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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

5. Relative effects of LDL-C on ischemic stroke and coronary disease A Mendelian randomization study

Author

Valdes-Marquez, E, Parish, S, Clarke, R, Stari, T, Worrall, BB, Hopewell, JC, Slowik, A, Hofman, A, Algra, A, Reiner, AP, Doney, ASF, Gschwendtner, A, Ilinca, A, Giese, A-K, Lindgren, A, Vicente, AM, Norrving, B, Nordestgaard, BG, Mitchell, BD, Psaty, BM, Carty, CL, Sudlow, CLM, Anderson, C, Levi, CR, Satizabal, CL, Palmer, CNA, Gamble, DM, Woo, D, Saleheen, D, Ringelstein, EB, Valdimarsson, EM, Holliday, EG, Davies, G, Chauhan, G, Pasterkamp, G, Boncoraglio, GB, Kuhlenbaeumer, G, Thorleifsson, G, Falcone, GJ, Pare, G, Schmidt, H, Delavaran, H, Markus, HS, Aparicio, HJ, Deary, I, Cotlarciuc, I, Fernandez-Cadenas, I, Meschia, JF, Liu, J, Montaner, J, Pera, J, Cole, J, Attia, JR, Rosand, J, Ferro, JM, Bis, JC, Furie, K, Stefansson, K, Berger, K, Kostulas, K, Rannikmae, K, Ikram, MA, Benn, M, Dichgans, M, Pandolfo, M, Traylor, M, Walters, M, Sale, M, Nalls, MA, Fornage, M, van Zuydam, NR, Sharma, P, Abrantes, P, de Bakker, PIW, Higgins, P, Lichtner, P, Rothwell, PM, Amouyel, P, Yang, Q, Malik, R, Schmidt, R, Lemmens, R, van der Laan, SW, Pulit, SL, Abboud, S, Oliveira, SA, Gretarsdottir, S, Debette, S, Williams, SR, Bevan, S, Kittner, SJ, Seshadri, S, Mosley, T, Battey, TWK, Tatlisumak, T, Thorsteinsdottir, U, Thijs, VNS, Longstreth, WT, Zhao, W, Chen, W-M, Cheng, Y-C, Valdes-Marquez, E, Parish, S, Clarke, R, Stari, T, Worrall, BB, Hopewell, JC, Slowik, A, Hofman, A, Algra, A, Reiner, AP, Doney, ASF, Gschwendtner, A, Ilinca, A, Giese, A-K, Lindgren, A, Vicente, AM, Norrving, B, Nordestgaard, BG, Mitchell, BD, Psaty, BM, Carty, CL, Sudlow, CLM, Anderson, C, Levi, CR, Satizabal, CL, Palmer, CNA, Gamble, DM, Woo, D, Saleheen, D, Ringelstein, EB, Valdimarsson, EM, Holliday, EG, Davies, G, Chauhan, G, Pasterkamp, G, Boncoraglio, GB, Kuhlenbaeumer, G, Thorleifsson, G, Falcone, GJ, Pare, G, Schmidt, H, Delavaran, H, Markus, HS, Aparicio, HJ, Deary, I, Cotlarciuc, I, Fernandez-Cadenas, I, Meschia, JF, Liu, J, Montaner, J, Pera, J, Cole, J, Attia, JR, Rosand, J, Ferro, JM, Bis, JC, Furie, K, Stefansson, K, Berger, K, Kostulas, K, Rannikmae, K, Ikram, MA, Benn, M, Dichgans, M, Pandolfo, M, Traylor, M, Walters, M, Sale, M, Nalls, MA, Fornage, M, van Zuydam, NR, Sharma, P, Abrantes, P, de Bakker, PIW, Higgins, P, Lichtner, P, Rothwell, PM, Amouyel, P, Yang, Q, Malik, R, Schmidt, R, Lemmens, R, van der Laan, SW, Pulit, SL, Abboud, S, Oliveira, SA, Gretarsdottir, S, Debette, S, Williams, SR, Bevan, S, Kittner, SJ, Seshadri, S, Mosley, T, Battey, TWK, Tatlisumak, T, Thorsteinsdottir, U, Thijs, VNS, Longstreth, WT, Zhao, W, Chen, W-M, and Cheng, Y-C

Abstract

OBJECTIVE: To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach. METHODS: We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity. RESULTS: A 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD. CONCLUSIONS: In contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.

Published
2019

8. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

Author

Traylor, M, Farrall, M, Holliday, EG, Sudlow, C, Hopewell, JC, Cheng, YC, Fornage, M, Ikram, MA, Malik, R, Bevan, S, Thorsteinsdottir, U, Nalls, MA, Longstreth, WT, Wiggins, KL, Yadav, S, Parati, EA, DeStefano, AL, Worrall, BB, Kittner, SJ, Khan, MS, Reiner, AP, Helgadottir, A, Achterberg, S, Fernandez-Cadenas, I, Abboud, S, Schmidt, R, Walters, M, Chen, WM, Ringelstein, EB, O'Donnell, M, Ho, WK, Pera, J, Lemmens, R, Norrving, B, Higgins, P, Benn, M, Sale, M, Kuhlenbäumer, G, Doney, ASF, Vicente, AM, Delavaran, H, Algra, A, Davies, G, Oliveira, SA, Palmer, CNA, Deary, I, Schmidt, H, Pandolfo, M, Montaner, J, Carty, C, de Bakker, PIW, Kostulas, K, Ferro, JM, van Zuydam, NR, Valdimarsson, E, Nordestgaard, BG, Lindgren, A, Thijs, V, Slowik, A, Saleheen, D, Paré, G, Berger, K, Thorleifsson, G, Hofman, A, Mosley, TH, Mitchell, BD, Furie, K, Clarke, R, Levi, C, Seshadri, S, Gschwendtner, A, Boncoraglio, GB, Sharma, P, Bis, JC, Gretarsdottir, S, Psaty, BM, Rothwell, PM, Rosand, J, Radiology & Nuclear Medicine, Cardiology, and Epidemiology

Subjects
musculoskeletal diseases, medicine.medical_specialty, Neurology, endocrine system diseases, infarction, Population, Clinical Neurology, MEDLINE, population, Genome-wide association study, Disease, Bioinformatics, Article, diseases, Brain Ischemia, Doenças Cardio e Cérebro-vasculares, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, map, Databases, Genetic, Humans, Medicine, Genetic Predisposition to Disease, education, Stroke, 030304 developmental biology, Genetic association, sequence variants, 0303 health sciences, education.field_of_study, common, business.industry, prkch, nutritional and metabolic diseases, medicine.disease, 3. Good health, Meta-analysis, loci, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10-16) and ZFHX3 (p=2·28×10-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10-5) and HDAC9 (p=2·03×10-12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p

Published
2012

9. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Author

Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CCA, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Bo, N, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, YC, Woo, D, Nalls, MA, Müller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, MG, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, MacLeod, MJ, Slowik, A, and Walters, M

Subjects
medicine.medical_specialty, Neurology, Genotype, Locus (genetics), Genome-wide association study, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Histone Deacetylases, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Odds Ratio, medicine, Genetics, Humans, Genetic Predisposition to Disease, 030304 developmental biology, 0303 health sciences, Atrial fibrillation, Odds ratio, medicine.disease, Confidence interval, 3. Good health, Repressor Proteins, Stroke, Chromosomes, Human, Pair 7, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes. © 2012 Nature America, Inc. All rights reserved.

Published
2012

10. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta-analysis of genome-wide association studies

Author

Traylor, M. (Matthew), Farrall, M. (Martin), Holliday, E.G. (Elizabeth), Sudlow, C. (Cathie), Hopewell, J., Cheng, Y.-C. (Yu-Ching), Fornage, M. (Myriam), Ikram, M.A. (Arfan), Malik, R. (Rainer), Bevan, S. (Steve), Thorsteinsdottir, U. (Unnur), Nalls, M.A. (Michael), Longstreth Jr, W.T., Wiggins, K.L. (Kerri), Yadav, S. (Sunaina), Parati, E.A. (Eugenio), DeStefano, A.L. (Anita), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Khan, M.I. (Muhammad), Reiner, A. (Alexander), Helgadottir, H.T. (Hafdis), Achterberg, S. (Sefanja), Fernandez-Cadenas, I. (Israel), Abboud, S. (Shimon), Schmidt, R. (Reinhold), Walters, M.R. (Matthew), Chen, W-M., Ringelstein, E.B. (E. Bernd), O'Donnell, M. (Martin), Ho, W.K. (Weang Kee), Pera, M.F. (Martin ), Lemmens, R. (Robin), Norrving, B. (Bo), Higgins, P. (Peter), Benn, M. (Marianne), Sale, P. (Patrizio), Kuhlenbäumer, G. (Gregor), Doney, A.S.F. (Alex), Vicente, A.M. (Astrid M), Delavaran, H. (Hossein), Algra, A. (Ale), Davies, G. (Gail), Oliveira, S.A. (Sofia), Palmer, C.N.A. (Colin), Deary, I.J. (Ian), Pandolfo, M. (Massimo), Montaner, J. (Joan), Carty, C. (Cara), Bakker, P.I.W. (Paul) de, Kostulas, K. (Konstantinos), Ferro, M.T. (María), Zuydam, N.R. (Natalie) van, Valdimarsson, E. (Einar), Nordestgaard, B.G. (Børge), Lindgren, A. (Arne), Thijs, V. (Vincent), Slowik, A. (Agnieszka), Saleheen, D., Paré, G. (Guillaume), Berger, K. (Klaus), Thorleifsson, G. (Gudmar), Hofman, A. (Albert), Mosley, T.H. (Thomas), Mitchell, B.D. (Braxton), Furie, K.L. (Karen), Clarke, R. (Robert), Levi, C. (Christopher), Seshadri, S. (Sudha), Gschwendtner, A. (Andreas), Boncoraglio, G. (Giorgio Battista), Sharma, P. (Pankaj), Bis, J.C. (Joshua), Gretarsdottir, S. (Solveig), Psaty, B.M. (Bruce), Rothwell, P.M. (Peter), Rosand, J. (Jonathan), Meschia, J.F. (James F.), Zwart, J-A. (John-Anker), Kubisch, C. (Christian), Markus, H.S. (Hugh), Traylor, M. (Matthew), Farrall, M. (Martin), Holliday, E.G. (Elizabeth), Sudlow, C. (Cathie), Hopewell, J., Cheng, Y.-C. (Yu-Ching), Fornage, M. (Myriam), Ikram, M.A. (Arfan), Malik, R. (Rainer), Bevan, S. (Steve), Thorsteinsdottir, U. (Unnur), Nalls, M.A. (Michael), Longstreth Jr, W.T., Wiggins, K.L. (Kerri), Yadav, S. (Sunaina), Parati, E.A. (Eugenio), DeStefano, A.L. (Anita), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Khan, M.I. (Muhammad), Reiner, A. (Alexander), Helgadottir, H.T. (Hafdis), Achterberg, S. (Sefanja), Fernandez-Cadenas, I. (Israel), Abboud, S. (Shimon), Schmidt, R. (Reinhold), Walters, M.R. (Matthew), Chen, W-M., Ringelstein, E.B. (E. Bernd), O'Donnell, M. (Martin), Ho, W.K. (Weang Kee), Pera, M.F. (Martin ), Lemmens, R. (Robin), Norrving, B. (Bo), Higgins, P. (Peter), Benn, M. (Marianne), Sale, P. (Patrizio), Kuhlenbäumer, G. (Gregor), Doney, A.S.F. (Alex), Vicente, A.M. (Astrid M), Delavaran, H. (Hossein), Algra, A. (Ale), Davies, G. (Gail), Oliveira, S.A. (Sofia), Palmer, C.N.A. (Colin), Deary, I.J. (Ian), Pandolfo, M. (Massimo), Montaner, J. (Joan), Carty, C. (Cara), Bakker, P.I.W. (Paul) de, Kostulas, K. (Konstantinos), Ferro, M.T. (María), Zuydam, N.R. (Natalie) van, Valdimarsson, E. (Einar), Nordestgaard, B.G. (Børge), Lindgren, A. (Arne), Thijs, V. (Vincent), Slowik, A. (Agnieszka), Saleheen, D., Paré, G. (Guillaume), Berger, K. (Klaus), Thorleifsson, G. (Gudmar), Hofman, A. (Albert), Mosley, T.H. (Thomas), Mitchell, B.D. (Braxton), Furie, K.L. (Karen), Clarke, R. (Robert), Levi, C. (Christopher), Seshadri, S. (Sudha), Gschwendtner, A. (Andreas), Boncoraglio, G. (Giorgio Battista), Sharma, P. (Pankaj), Bis, J.C. (Joshua), Gretarsdottir, S. (Solveig), Psaty, B.M. (Bruce), Rothwell, P.M. (Peter), Rosand, J. (Jonathan), Meschia, J.F. (James F.), Zwart, J-A. (John-Anker), Kubisch, C. (Christian), and Markus, H.S. (Hugh)

Abstract

Background: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10-16) and ZFHX3 (p=2·28×10-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10-5) and HDAC9 (p=2·03×10-12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10-6. However, we were unable to replicate any of these novel associations in the replication cohort. Interpretation: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Funding: Wellcome Trust, UK Medic

Published
2012
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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, 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.

13. 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

14. Recovery, Functional Status, and Health-Related Quality of Life Status up to 4 Years after First-Ever Stroke Onset: A Population-Based Study.

Author

Aked J, Delavaran H, Wennerström F, and Lindgren AG

Abstract

Background: Stroke is a leading cause of acquired disability in adults worldwide, and the burden of stroke is projected to increase. Current long-term stroke outcome data including functional status, activity, and participation limitations as well as information on health-related quality of life (HRQoL) are vital for future rehabilitation and resource planning of stroke survivors., Methods: First-ever stroke survivors from a population-based cohort with ischemic stroke or intracerebral hemorrhage were followed up 3-4 years after stroke onset via clinic appointments, home visits, or telephone. Ischemic stroke was stratified by clinical syndrome (Oxfordshire Community Stroke Project classification) and pathogenetic mechanism (TOAST classification). We assessed the participants' functional status and independence with the modified Rankin Scale (mRS) and Barthel Index (BI) and their HRQoL across several domains (Short Form Questionnaire-36, EuroQoL-5D, and Stroke Impact Scale (SIS)). We used logistic and linear regression analyses to analyze potential baseline predictors of 3-4-year outcome., Results: Four hundred individuals were included; 151 died before clinical follow-up and 47 (12%) were lost to detailed follow-up. Two hundred and two individuals (median age: 72, IQR: 65-79; 40% female) were followed up after a median of 3.2 years (IQR: 3.1-3.5). Nineteen individuals (9%) had a recurrent stroke during the 3-4-year follow-up period. Among the 202 follow-up attendees, 147 (73%) had favorable functional outcome (mRS ≤2) and 134 (69%) of the 195 respondents reported good-excellent HRQoL according to SF-36. Age (HR: 1.03; 95% CI: 1.00-1.05), initial stroke severity (HR: 1.16; 95% CI: 1.10-1.22; p &lt; 0.001), living with in-home care or in care facility at baseline (HR: 8.77; 95% CI: 2.98-25.64), and recurrent stroke (HR: 3.58; 95% CI: 1.47-8.77) were predictors of poor functional outcome (mRS&gt;2). Poor functional outcome/death was less common among IS due to Other Causes and Small Artery Occlusion than other pathogenetic mechanisms (20% and 33% vs. 56-68%; p &lt; 0.01). SIS respondents with poor functional outcomes (n = 32) reported worst outcome in the hand domain of SIS (median: 28/100; IQR: 0-73)., Conclusions: Most 3-4-year stroke survivors have favorable functional outcomes and are independent in ADL in a population-based cohort. Despite its relative rarity, recurrent stroke was a predictor of poor functional outcome, emphasizing the need of adequate secondary prevention., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Published
2024
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15. Development of a new model for health assessment in agroecosystems.

Author

Delavaran H, Kazemi H, Kamkar B, and Gherekhloo J

Subjects
Biodiversity, Environmental Monitoring, Soil, Weed Control, Agriculture, Ecosystem
Abstract

Healthy agroecosystems provide a range of ecosystem services, and the lack of information about the importance of their health degree leads to the unsustainability of these agroecosystems. To assess the health status of agroecosystems, a model was developed using spatial analysis-based procedures in Geographic Information System (GIS) media, surveyed data, and field monitoring at Gorgan University of Agricultural Sciences and Natural Resources. Initially, a survey-based study was conducted in 50 barley fields of Bandar-e-Torkaman County, north of Iran, during the 2016-2017 years. Then, the health index maps were provided by spatial analysis-based functions in GIS media. For accurate estimation of health status in barley agroecosystems, some meteorological variables were layered. Finally, the health status of the agroecosystems was determined based on six indices, including pesticides consumption rate, chemical fertilizers consumption rate, crop yield, and cultivar type, soil organic matter, and biodiversity indices. When all the layers overlaid, only 12% of the surveyed agroecosystems were located in the healthy class. The use of proper tillage methods, the appropriate weed control operations, the optimum consumption of high-quality pesticides, high soil organic matter, and grain yield > 2.6 ton ha -1 were the main reasons for obtaining of health degree in these agroecosystems. In contrast, the consumption of low-quality pesticides, the use of inappropriate tillage tools and machinery, the little knowledge of the farmers about the optimum rates and consumption methods of pesticides and chemical fertilizers, and resistance of some weeds to herbicides were identified as the most essential reasons for non-health status in the most surveyed barley agroecosystems., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Published
2022
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16. Survival, causes of death and recurrence up to 3 years after stroke: A population-based study.

Author

Aked J, Delavaran H, and Lindgren AG

Subjects
Cause of Death, Follow-Up Studies, Humans, Prognosis, Recurrence, Risk Factors, Brain Ischemia epidemiology, Stroke epidemiology
Abstract

Background and Purpose: Up-to-date population-based information about long-term survival, causes of death and recurrence after stroke is needed., Methods: Four hundred consecutive individuals in a population-based cohort of first-ever stroke between 2015 and 2016 in Lund, Sweden, were followed up to 3 years regarding (i) survival (Swedish Population Register); (ii) causes of death (Swedish Causes of Death Register); and (iii) stroke recurrence (interview and medical chart review). Index and recurrent ischaemic stroke cases were classified using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) and Oxfordshire Community Stroke Project; and comorbidities were classified using the Charlson Comorbidity Index. Cox regression was used to determine predictors for 3-year mortality. Survival rates were compared with three local studies over a 30-year timespan., Results: Amongst 400 first-ever stroke patients, 265 (66%) survived 3 years post-stroke. Age (hazard ratio [HR] 1.09; 95% confidence interval [CI] 1.06-1.11), stroke severity (HR 1.11; 95% CI 1.08-1.13) and comorbidities (HR 1.36; 95% CI 1.22-1.53) were independently related to 3-year mortality. Amongst index ischaemic stroke patients, survival was lowest amongst those with cardio-aortic embolism (51/91; 56%). Cerebrovascular disease (54/135; 40%) and ischaemic heart disease (25/135; 19%) were the most common causes of death. Within 3 years, 30 (8%) had recurrent stroke. Amongst patients with index ischaemic stroke, 16/29 (55%) had a different TOAST pathogenetic mechanism or hemorrhagic stroke upon recurrence. Stroke survival improved between 1983-1985 and 2015-2016 (p = 0.002), but no significant change was observed between 2001-2002 and 2015-2016 (p = 0.48)., Conclusions: Stroke survival rates are relatively high, but their improvement over recent decades may be slowing down, possibly due to the composition of the first-ever stroke population. The common occurrence of changed pathogenetic mechanisms between first-ever and recurrent stroke highlights the value of reassessment in recurrent stroke., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2021
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17. Falls After Stroke: A Follow-up after Ten Years in Lund Stroke Register.

Author

Jönsson AC, Lindgren I, Delavaran H, Norrving B, and Lindgren A

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Incidence, Male, Middle Aged, Registries, Risk Assessment, Risk Factors, Stroke diagnosis, Sweden epidemiology, Time Factors, Accidental Falls prevention & control, Stroke epidemiology, Survivors
Abstract

Objectives: To evaluate incidence of self-reported falls and associated factors in a ten-year perspective after stroke., Methods: From a population-based cohort of first-ever stroke patients (n = 416) included in the Lund Stroke Register between March 1, 2001, and February 28, 2002, we performed a follow up of all 145 survivors ten years after stroke. We collected data on age, gender, main stroke type, living and housing situation, general health status (question 1 in the Short Form Health Survey (SF-36), dizziness, physical activity, Barthel Index, mobility aids, moving ability inside/outside, and health-related quality of life as defined by the EuroQol 3 dimension scale (EQ-5D-3L). Factors that may relate to falls were compared between those who had experienced falls after stroke or not., Results: Ten years after stroke, 49 patients (34 %) reported falls and 96 patients (66 %) reported no falls. Compared to patients with no falls, those who reported falls were older (median age 83.3 years vs 75.6 years; p < 0.001), more often lived alone, were more dependent in daily living, had less physical activity, poorer general health status, more often needed mobility aids, were more often unable to move alone outside, and had poorer health-related quality of life in all items in EQ-5D-3L except pain/discomfort., Conclusions: Falls had occurred in approximately one third of the participants ten years after the stroke, and were strongly associated with several measures of frailty. Our results indicate that fall prevention should in particular focus on those at high risk of falls., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Published
2021
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18. Completeness of case ascertainment in Swedish hospital-based stroke registers.

Author

Aked J, Delavaran H, Norrving B, and Lindgren A

Subjects
Adult, Aged, Cohort Studies, Female, Hospitals, Humans, Male, Middle Aged, Selection Bias, Sweden epidemiology, Registries standards, Stroke epidemiology
Abstract

Background: There is a worldwide development toward using data from hospital-based stroke registers to estimate epidemiological trends. However, incomplete case ascertainment may cause selection bias. We examined the completeness of case ascertainment and selection bias in two hospital-based Swedish stroke registers., Methods: First-ever stroke cases between March 2015 and February 2016 in the catchment area of Skåne University Hospital, Lund, Sweden, were included from multiple overlapping sources: two hospital-based stroke registers, Riksstroke-Lund and Lund Stroke Register (LSR); local outpatient and inpatient registers; primary care registers; and autopsy registers. The resulting population-based cohort was used as reference to assess completeness of case ascertainment and patient characteristics in Riksstroke-Lund and LSR., Results: In total, 400 stroke patients were identified. Riksstroke-Lund detected 328 (82%) patients, whereas LSR detected 363 (91%). Patients undetected by hospital-based registers had higher 28-day case fatality than those detected (44% vs 9%; P = .001). Patients only detected in primary care (n = 11) more often lived in healthcare facilities compared with those detected by hospital-based registers (57% vs 7%; P = .001). Patients not detected by Riksstroke-Lund, but detected by population-based sources, had less severe strokes (median NIHSS 3 vs 5; P = .013)., Conclusions: Some first-ever stroke patients, such as those with high early case fatality and those with mild stroke, may go undetected with hospital-based screening used in clinical stroke registers. This can result in selection bias due to not identifying specific groups of patients including some with high early case fatality and those living in healthcare facilities., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2020
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19. Temporal Trends of Stroke Epidemiology in Southern Sweden: A Population-Based Study on Stroke Incidence and Early Case-Fatality.

Author

Aked J, Delavaran H, Norrving B, and Lindgren A

Subjects
Adult, Age of Onset, Aged, Aged, 80 and over, Female, Humans, Incidence, Male, Middle Aged, Stroke mortality, Survival Rate, Sweden epidemiology, Stroke epidemiology
Abstract

Background: Up-to-date epidemiological stroke studies are important for healthcare planning and evaluating prevention strategies. This population-based study investigates temporal trends in stroke incidence and case-fatality in southern Sweden., Methods: First-ever stroke cases in the local catchment area of Skåne University Hospital in Lund, Sweden, between March, 2015 and February, 2016, were included from several sources, including 2 prospective hospital-based registers, retrospective screening of primary care visits, and autopsy registers. Stroke incidence and 28-day case-fatality rates were compared with data from this area obtained through similar methodology between March, 2001 and February, 2002., Results: Altogether, 456 and 413 first-ever stroke patients were identified during the earlier and later time periods respectively. The age- and sex-standardized stroke incidence rates decreased from 246 (95% CI 224-270) to 165 (95% CI 149-182) per 100,000 people. However, incidence remained unaltered among those <65 years. Early case-fatality decreased from 14 to 11% (p = 0.165). -Conclusion: First-ever stroke incidence in southern Sweden has decreased with 33% since the beginning of this millenni-um. Incidence rates have decreased among the elderly but remain unchanged among younger age groups. Our findings warrant further studies on trends in risk factor profiles and effects of prevention strategies, and heightened focus on stroke in the young., (© 2018 S. Karger AG, Basel.)

Published
2018
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20. Spontaneous Recovery of Upper Extremity Motor Impairment After Ischemic Stroke: Implications for Stem Cell-Based Therapeutic Approaches.

Author

Delavaran H, Aked J, Sjunnesson H, Lindvall O, Norrving B, Kokaia Z, and Lindgren A

Subjects
Adult, Aged, Brain Ischemia complications, Diffusion Magnetic Resonance Imaging methods, Disability Evaluation, Female, Follow-Up Studies, Humans, Male, Middle Aged, Movement Disorders diagnostic imaging, Movement Disorders pathology, Neurologic Examination, Quality of Life psychology, Retrospective Studies, Stroke diagnostic imaging, Stroke etiology, Stroke psychology, Young Adult, Movement Disorders etiology, Recovery of Function physiology, Stroke complications, Stroke Rehabilitation, Upper Extremity physiopathology
Abstract

Preclinical studies suggest that stem cell therapy (SCT) may improve sensorimotor recovery after stroke. Upper extremity motor impairment (UEMI) is common after stroke, often entailing substantial disability. To evaluate the feasibility of post-stroke UEMI as a target for SCT, we examined a selected sample of stroke patients potentially suitable for SCT, aiming to assess the frequency and recovery of UEMI, as well as its relation to activity limitations and participation restrictions. Patients aged 20-75 years with first-ever ischemic stroke, and National Institutes of Health Stroke Scale (NIHSS) scores 1-18, underwent brain diffusion-weighted MRI within 4 days of stroke onset (n = 108). Survivors were followed up after 3-5 years, including assessment with NIHSS, Fugl-Meyer assessment of upper extremity (FMA-UE), modified Rankin Scale (mRS), and Stroke Impact Scale (SIS). UEMI was defined as NIHSS arm/hand score ≥1. UEMI recovery was evaluated with change in NIHSS arm/hand scores between baseline and follow-up. Of 97 survivors, 84 were available to follow-up. Among 76 subjects (of 84) without recurrent stroke, 41 had UEMI at baseline of which 10 had residual UEMI at follow-up. The FMA-UE showed moderate-severe impairment in seven of 10 survivors with residual UEMI. UEMI was correlated to mRS (r s  = 0.49, p < 0.001) and the SIS social participation domain (r s  = -0.38, p = 0.001). Nearly 25% of the subjects with UEMI at baseline had residual impairment after 3-5 years, whereas about 75% showed complete recovery. Most of the subjects with residual UEMI had moderate-severe impairment, which correlated strongly to dependency in daily activities and social participation restrictions. Our findings suggest that SCT targeting post-stroke UEMI may be clinically valuable with significant meaningful benefits for patients but also emphasize the need of early prognostication to detect patients that will have residual impairment in order to optimize patient selection for SCT.

Published
2017
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21. Attitudes to Stem Cell Therapy Among Ischemic Stroke Survivors in the Lund Stroke Recovery Study.

Author

Aked J, Delavaran H, Lindvall O, Norrving B, Kokaia Z, and Lindgren A

Subjects
Aged, Brain Ischemia psychology, Female, Humans, Male, Middle Aged, Stroke psychology, Brain Ischemia therapy, Health Knowledge, Attitudes, Practice, Patients psychology, Stem Cell Transplantation psychology, Stroke therapy
Abstract

Preclinical studies suggest that stem cell therapy (SCT) may improve poststroke recovery, and clinical trials investigating safety are ongoing. However, knowledge about patients' attitudes to SCT in stroke is limited. We evaluated the knowledge and attitudes to this therapeutic approach as well as possible factors influencing this among stroke patients potentially suitable for SCT. Consecutive first-ever acute ischemic stroke patients aged 20-75 years with NIH stroke scale scores 1-18 were included. Exclusion criteria were severe comorbidities or infratentorial stroke. Clinical follow-up after 3-5 years assessed severity of residual stroke symptoms, cognitive function, functional status, patient-reported outcome, and comorbidity, and after receiving standardized information, the participants also completed an eight-item questionnaire on knowledge and attitudes about SCT. The relationships between clinical variables and positive attitude to SCT were assessed with logistic regression analyses. Of 108 patients included at baseline, 84 participated at follow-up and completed the questionnaire. In total, 12% had prior knowledge of SCT. When informed, 63% were positive toward it and 36% reported willingness to participate in SCT trials. Only 5%-8% expressed ethical considerations regarding different stem cell sources. Positive attitudes to SCT were associated with male gender (OR: 3.74; 95% CI: 1.45-9.61; P < 0.01) and better patient-reported outcome (OR: 1.02; 95% CI: 1.00-1.04; P < 0.05). In conclusion, stroke patients had limited prior knowledge of SCT, yet attitudes were positive among the majority after receiving standardized and neutral information. Gender and degree of stroke recovery may influence attitudes to SCT, indicating a need for targeted information to improve knowledge about SCT.

Published
2017
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22. Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

Author

Ay H, Arsava EM, Andsberg G, Benner T, Brown RD Jr, Chapman SN, Cole JW, Delavaran H, Dichgans M, Engström G, Giralt-Steinhauer E, Grewal RP, Gwinn K, Jern C, Jimenez-Conde J, Jood K, Katsnelson M, Kissela B, Kittner SJ, Kleindorfer DO, Labovitz DL, Lanfranconi S, Lee JM, Lehm M, Lemmens R, Levi C, Li L, Lindgren A, Markus HS, McArdle PF, Melander O, Norrving B, Peddareddygari LR, Pedersén A, Pera J, Rannikmäe K, Rexrode KM, Rhodes D, Rich SS, Roquer J, Rosand J, Rothwell PM, Rundek T, Sacco RL, Schmidt R, Schürks M, Seiler S, Sharma P, Slowik A, Sudlow C, Thijs V, Woodfield R, Worrall BB, and Meschia JF

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, National Institute of Neurological Disorders and Stroke (U.S.), Phenotype, United States, Stroke classification, Stroke etiology, Stroke pathology
Abstract

Background and Purpose: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium., Methods: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases., Results: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75)., Conclusions: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke., (© 2014 American Heart Association, Inc.)

Published
2014
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23. Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

Author

McArdle PF, Kittner SJ, Ay H, Brown RD Jr, Meschia JF, Rundek T, Wassertheil-Smoller S, Woo D, Andsberg G, Biffi A, Brenner DA, Cole JW, Corriveau R, de Bakker PI, Delavaran H, Dichgans M, Grewal RP, Gwinn K, Huq M, Jern C, Jimenez-Conde J, Jood K, Kaplan RC, Katschnig P, Katsnelson M, Labovitz DL, Lemmens R, Li L, Lindgren A, Markus HS, Peddareddygari LR, Pedersén A, Pera J, Redfors P, Roquer J, Rosand J, Rost NS, Rothwell PM, Sacco RL, Sharma P, Slowik A, Sudlow C, Thijs V, Tiedt S, Valenti R, and Worrall BB

Subjects
Adult, Aged, Aged, 80 and over, Brain Ischemia classification, Europe, Female, Humans, Male, Middle Aged, National Institute of Neurological Disorders and Stroke (U.S.) standards, Phenotype, Stroke classification, United States, Brain Ischemia diagnosis, Diagnostic Techniques and Procedures standards, Stroke diagnosis
Abstract

Objective: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems., Methods: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems., Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58)., Conclusion: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner., (© 2014 American Academy of Neurology.)

Published
2014
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24. Functional status and patient-reported outcome 10 years after stroke: the Lund Stroke Register.

Author

Jönsson AC, Delavaran H, Iwarsson S, Ståhl A, Norrving B, and Lindgren A

Subjects
Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pain etiology, Pain mortality, Pain physiopathology, Sweden, Activities of Daily Living, Anxiety mortality, Anxiety physiopathology, Depression mortality, Depression physiopathology, Registries, Stroke mortality, Stroke physiopathology, Stroke therapy
Abstract

Background and Purpose: Long-term studies of outcome after stroke are scarce. Our aim was to study functional status and patient-reported outcome 10 years after a first-ever stroke., Methods: Ten-year follow-up was conducted among the survivors from a population-based group of 416 patients included in the Lund Stroke Register, Sweden, between March 1, 2001, and February 28, 2002. The Barthel index was used to assess the functional status and the modified Rankin Scale to assess the degree of disability. The EQ-5D scale was used for survivors' self-reports about health outcome and the specific Short-Form 36 (SF-36) question for rating their overall health. The patients also reported their frequency of physical activity., Results: Among 145 survivors 10 years after stroke (median age, 78 years), 59% were men, 90% lived in their ordinary housing, 73% were assessed as independent, and 71% had no or slight disability. The need of assistance with mobility and self-care was reported by 14% and with usual activities by 22%. Moderate pain was reported by 39%, and 4% had a high degree of pain. Moderate anxiety/depression was reported by 28% and high degree only by 1%. Overall health status was reported in positive terms by more than two thirds of the survivors. Almost half the cohort reported the same frequency of physical activity (≥4× weekly) as before stroke onset., Conclusions: This study indicates that 10-year stroke survivors in Sweden are mostly independent in daily activities and report good overall health and frequent physical activity, although half of them are ≥78 years., (© 2014 American Heart Association, Inc.)

Published
2014
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25. Multiplicity of risk factors in ischemic stroke patients: relations to age, sex, and subtype--a study of 2,505 patients from the lund stroke register.

Author

Starby H, Delavaran H, Andsberg G, Lövkvist H, Norrving B, and Lindgren A

Subjects
Adult, Age Factors, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Prevalence, Registries, Risk Factors, Sex Factors, Brain Ischemia epidemiology, Stroke epidemiology
Abstract

Background: The prevalence of risk factors for ischemic stroke may vary between different groups of stroke patients. We examined the distribution of individual well-established risk factors as well as the multiplicity of risk factors in different age groups and among subtypes., Methods: In the Lund Stroke Register, we consecutively enrolled 2,505 patients with first-ever ischemic stroke from 2001 to 2009 and registered hypertension, diabetes mellitus, heart disease, current smoking, hypercholesterolemia as well as stroke subtype., Results: Among young patients (<55 years), at least 50% had ≥2 risk factors and 20-25% had ≥3 risk factors. In patients aged 55 years or older, the proportion with ≥2 risk factors was 70-80% and with ≥3 risk factors 35-45%. Men and women had a similar burden of risk factors. Approximately 50% of the cases classified as cardioembolism (CE) and large artery atherosclerosis (LAA) had ≥3 risk factors, which was significantly more than the other TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes (CE p < 0.001, LAA p = 0.001)., Conclusions: The prevalence of well-established risk factors is similar among young and old stroke patients with large proportions (50-80%) having ≥2 risk factors. Even though the prevalence of well-established risk factors differs between pathogenetic subtypes, these risk factors as well as the multiplicity of risk factors seem to be of clinical importance in all major subtypes of ischemic stroke., (© 2014 S. Karger AG, Basel.)

Published
2014
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26. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.

Author

Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M, Ikram MA, Malik R, Bevan S, Thorsteinsdottir U, Nalls MA, Longstreth W, Wiggins KL, Yadav S, Parati EA, Destefano AL, Worrall BB, Kittner SJ, Khan MS, Reiner AP, Helgadottir A, Achterberg S, Fernandez-Cadenas I, Abboud S, Schmidt R, Walters M, Chen WM, Ringelstein EB, O'Donnell M, Ho WK, Pera J, Lemmens R, Norrving B, Higgins P, Benn M, Sale M, Kuhlenbäumer G, Doney AS, Vicente AM, Delavaran H, Algra A, Davies G, Oliveira SA, Palmer CN, Deary I, Schmidt H, Pandolfo M, Montaner J, Carty C, de Bakker PI, Kostulas K, Ferro JM, van Zuydam NR, Valdimarsson E, Nordestgaard BG, Lindgren A, Thijs V, Slowik A, Saleheen D, Paré G, Berger K, Thorleifsson G, Hofman A, Mosley TH, Mitchell BD, Furie K, Clarke R, Levi C, Seshadri S, Gschwendtner A, Boncoraglio GB, Sharma P, Bis JC, Gretarsdottir S, Psaty BM, Rothwell PM, Rosand J, Meschia JF, Stefansson K, Dichgans M, and Markus HS

Subjects
Brain Ischemia diagnosis, Databases, Genetic trends, Genome-Wide Association Study trends, Humans, Risk Factors, Stroke diagnosis, Brain Ischemia genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Stroke genetics
Abstract

Background: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes., Methods: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls., Findings: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort., Interpretation: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes., Funding: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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27. A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene.

Author

Lövkvist H, Olsson S, Höglund P, Melander O, Jern C, Sjögren M, Engström G, Smith JG, Hedblad B, Andsberg G, Delavaran H, Jood K, Kristoffersson U, Luthman H, Norrving B, and Lindgren A

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Case-Control Studies, Coronary Artery Disease genetics, Cyclic Nucleotide Phosphodiesterases, Type 4, Diabetes Mellitus genetics, Female, Genetic Predisposition to Disease, Genetic Testing, Genotyping Techniques, Humans, Hypertension genetics, Male, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Smoking genetics, Sweden, Young Adult, Cyclic Nucleotide Phosphodiesterases, Type 3 genetics, Ischemia genetics, Stroke genetics
Abstract

Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmö Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants <55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10,500 patients and 10,102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR=0.93; 95% confidence interval (CI): 0.83-1.05). Significant associations were not found for hypertensive participants or participants with age <55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR=0.96; 95% CI: 0.89-1.04) with significant heterogeneity for random effect (P=0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either.

Published
2012
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