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

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Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, Y-C, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Guonason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, C-Y, Wong, TY, Ikram, MK, van der Lee, JS, Amin, N, Chouraki, V, DeStefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, DeCarli, C, Wardlaw, JM, del Valdes Hernandez, MC, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, H-W, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Volker, U, Levi, C, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rosand, J, Woo, D, Cole, JW, Meschia, JF, Slowik, A, Thijs, V, Lindgren, A, Melander, O, Grewal, RP, Rundek, T, Rexrode, K, Rothwell, PM, Arnett, DK, Jern, C, Johnson, JA, Benavente, OR, Wasssertheil-Smoller, S, Lee, J-M, Wong, Q, Mitchell, BD, Rich, SS, McArdle, PF, Geerlings, MI, van der Graaf, Y, de Bakker, PIW, Asselbergs, FW, Srikanth, V, Thomson, R, McWhirter, R ORCID: 0000-0002-9409-8074, Moran, C, Callisaya, M ORCID: 0000-0003-2122-1622, Phan, T, Rutten-Jacobs, LCA, Bevan, S, Tzourio, C, Mather, KA, Sachdev, PS, van Duijn, CM, Worrall, BB, Dichgans, M, Kittner, SJ, Markus, HS, Ikram, MA, Fornage, M, Launer, LJ, Seshadri, S, Longstreth, WT and Debette, S 2019 , 'Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting' , Neurology, vol. 92, no. 5 , e486-e503 , doi: 10.1212/WNL.0000000000006851.

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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 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 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 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Item Type: Article
Authors/Creators:Chauhan, G and Adams, HHH and Satizabal, CL and Bis, JC and Teumer, A and Sargurupremraj, M and Hofer, E and Trompet, S and Hilal, S and Smith, AV and Jian, X and Malik, R and Traylor, M and Pulit, SL and Amouyel, P and Mazoyer, B and Zhu, Y-C and Kaffashian, S and Schilling, S and Beecham, GW and Montine, TJ and Schellenberg, GD and Kjartansson, O and Guonason, V and Knopman, DS and Griswold, ME and Windham, BG and Gottesman, RF and Mosley, TH and Schmidt, R and Saba, Y and Schmidt, H and Takeuchi, F and Yamaguchi, S and Nabika, T and Kato, N and Rajan, KB and Aggarwal, NT and De Jager, PL and Evans, DA and Psaty, BM and Rotter, JI and Rice, K and Lopez, OL and Liao, J and Chen, C and Cheng, C-Y and Wong, TY and Ikram, MK and van der Lee, JS and Amin, N and Chouraki, V and DeStefano, AL and Aparicio, HJ and Romero, JR and Maillard, P and DeCarli, C and Wardlaw, JM and del Valdes Hernandez, MC and Luciano, M and Liewald, D and Deary, IJ and Starr, JM and Bastin, ME and Maniega, SM and Slagboom, PE and Beekman, M and Deelen, J and Uh, H-W and Lemmens, R and Brodaty, H and Wright, MJ and Ames, D and Boncoraglio, GB and Hopewell, JC and Beecham, AH and Blanton, SH and Wright, CB and Sacco, RL and Wen, W and Thalamuthu, A and Armstrong, NJ and Chong, E and Schofield, PR and Kwok, JB and van der Grond, J and Stott, DJ and Ford, I and Jukema, JW and Vernooij, MW and Hofman, A and Uitterlinden, AG and van der Lugt, A and Wittfeld, K and Grabe, HJ and Hosten, N and von Sarnowski, B and Volker, U and Levi, C and Jimenez-Conde, J and Sharma, P and Sudlow, CLM and Rosand, J and Woo, D and Cole, JW and Meschia, JF and Slowik, A and Thijs, V and Lindgren, A and Melander, O and Grewal, RP and Rundek, T and Rexrode, K and Rothwell, PM and Arnett, DK and Jern, C and Johnson, JA and Benavente, OR and Wasssertheil-Smoller, S and Lee, J-M and Wong, Q and Mitchell, BD and Rich, SS and McArdle, PF and Geerlings, MI and van der Graaf, Y and de Bakker, PIW and Asselbergs, FW and Srikanth, V and Thomson, R and McWhirter, R and Moran, C and Callisaya, M and Phan, T and Rutten-Jacobs, LCA and Bevan, S and Tzourio, C and Mather, KA and Sachdev, PS and van Duijn, CM and Worrall, BB and Dichgans, M and Kittner, SJ and Markus, HS and Ikram, MA and Fornage, M and Launer, LJ and Seshadri, S and Longstreth, WT and Debette, S
Keywords: brain infarct, genetic risk factors
Journal or Publication Title: Neurology
Publisher: Lippincott Williams & Wilkins
ISSN: 0028-3878
DOI / ID Number: 10.1212/WNL.0000000000006851
Copyright Information:

Copyright 2019 the authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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