NL, Pera J, Perola M, Pezzini A, Pileggi S, Rabionet R, Riba-Llena I, Ribasés M, Romero JR, Roquer J, Rudd AG, Sarin AP, Sarju R, Sarnowski C, Sasaki M, Satizabal CL, Satoh M, Sattar N, Sawada N, Sibolt G, Sigurdsson Á, Smith A, Sobue K, Soriano-Tárraga C, Stanne T, Stine OC, Stott DJ, Strauch K, Takai T, Tanaka H, Tanno K, Teumer A, Tomppo L, Torres-Aguila NP, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Völzke H, Wakai K, Weir D, Williams SR, Wolfe CD, Wong Q, Xu H, Yamaji T, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JM, Kamatani Y, Debette S, Dichgans M., Larsson, Susanna C [0000-0003-0118-0341], Apollo - University of Cambridge Repository, and Neurology
Subjects: medicine.medical_specialty, Neurology, Heredity, Neurologi, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Calcium, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Internal medicine, Mendelian randomization, Medicine, Humans, Magnesium, 030212 general & internal medicine, Stroke, Herència (Biologia), Genètica humana, business.industry, Neurosciences, Mendelian Randomization Analysis, Odds ratio, medicine.disease, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], Intracranial Embolism, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Neurovetenskaper
Abstract: Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019
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24. A Phase 2b, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of intravenous prasinezumab in early-stage Parkinson's disease (PADOVA): Rationale, design, and baseline data.

Author: Nikolcheva T, Pagano G, Pross N, Simuni T, Marek K, Postuma RB, Pavese N, Stocchi F, Seppi K, Monnet A, Shariati N, Ricci B, Rutten-Jacobs L, Respondek G, Kustermann T, Taylor KI, Trundell D, Fontoura P, Doody R, Svoboda H, and Bonni A
Subjects: Humans, Double-Blind Method, Male, Female, Aged, Middle Aged, Levodopa administration & dosage, Administration, Intravenous, Monoamine Oxidase Inhibitors administration & dosage, Monoamine Oxidase Inhibitors adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Disease Progression, Outcome Assessment, Health Care, Parkinson Disease drug therapy, Antiparkinson Agents administration & dosage
Abstract: Introduction: Prasinezumab was shown to potentially delay motor progression in individuals with early-stage Parkinson's disease (PD) who were either treatment-naïve or on monoamine oxidase type B inhibitor (MAO-Bi) therapy in the PASADENA study. We report the rationale, design, and baseline patient characteristics of the PADOVA study, designed to evaluate prasinezumab in an early-stage PD population receiving standard-of-care (SOC) symptomatic medications., Methods: PADOVA (NCT04777331) is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, in which individuals with early-stage PD on SOC stable symptomatic monotherapy (levodopa or MAO-Bi) receive intravenous prasinezumab 1500 mg every 4 weeks. The primary endpoint is time to confirmed motor progression, defined as ≥5 points increase from baseline on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in practically defined OFF-medication state., Results: 586 participants were enrolled between May 5th, 2021 and March 22nd, 2023. At baseline, 74.2 % and 25.8 % of participants were receiving levodopa and MAO-Bi, respectively. Mean age was 64.2 years and 63.5 % were male. Mean time from diagnosis was 18.6 months, 85 % of participants were in Hoehn & Yahr (H&Y) Stage 2, and mean MDS-UPDRS Part III score was 24.5. Compared with the PASADENA population, PADOVA participants were older (∼5 years), with longer disease duration (∼8 months), and slightly more advanced based on H&Y stage (10 % more in Stage 2) and MDS-UPDRS Part III (∼3 points more)., Conclusions: PADOVA has successfully recruited an early-stage PD population to test the effect of prasinezumab when added to background SOC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tania Nikolcheva reports financial support was provided by F Hoffmann-La Roche Ltd. Tania Nikolcheva reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Gennaro Pagano reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Nathalie Pross reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Gesine Respondek reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Annabelle Monnet reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Nima Shariati reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Benedicte Ricci reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Loes Rutten-Jacobs reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Thomas Kustermann reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Kirsten I. Taylor reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Azad Bonni reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Dylan Trundell reports a relationship with F Hoffmann-La Roche Ltd that includes: equity or stocks. Dylan Trundell reports a relationship with Roche Products Ltd that includes: employment. Hanno Svoboda reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Tanya Simuni reports a relationship with Acurex that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Adamas that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with AskBio that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Amneal that includes: consulting or advisory and funding grants. Tanya Simuni reports a relationship with Blue Rock Therapeutics that includes: consulting or advisory. Tanya Simuni reports a relationship with Critical Path for Parkinson's Consortium that includes: consulting or advisory. Tanya Simuni reports a relationship with Denali that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with The Michael J Fox Foundation that includes: consulting or advisory. Tanya Simuni reports a relationship with NeuroDerm Ltd that includes: board membership, consulting or advisory, and funding grants. Tanya Simuni reports a relationship with Sanofi that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Sinopia that includes: consulting or advisory. Tanya Simuni reports a relationship with Roche that includes: board membership, consulting or advisory, and funding grants. Tanya Simuni reports a relationship with Takeda that includes: consulting or advisory. Tanya Simuni reports a relationship with Vanqua Bio, Inc. that includes: consulting or advisory. Tanya Simuni reports a relationship with UCB that includes: board membership and funding grants. Tanya Simuni reports a relationship with Biogen that includes: funding grants. Tanya Simuni reports a relationship with Prevail Therapeutics that includes: funding grants. Tanya Simuni reports a relationship with National Institute of Neurological Disorders and Stroke that includes: consulting or advisory. Tanya Simuni reports a relationship with Parkinson's Foundation that includes: consulting or advisory. Kenneth Marek reports a relationship with Michael J Fox Foundation for Parkinson's Research that includes: consulting or advisory. Kenneth Marek reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Kenneth Marek reports a relationship with UCB that includes: consulting or advisory. Kenneth Marek reports a relationship with Denali that includes: consulting or advisory. Kenneth Marek reports a relationship with Takeda that includes: consulting or advisory. Kenneth Marek reports a relationship with Biohaven Ltd that includes: consulting or advisory. Kenneth Marek reports a relationship with Neuron23 that includes: consulting or advisory. Kenneth Marek reports a relationship with Aprinoia that includes: consulting or advisory. Kenneth Marek reports a relationship with Prothena that includes: consulting or advisory. Kenneth Marek reports a relationship with Calico that includes: consulting or advisory. Kenneth Marek reports a relationship with Inhibikase that includes: consulting or advisory. Kenneth Marek reports a relationship with Invicro that includes: consulting or advisory. Kenneth Marek reports a relationship with Koneksa that includes: consulting or advisory. Kenneth Marek reports a relationship with Lilly that includes: consulting or advisory. Ronald B. Postuma reports a relationship with Fonds de la Recherche en Sante that includes: funding grants. Ronald B. Postuma reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Ronald B. Postuma reports a relationship with The Michael J Fox Foundation that includes: funding grants. Ronald B. Postuma reports a relationship with Webster Foundation that includes: funding grants. Ronald B. Postuma reports a relationship with Roche that includes: funding grants. Ronald B. Postuma reports a relationship with National Institutes of Health that includes: funding grants. Ronald B. Postuma reports a relationship with Takeda that includes: funding grants. Ronald B. Postuma reports a relationship with Biogen that includes: funding grants. Ronald B. Postuma reports a relationship with Abbvie that includes: funding grants. Ronald B. Postuma reports a relationship with Curasen that includes: funding grants. Ronald B. Postuma reports a relationship with Lilly that includes: funding grants. Ronald B. Postuma reports a relationship with Novartis that includes: funding grants. Ronald B. Postuma reports a relationship with Eisai that includes: funding grants. Ronald B. Postuma reports a relationship with Paladin that includes: funding grants. Ronald B. Postuma reports a relationship with Merck that includes: funding grants. Ronald B. Postuma reports a relationship with Vaxxinity that includes: funding grants. Ronald B. Postuma reports a relationship with Korro that includes: funding grants. Ronald B. Postuma reports a relationship with Bristol Myers Squibb that includes: funding grants. Ronald B. Postuma reports a relationship with International Parkinson and Movement Disorder Society that includes: board membership and funding grants. Nicola Pavese reports a relationship with Britannia that includes: board membership and funding grants. Nicola Pavese reports a relationship with Boston Scientific that includes: board membership and funding grants. Nicola Pavese reports a relationship with Benevolent AI that includes: board membership. Nicola Pavese reports a relationship with F Hoffmann-La Roche inc that includes: board membership. Nicola Pavese reports a relationship with AbbVie Inc that includes: board membership and funding grants. Nicola Pavese reports a relationship with GE Healthcare that includes: funding grants. Nicola Pavese reports a relationship with Independent Research Fund Denmark that includes: funding grants. Nicola Pavese reports a relationship with Danish Parkinson's Disease Association that includes: funding grants. Nicola Pavese reports a relationship with Parkinson's UK that includes: funding grants. Nicola Pavese reports a relationship with Center of Excellence in Neurodegeneration network award that includes: funding grants. Nicola Pavese reports a relationship with GE Healthcare Grant that includes: funding grants. Nicola Pavese reports a relationship with Multiple System Atrophy Trust that includes: funding grants. Nicola Pavese reports a relationship with Weston Brain Institute that includes: funding grants. Nicola Pavese reports a relationship with EU Joint Programme Neurodegenerative Disease Research that includes: funding grants. Nicola Pavese reports a relationship with EU Horizon 2020 research that includes: funding grants. Nicola Pavese reports a relationship with The Michael J Fox Foundation for Parkinson's Research that includes: funding grants. Nicola Pavese reports a relationship with F Hoffmann-La Roche Ltd that includes: funding grants. Fabrizio Stocchi reports a relationship with AbbVie that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Bial Pharma that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Biogen Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with H. Lundbeck A S that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Mitsubishi Tanabe Pharma America Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Sunovion Pharmaceuticals Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Teva Pharmaceutical Industries that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Zambon that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Britannia that includes: consulting or advisory. Klaus Seppi reports a relationship with FWF Austrian Science Fund that includes: funding grants. Klaus Seppi reports a relationship with The Michael J Fox Foundation that includes: funding grants. Klaus Seppi reports a relationship with International Parkinson and Movement Disorder Society that includes: funding grants. Klaus Seppi reports a relationship with AOP Orphan Pharmaceuticals AG that includes: funding grants. Klaus Seppi reports a relationship with EU (all to the institution) that includes: funding grants. Klaus Seppi reports a relationship with Ono Pharma UK Ltd that includes: consulting or advisory. Klaus Seppi reports a relationship with Lundbeck that includes: consulting or advisory. Klaus Seppi reports a relationship with Ever Pharma that includes: consulting or advisory. Klaus Seppi reports a relationship with Teva that includes: speaking and lecture fees. Klaus Seppi reports a relationship with UCB that includes: speaking and lecture fees. Klaus Seppi reports a relationship with AOP Orphan Pharmaceuticals AG that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Roche that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Grünenthal that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Stada that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Licher Pharma that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Biogen that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Bial that includes: consulting or advisory and speaking and lecture fees. Klaus Seppi reports a relationship with AbbVie that includes: consulting or advisory and speaking and lecture fees. Klaus Seppi reports a relationship with Stada that includes: consulting or advisory. Paulo Fontoura reports a relationship with F Hoffmann-La Roche Ltd that includes: equity or stocks, and relationships with Harness Therapeutics and Stalicla SA that includes: employment, equity or stocks, and a relationship with Xaira Therapeutics that includes: employment, equity or stocks. Rachelle Doody reports a relationship with F Hoffmann-La Roche Ltd that includes: past employment, current stock and stock options. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2025
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25. Real-world evidence on the dosing and safety of C.E.R.A. in pediatric dialysis patients: findings from the International Pediatric Dialysis Network registries.

Author: Kohlhas L, Studer M, Rutten-Jacobs L, Reigner SM, Sander A, Yap HK, Vondrak K, Coccia PA, Cano F, Schmitt CP, Warady BA, and Schaefer F
Subjects: Humans, Child, Adolescent, Renal Dialysis adverse effects, Retrospective Studies, Prospective Studies, Hemoglobins analysis, Treatment Outcome, Registries, Erythropoietin, Renal Insufficiency, Chronic therapy, Renal Insufficiency, Chronic drug therapy, Kidney Failure, Chronic therapy
Abstract: Background: This retrospective real-world study used data from two registries, International Pediatric Peritoneal Dialysis Network (IPPN) and International Pediatric Hemodialysis Network (IPHN), to characterize the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) in pediatric patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) or hemodialysis (HD)., Methods: IPPN and IPHN collect prospective data (baseline and every 6 months) from pediatric PD and HD centers worldwide. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events, and deaths were extracted for patients on C.E.R.A. treatment (IPPN: 2007-2021; IPHN: 2013-2021)., Results: We analyzed 177 patients on PD (median age 10.6 years) and 52 patients on HD (median age 14.1 years) who had ≥ 1 observation while being treated with C.E.R.A. The median (interquartile range [IQR]) observation time under C.E.R.A. exposure was 6 (0-12.5) and 12 (0-18) months, respectively. Hemoglobin concentrations were stable over time; respective means (standard deviation) at last observation were 10.9 (1.7) g/dL and 10.4 (1.7) g/dL. Respective median (IQR) monthly C.E.R.A. doses at last observation were 3.5 (2.3-5.1) µg/kg, or 95 (62-145) µg/m 2 and 2.1 (1.2-3.4) µg/kg, or 63 (40-98) µg/m 2 . Non-elective hospitalizations occurred in 102 (58%) PD and 32 (62%) HD patients. Seven deaths occurred (19.8 deaths per 1000 observation years)., Conclusions: C.E.R.A. was associated with efficient maintenance of hemoglobin concentrations in pediatric patients with CKD on dialysis, and appeared to have a favorable safety profile. The current analysis revealed no safety signals., (© 2023. The Author(s).)
Published: 2024
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26. Racial and ethnic diversity in global neuroscience clinical trials.

Author: Rutten-Jacobs L, McIver T, Reyes A, Pereira M, Rosenthal R, Parusel CT, Wagner KR, and Doody R
Abstract: Background: Despite efforts to increase diversity in neuroscience trials, racial and ethnic minority groups remain underrepresented. Disparities in clinical trial participation could reflect unequal opportunities to participate and may contribute to decreased generalizability of findings and failure to identify important differences in efficacy and safety outcomes., Methods: We retrospectively reviewed the F. Hoffmann-La Roche database for global, multicenter, neuroscience clinical trials from February 2016 to February 2021 and summarized and stratified race and ethnicity distributions by clinical trial therapeutic area and by country. These data were then compared to national population data for each study's targeted age group (available for studies conducted in the US, Canada, and the UK). The underrepresentation or overrepresentation of each racial and ethnic group was summarized., Results: The analysis population included 8015 participants from 47 countries. Globally, 85.6 % of participants were White, 7.1 % were Asian, 1.6 % were Black, 1.3 % were American Indian or Alaska Native, less than 0.1 % were Native Hawaiian or other Pacific Islander, 0.7 % were of multiple races, and 3.6 % were of other/unknown race. White individuals predominated in all but one trial. Black individuals were underrepresented in all trials but one. Asian individuals were overrepresented in approximately 20 % of trials. In the US, 7.3 % of participants were of Hispanic or Latino ethnicity vs 16.4 % of the US population., Conclusion: The findings and learnings from this summary and analysis demonstrate the need for continued awareness and new approaches in designing studies that reflect population diversity., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LR-J, AR, MP, RR, CTP, and KRW are employees of and may own stock or stock options in F. Hoffmann-La Roche Ltd. TM is an employee of and may own stock or stock options in Roche Products Ltd. RD is an employee of and may own stock or stock options in F. Hoffmann-La Roche Ltd and Genentech, a Member of the Roche Group., (© 2024 The Authors. Published by Elsevier Inc.)
Published: 2024
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27. Natural history and burden of Huntington's disease in the UK: A population-based cohort study.

Author: Furby H, Siadimas A, Rutten-Jacobs L, Rodrigues FB, and Wild EJ
Subjects: Cohort Studies, Humans, Incidence, United Kingdom epidemiology, Huntington Disease diagnosis, Neurodegenerative Diseases
Abstract: Background: Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population., Methods: This cohort study utilised data from general practitioner medical records to estimate the prevalence and incidence of HD between January 2000 and December 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis., Results: Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis., Conclusions: This study demonstrates the significant and progressive clinical burden in individuals with HD up to 18 years after first recorded diagnosis., (© 2022 F. Hoffmann La Roche. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
Published: 2022
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28. Health utility in preclinical and prodromal Alzheimer's disease for establishing the value of new disease-modifying treatments-EQ-5D data from the Swedish BioFINDER study.

Author: Gustavsson A, Raket LL, Lilja M, Rutten-Jacobs L, Fues Wahl H, Bagijn M, Stomrud E, Hansson O, and Palmqvist S
Subjects: Aged, Biomarkers cerebrospinal fluid, Disease Progression, Female, Humans, Male, Surveys and Questionnaires, Sweden, tau Proteins cerebrospinal fluid, Alzheimer Disease cerebrospinal fluid, Amyloid beta-Peptides cerebrospinal fluid, Cognitive Dysfunction metabolism, Prodromal Symptoms, Quality of Life psychology
Abstract: Quality of life and health utility are important outcomes for patients with Alzheimer's disease (AD) and central for demonstrating the value of new treatments. Estimates in biomarker-confirmed AD populations are missing, potentially delaying payer approval of treatment. We examined whether health utility, assessed with the EuroQoL-5 3-level version (EQ-5D-3L), differed between individuals with a positive or negative amyloid beta (Aβ) biomarker in patients with mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants from the Swedish BioFINDER study (n = 578). Participants with prodromal AD (Aβ-positive MCI) reported better health utility (n = 79, mean = 0.81, 95% confidence interval [CI] 0.77-0.85) than Aβ-negative MCI (mean = 0.71, 95% CI 0.64-0.78), but worse than controls (Aβ-negative CU, mean = 0.87, 95% CI 0.86-0.89). Health utility in preclinical AD (Aβ-positive CU; mean = 0.86, 95% CI 0.83-0.89) was similar to controls. This relatively good health utility in prodromal AD suggests a larger value of delaying progression to dementia than previously anticipated and a great value of delaying clinical progression in preclinical AD., (© 2021 the Alzheimer's Association.)
Published: 2021
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29. Risk Prediction Using Polygenic Risk Scores for Prevention of Stroke and Other Cardiovascular Diseases.

Author: Abraham G, Rutten-Jacobs L, and Inouye M
Subjects: Genetic Predisposition to Disease genetics, Humans, Risk Factors, Cardiovascular Diseases prevention & control, Coronary Artery Disease prevention & control, Multifactorial Inheritance physiology, Stroke prevention & control
Abstract: Early prediction of risk of cardiovascular disease (CVD), including stroke, is a cornerstone of disease prevention. Clinical risk scores have been widely used for predicting CVD risk from known risk factors. Most CVDs have a substantial genetic component, which also has been confirmed for stroke in recent gene discovery efforts. However, the role of genetics in prediction of risk of CVD, including stroke, has been limited to testing for highly penetrant monogenic disorders. In contrast, the importance of polygenic variation, the aggregated effect of many common genetic variants across the genome with individually small effects, has become more apparent in the last 5 to 10 years, and powerful polygenic risk scores for CVD have been developed. Here we review the current state of the field of polygenic risk scores for CVD including stroke, and their potential to improve CVD risk prediction. We present findings and lessons from diseases such as coronary artery disease as these will likely be useful to inform future research in stroke polygenic risk prediction.
Published: 2021
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30. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.

Author: Traylor M, Persyn E, Tomppo L, Klasson S, Abedi V, Bakker MK, Torres N, Li L, Bell S, Rutten-Jacobs L, Tozer DJ, Griessenauer CJ, Zhang Y, Pedersen A, Sharma P, Jimenez-Conde J, Rundek T, Grewal RP, Lindgren A, Meschia JF, Salomaa V, Havulinna A, Kourkoulis C, Crawford K, Marini S, Mitchell BD, Kittner SJ, Rosand J, Dichgans M, Jern C, Strbian D, Fernandez-Cadenas I, Zand R, Ruigrok Y, Rost N, Lemmens R, Rothwell PM, Anderson CD, Wardlaw J, Lewis CM, and Markus HS
Subjects: Australia, Europe, Genetic Predisposition to Disease genetics, Humans, Magnetic Resonance Imaging, Stroke, Lacunar diagnosis, United States, Genetic Predisposition to Disease epidemiology, Genome-Wide Association Study, Stroke, Lacunar epidemiology, Stroke, Lacunar genetics
Abstract: Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease., Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation., Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke., Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk., Funding: British Heart Foundation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Published: 2021
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31. Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Author: Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Bis JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Björkegren JLM, Codoni V, Civelek M, Smith NL, Trégouët DA, Christophersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliott P, Chambers JC, Takeuchi F, Johnson AD, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, and Dichgans M
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019
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32. Causal Impact of Type 2 Diabetes Mellitus on Cerebral Small Vessel Disease: A Mendelian Randomization Analysis.

Author: Liu J, Rutten-Jacobs L, Liu M, Markus HS, and Traylor M
Subjects: Aged, Aged, 80 and over, Cerebral Hemorrhage complications, Cerebral Small Vessel Diseases complications, Diabetes Mellitus, Type 2 complications, Female, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Risk Factors, Stroke, Lacunar complications, Cerebral Hemorrhage therapy, Cerebral Small Vessel Diseases therapy, Diabetes Mellitus, Type 2 therapy, Mendelian Randomization Analysis, Stroke, Lacunar therapy
Abstract: Background and Purpose: The relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization., Methods: Five CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank., Results: T2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P =0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P =0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P =0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P =0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P =0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P =0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P =0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P =0.008) after adjusting for potential confounders., Conclusions: Our Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA., (© 2018 The Authors.)
Published: 2018
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33. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Author: Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Bis JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Björkegren JLM, Codoni V, Civelek M, Smith NL, Trégouët DA, Christophersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliott P, Chambers JC, Takeuchi F, Johnson AD, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, and Dichgans M
Subjects: Computational Biology, Databases, Genetic, Epigenesis, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, INDEL Mutation, Linkage Disequilibrium, Male, Models, Genetic, Polymorphism, Single Nucleotide, Risk Factors, Stroke classification, Stroke physiopathology, Stroke genetics
Abstract: Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
Published: 2018
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34. New insights into mechanisms of small vessel disease stroke from genetics.

Author: Tan R, Traylor M, Rutten-Jacobs L, and Markus H
Subjects: Alopecia genetics, Alopecia metabolism, Blood-Brain Barrier physiology, CADASIL genetics, CADASIL metabolism, Cerebral Infarction genetics, Cerebral Infarction metabolism, Cerebral Small Vessel Diseases metabolism, Collagen genetics, Extracellular Matrix physiology, Extracellular Matrix Proteins physiology, Genetic Predisposition to Disease, Humans, Leukoencephalopathies genetics, Leukoencephalopathies metabolism, Spinal Diseases genetics, Spinal Diseases metabolism, Cerebral Small Vessel Diseases genetics
Abstract: Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD., (© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)
Published: 2017
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35. Genetics of stroke in a UK African ancestry case-control study: South London Ethnicity and Stroke Study.

Author: Traylor M, Rutten-Jacobs L, Curtis C, Patel H, Breen G, Newhouse S, Lewis CM, and Markus HS
Abstract: Objective: Despite epidemiologic data showing an increased stroke incidence in African ancestry populations, genetic studies in this group have so far been limited, and there has been little characterization of the genetic contribution to stroke liability in this population, particularly for stroke subtypes., Methods: We evaluated the evidence that genetic factors contribute to stroke and stroke subtypes in a population of 917 African and African Caribbean stroke cases and 868 matched controls from London, United Kingdom. We (1) estimated the heritability of stroke in this population using genomic-relatedness matrix-restricted maximum likelihood approaches, (2) assessed loci associated with stroke in Europeans in our population, and (3) evaluated the influence of genetic factors underlying cardiovascular risk factors on stroke using polygenic risk scoring., Results: Our results indicate a substantial genetic contribution to stroke risk in African ancestry populations (h 2 = 0.35 [SE = 0.19], p = 0.043). Polygenic risk scores indicate that cardiovascular risk scores contribute to the genetic liability (odds ratio [OR] 1.09 [95% confidence interval (CI) 1.01-1.17], p = 0.029) and point to a strong influence of type 2 diabetes in large vessel stroke (OR 1.62 [95% CI 1.19-2.22], p = 0.0024). Single nucleotide polymorphisms associated with ischemic stroke in Europeans shared direction of effect in SLESS ( p = 0.031), suggesting that disease mechanisms are shared across ancestries., Conclusions: Stroke in African ancestry populations is highly heritable and influenced by genetic determinants underlying cardiovascular risk factors. In addition, stroke loci identified in Europeans share direction of effect in African populations. Future genome-wide association studies must focus on incorporating African ancestry individuals.
Published: 2017
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36. Post-stroke epilepsy in young adults: a long-term follow-up study.

Author: Arntz R, Rutten-Jacobs L, Maaijwee N, Schoonderwaldt H, Dorresteijn L, van Dijk E, and de Leeuw FE
Subjects: Adolescent, Adult, Cerebral Hemorrhage physiopathology, Epilepsy physiopathology, Female, Follow-Up Studies, Humans, Ischemic Attack, Transient physiopathology, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Quality of Life, Risk, Seizures physiopathology, Stroke physiopathology, Surveys and Questionnaires, Cerebral Hemorrhage complications, Epilepsy etiology, Ischemic Attack, Transient complications, Seizures etiology, Stroke complications
Abstract: Background: Little is known about the incidence and risk of seizures after stroke in young adults. Especially in the young seizures might dramatically influence prognosis and quality of life. We therefore investigated the long-term incidence and risk of post-stroke epilepsy in young adults with a transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH)., Methods and Findings: We performed a prospective cohort study among 697 consecutive patients with a first-ever TIA, IS or ICH, aged 18-50 years, admitted to our hospital between 1-1-1980 till 1-11-2010. The occurrence of epilepsy was assessed by standardized questionnaires and verified by a neurologist. Cumulative risks were estimated with Kaplan-Meier analysis. Cox proportional hazard models were used to calculate relative risks. After mean follow-up of 9.1 years (SD 8.2), 79 (11.3%) patients developed post-stroke epilepsy and 39 patients (5.6%) developed epilepsy with recurrent seizures. Patients with an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Cumulative risk of epilepsy was 31%, 16% and 5% for patients with an ICH, IS and TIA respectively (Logrank test ICH and IS versus TIA p<0.001). Cumulative risk of epilepsy with recurrent seizures was 23%, 8% and 4% respectively (Logrank ICH versus IS p = 0.05, ICH versus TIA p<0.001, IS versus TIA p = 0.01). In addition a high NIHSS was a significant predictor of both epilepsy and epilepsy with recurrent seizures (HR 1.07, 95% CI 1.03-1.11 and 1.08, 95% CI 1.02-1.14)., Conclusions: Post-stroke epilepsy is much more common than previously thought. Especially patients with an ICH and a high NIHSS are at high risk. This calls upon the question whether a subgroup could be identified which benefits from the use of prophylactic antiepileptic medication. Future studies should be executed to investigate risk factors and the effect of post-stroke epilepsy on quality of life.
Published: 2013
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