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

Chauhan, Ganesh; Adams, Hieab H. H.; Satizabal, Claudia L.; Bis, Joshua C.; Teumer, Alexander; Sargurupremraj, Muralidharan; Hofer, Edith; Trompet, Stella; Hilal, Saima; Smith, Albert Vernon; Jian, Xueqiu; Malik, Rainer; Traylor, Matthew; Pulit, Sara L.; Amouyel, Philippe; Mazoyer, Bernard; Zhu, Yi-Cheung; Kaffashian, Sara; Schilling, Sabrina; Beecham, Gary W.; Montine, Thomas J.; Schellenberg, G. D.; Kjartansson, O.; Guðnason, V.; Knopman, D. S.; Griswold, M. E.; Windham, B. G.; Gottesman, R. F.; Mosley, T. H.; Schmidt, R.; Saba, Y.; Schmidt, H.; Takeuchi, F.; Yamaguchi, S.; Nabika, T.; Kato, N; Rajan, K. B.; Aggarwal, N. T.; De Jager, P. L.; Evans, D. A.; Psaty, B M.; Rotter, J. I.; Rice, K.; Lopez, O. L.; Liao, J.; Chen, Christopher; Cheng, C.Y.; Wong, T. Y.; Ikram, M. K.; van der Lee, S. J.; Amin, N.; Chouraki, V.; Destefano, A. L.; Aparicio, H. J.; Romero, J. R.; Maillard, P.; Decarli, C.; Wardlaw, J. M.; Del C. Valdés Hernández, M.; Luciano, M.; Liewald, D.; Deary, I. J.; Starr, J. M.; Bastin, M. E.; Maniega, S. M.; Slagboom, P. E.; Beekman, M.; Deelen, J.; Uh, H. W.; Lemmens, R.; Brodaty, H.; Wright, MJ.; Ames, D.; Boncoraglio, G. B.; Hopewell, J. C.; Beecham, A. H.; Blanton, S. H.; Wright, C. B.; Sacco, R. L.; Wen, W.; Thalamuthu, A.; Armstrong, N. J.; Chong, E.; Schofield, P. R.; Kwok, J. B.; van der Grond, J.; Stott, D. J.; Ford, I.; Jukema, J. W.; Vernooij, M. W.; Hofman, A.; Uitterlinden, A. G.; van der Lugt, A.; Wittfeld, K.; Grabe, H. J.; Hosten, N.; von Sarnowski, B.; Völker, U.; Levi, Christopher; Jimenez-Conde, J.; Sharma, P.; Sudlow, C. L. M.; Woo, D.; Cole, J. W.; Mechia, J. F.; Rosand, J.; Slowik, A.; Thijs, V.; Lindgren, A.; Melander, O.; Grewal, R. P.; Rundek, T.; Arnett, D. K.; Jern, C.; Johnson, J. A.; Benavente, O. R.; Rexrode, K.; Asselbergs, F. R.; Srikanth, V.; Thomson, R.; McWhirter, R.; Moran, C.; Callisaya, M.; Phan, T.; Rutten-Jacobs, L. C. A.; Bevan, S.; Tzourio, C.; Mather, K. A.; Sachdev, P. S.; van Duijn, C. M.; Worrall, B. B.; Dichgans, M.; Kittner, S. J.; Markus, H. S.; Ikram, M. A.; Fornage, M.; Launer, L. J.; Seshadri, S.; Longstreth, W. T.; Debette, S.

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

journal contribution

posted on 2025-05-09, 17:26 authored by Ganesh Chauhan, Hieab H. H. Adams, Claudia L. Satizabal, Joshua C. Bis, Alexander Teumer, Muralidharan Sargurupremraj, Edith Hofer, Stella Trompet, Saima Hilal, Albert Vernon Smith, Xueqiu Jian, Rainer Malik, Matthew Traylor, Sara L. Pulit, Philippe Amouyel, Bernard Mazoyer, Yi-Cheung Zhu, Sara Kaffashian, Sabrina Schilling, Gary W. Beecham, Thomas J. Montine, G. D. Schellenberg, O. Kjartansson, V. Guðnason, D. S. Knopman, M. E. Griswold, B. G. Windham, R. F. Gottesman, T. H. Mosley, R. Schmidt, Y. Saba, H. Schmidt, F. Takeuchi, S. Yamaguchi, T. Nabika, N Kato, K. B. Rajan, N. T. Aggarwal, P. L. De Jager, D. A. Evans, B M. Psaty, J. I. Rotter, K. Rice, O. L. Lopez, J. Liao, Christopher ChenChristopher Chen, C.Y. Cheng, T. Y. Wong, M. K. Ikram, S. J. van der Lee, N. Amin, V. Chouraki, A. L. Destefano, H. J. Aparicio, J. R. Romero, P. Maillard, C. Decarli, J. M. Wardlaw, M. Del C. Valdés Hernández, M. Luciano, D. Liewald, I. J. Deary, J. M. Starr, M. E. Bastin, S. M. Maniega, P. E. Slagboom, M. Beekman, J. Deelen, H. W. Uh, R. Lemmens, H. Brodaty, MJ. Wright, D. Ames, G. B. Boncoraglio, J. C. Hopewell, A. H. Beecham, S. H. Blanton, C. B. Wright, R. L. Sacco, W. Wen, A. Thalamuthu, N. J. Armstrong, E. Chong, P. R. Schofield, J. B. Kwok, J. van der Grond, D. J. Stott, I. Ford, J. W. Jukema, M. W. Vernooij, A. Hofman, A. G. Uitterlinden, A. van der Lugt, K. Wittfeld, H. J. Grabe, N. Hosten, B. von Sarnowski, U. Völker, Christopher LeviChristopher Levi, J. Jimenez-Conde, P. Sharma, C. L. M. Sudlow, D. Woo, J. W. Cole, J. F. Mechia, J. Rosand, A. Slowik, V. Thijs, A. Lindgren, O. Melander, R. P. Grewal, T. Rundek, D. K. Arnett, C. Jern, J. A. Johnson, O. R. Benavente, K. Rexrode, F. R. Asselbergs, V. Srikanth, R. Thomson, R. McWhirter, C. Moran, M. Callisaya, T. Phan, L. C. A. Rutten-Jacobs, S. Bevan, C. Tzourio, K. A. Mather, P. S. Sachdev, C. M. van Duijn, B. B. Worrall, M. Dichgans, S. J. Kittner, H. S. Markus, M. A. Ikram, M. Fornage, L. J. Launer, S. Seshadri, W. T. Longstreth, S. Debette

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.

Funding

NHMRC

1045325

History

Journal title

Neurology

Volume

92

Issue

5

Pagination

e486-e503

Publisher

Lippincott Williams & Wilkins

Language

en, English

College/Research Centre

Faculty of Health and Medicine

School

School of Biomedical Sciences and Pharmacy

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Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Funding

NHMRC

1045325

History

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Issue

Pagination

Publisher

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College/Research Centre

School

Rights statement

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