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

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 Cheng Zhu, Sara Kaffashian, Sabrina Schilling, Gary W. Beecham & 130 others Thomas J. Montine, Gerard D. Schellenberg, Olafur Kjartansson, Vilmundur Guonason, David S. Knopman, Michael E. Griswold, B. Gwen Windham, Rebecca F Gottesman, Thomas H. Mosley, Reinhold Schmidt, Yasaman Saba, Helena Schmidt, Fumihiko Takeuchi, Shuhei Yamaguchi, Toru Nabika, Norihiro Kato, Kumar B. Rajan, Neelum T. Aggarwal, Philip L. De Jager, Denis A. Evans, Bruce M. Psaty, Jerome I. Rotter, Kenneth Rice, Oscar L. Lopez, Jiemin Liao, Christopher Chen, Ching Yu Cheng, Tien Y. Wong, Mohammad K. Ikram, J. Sven Van Der Lee, Najaf Amin, Vincent Chouraki, Anita L. DeStefano, Hugo J. Aparicio, Jose R. Romero, Pauline Maillard, Charles DeCarli, Joanna M. Wardlaw, Maria C. Del Valdes Hernandez, Michelle Luciano, David Liewald, Ian J. Deary, John M. Starr, Mark E. Bastin, Susana Muñoz Maniega, P. Eline Slagboom, Marian Beekman, Joris Deelen, Hae Won Uh, Robin Lemmens, Henry Brodaty, Margaret J. Wright, David Ames, Giorgio B. Boncoraglio, Jemma C. Hopewell, Ashley H. Beecham, Susan H. Blanton, Clinton B. Wright, Ralph L. Sacco, Wei Wen, Anbupalam Thalamuthu, Nicola J. Armstrong, Elizabeth Chong, Peter R. Schofield, John B. Kwok, Jeroen Van der Grond, David J. Stott, Ian Ford, J. Wouter Jukema, Meike W. Vernooij, Albert Hofman, Andre G. Uitterlinden, Aad Van der Lugt, Katharina Wittfeld, Hans J. Grabe, Norbert Hosten, Bettina Von Sarnowski, Uwe Volker, Christopher Levi, Jordi Jimenez-Conde, Pankaj Sharma, Cathie L.M. Sudlow, Jonathan Rosand, Daniel Woo, John W. Cole, James F. Meschia, Agnieszka Slowik, Vincent Thijs, Arne Lindgren, Olle Melander, Raji P. Grewal, Tatjana Rundek, Kathy Rexrode, Peter M. Rothwell, Donna K. Arnett, Christina Jern, Julie A. Johnson, Oscar R. Benavente, Sylvia Wasssertheil-Smoller, Jin Moo Lee, Quenna Wong, Braxton D. Mitchell, Stephen S. Rich, Patrick F. McArdle, Mirjam I. Geerlings, Yolanda Van der Graaf, Paul I.W. De Bakker, Folkert W. Asselbergs, Velandai Srikanth, Russell Thomson, Rebekah McWhirter, Chris Moran, Michele Callisaya, Thanh Phan, Loes C.A. Rutten-Jacobs, Steve Bevan, Christophe Tzourio, Karen A. Mather, Perminder S. Sachdev, Cornelia M. Van Duijn, Bradford B. Worrall, Martin Dichgans, Steven J. Kittner, Hugh S. Markus, Mohammad A. Ikram, Myriam Fornage, Lenore J. Launer, Sudha Seshadri, W. T. Longstreth, Stephanie Debette

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)E486-E503
JournalNeurology
Volume92
Issue number5
DOIs
StatePublished - Jan 29 2019
Externally publishedYes

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Life Style
Brain
Population
Genome-Wide Association Study
Blood Pressure
Phenotype
Meta-Analysis
Stroke
Hypertension
Genetic Loci

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Chauhan, G., Adams, H. H. H., Satizabal, C. L., Bis, J. C., Teumer, A., Sargurupremraj, M., ... Debette, S. (2019). Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting. Neurology, 92(5), E486-E503. https://doi.org/10.1212/WNL.0000000000006851

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 Cheng; Kaffashian, Sara; Schilling, Sabrina; Beecham, Gary W.; Montine, Thomas J.; Schellenberg, Gerard D.; Kjartansson, Olafur; Guonason, Vilmundur; Knopman, David S.; Griswold, Michael E.; Windham, B. Gwen; Gottesman, Rebecca F; Mosley, Thomas H.; Schmidt, Reinhold; Saba, Yasaman; Schmidt, Helena; Takeuchi, Fumihiko; Yamaguchi, Shuhei; Nabika, Toru; Kato, Norihiro; Rajan, Kumar B.; Aggarwal, Neelum T.; De Jager, Philip L.; Evans, Denis A.; Psaty, Bruce M.; Rotter, Jerome I.; Rice, Kenneth; Lopez, Oscar L.; Liao, Jiemin; Chen, Christopher; Cheng, Ching Yu; Wong, Tien Y.; Ikram, Mohammad K.; Van Der Lee, J. Sven; Amin, Najaf; Chouraki, Vincent; DeStefano, Anita L.; Aparicio, Hugo J.; Romero, Jose R.; Maillard, Pauline; DeCarli, Charles; Wardlaw, Joanna M.; Del Valdes Hernandez, Maria C.; Luciano, Michelle; Liewald, David; Deary, Ian J.; Starr, John M.; Bastin, Mark E.; Maniega, Susana Muñoz; Slagboom, P. Eline; Beekman, Marian; Deelen, Joris; Uh, Hae Won; Lemmens, Robin; Brodaty, Henry; Wright, Margaret J.; Ames, David; Boncoraglio, Giorgio B.; Hopewell, Jemma C.; Beecham, Ashley H.; Blanton, Susan H.; Wright, Clinton B.; Sacco, Ralph L.; Wen, Wei; Thalamuthu, Anbupalam; Armstrong, Nicola J.; Chong, Elizabeth; Schofield, Peter R.; Kwok, John B.; Van der Grond, Jeroen; Stott, David J.; Ford, Ian; Jukema, J. Wouter; Vernooij, Meike W.; Hofman, Albert; Uitterlinden, Andre G.; Van der Lugt, Aad; Wittfeld, Katharina; Grabe, Hans J.; Hosten, Norbert; Von Sarnowski, Bettina; Volker, Uwe; Levi, Christopher; Jimenez-Conde, Jordi; Sharma, Pankaj; Sudlow, Cathie L.M.; Rosand, Jonathan; Woo, Daniel; Cole, John W.; Meschia, James F.; Slowik, Agnieszka; Thijs, Vincent; Lindgren, Arne; Melander, Olle; Grewal, Raji P.; Rundek, Tatjana; Rexrode, Kathy; Rothwell, Peter M.; Arnett, Donna K.; Jern, Christina; Johnson, Julie A.; Benavente, Oscar R.; Wasssertheil-Smoller, Sylvia; Lee, Jin Moo; Wong, Quenna; Mitchell, Braxton D.; Rich, Stephen S.; McArdle, Patrick F.; Geerlings, Mirjam I.; Van der Graaf, Yolanda; De Bakker, Paul I.W.; Asselbergs, Folkert W.; Srikanth, Velandai; Thomson, Russell; McWhirter, Rebekah; Moran, Chris; Callisaya, Michele; Phan, Thanh; Rutten-Jacobs, Loes C.A.; Bevan, Steve; Tzourio, Christophe; Mather, Karen A.; Sachdev, Perminder S.; Van Duijn, Cornelia M.; Worrall, Bradford B.; Dichgans, Martin; Kittner, Steven J.; Markus, Hugh S.; Ikram, Mohammad A.; Fornage, Myriam; Launer, Lenore J.; Seshadri, Sudha; Longstreth, W. T.; Debette, Stephanie.

In: Neurology, Vol. 92, No. 5, 29.01.2019, p. E486-E503.

Research output: Contribution to journalArticle

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, YC, 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, CY, 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, HW, 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, JM, 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, Moran, C, Callisaya, M, 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 & Debette, S 2019, 'Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting', Neurology, vol. 92, no. 5, pp. E486-E503. https://doi.org/10.1212/WNL.0000000000006851
Chauhan G, Adams HHH, Satizabal CL, Bis JC, Teumer A, Sargurupremraj M et al. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting. Neurology. 2019 Jan 29;92(5):E486-E503. https://doi.org/10.1212/WNL.0000000000006851
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 Cheng ; Kaffashian, Sara ; Schilling, Sabrina ; Beecham, Gary W. ; Montine, Thomas J. ; Schellenberg, Gerard D. ; Kjartansson, Olafur ; Guonason, Vilmundur ; Knopman, David S. ; Griswold, Michael E. ; Windham, B. Gwen ; Gottesman, Rebecca F ; Mosley, Thomas H. ; Schmidt, Reinhold ; Saba, Yasaman ; Schmidt, Helena ; Takeuchi, Fumihiko ; Yamaguchi, Shuhei ; Nabika, Toru ; Kato, Norihiro ; Rajan, Kumar B. ; Aggarwal, Neelum T. ; De Jager, Philip L. ; Evans, Denis A. ; Psaty, Bruce M. ; Rotter, Jerome I. ; Rice, Kenneth ; Lopez, Oscar L. ; Liao, Jiemin ; Chen, Christopher ; Cheng, Ching Yu ; Wong, Tien Y. ; Ikram, Mohammad K. ; Van Der Lee, J. Sven ; Amin, Najaf ; Chouraki, Vincent ; DeStefano, Anita L. ; Aparicio, Hugo J. ; Romero, Jose R. ; Maillard, Pauline ; DeCarli, Charles ; Wardlaw, Joanna M. ; Del Valdes Hernandez, Maria C. ; Luciano, Michelle ; Liewald, David ; Deary, Ian J. ; Starr, John M. ; Bastin, Mark E. ; Maniega, Susana Muñoz ; Slagboom, P. Eline ; Beekman, Marian ; Deelen, Joris ; Uh, Hae Won ; Lemmens, Robin ; Brodaty, Henry ; Wright, Margaret J. ; Ames, David ; Boncoraglio, Giorgio B. ; Hopewell, Jemma C. ; Beecham, Ashley H. ; Blanton, Susan H. ; Wright, Clinton B. ; Sacco, Ralph L. ; Wen, Wei ; Thalamuthu, Anbupalam ; Armstrong, Nicola J. ; Chong, Elizabeth ; Schofield, Peter R. ; Kwok, John B. ; Van der Grond, Jeroen ; Stott, David J. ; Ford, Ian ; Jukema, J. Wouter ; Vernooij, Meike W. ; Hofman, Albert ; Uitterlinden, Andre G. ; Van der Lugt, Aad ; Wittfeld, Katharina ; Grabe, Hans J. ; Hosten, Norbert ; Von Sarnowski, Bettina ; Volker, Uwe ; Levi, Christopher ; Jimenez-Conde, Jordi ; Sharma, Pankaj ; Sudlow, Cathie L.M. ; Rosand, Jonathan ; Woo, Daniel ; Cole, John W. ; Meschia, James F. ; Slowik, Agnieszka ; Thijs, Vincent ; Lindgren, Arne ; Melander, Olle ; Grewal, Raji P. ; Rundek, Tatjana ; Rexrode, Kathy ; Rothwell, Peter M. ; Arnett, Donna K. ; Jern, Christina ; Johnson, Julie A. ; Benavente, Oscar R. ; Wasssertheil-Smoller, Sylvia ; Lee, Jin Moo ; Wong, Quenna ; Mitchell, Braxton D. ; Rich, Stephen S. ; McArdle, Patrick F. ; Geerlings, Mirjam I. ; Van der Graaf, Yolanda ; De Bakker, Paul I.W. ; Asselbergs, Folkert W. ; Srikanth, Velandai ; Thomson, Russell ; McWhirter, Rebekah ; Moran, Chris ; Callisaya, Michele ; Phan, Thanh ; Rutten-Jacobs, Loes C.A. ; Bevan, Steve ; Tzourio, Christophe ; Mather, Karen A. ; Sachdev, Perminder S. ; Van Duijn, Cornelia M. ; Worrall, Bradford B. ; Dichgans, Martin ; Kittner, Steven J. ; Markus, Hugh S. ; Ikram, Mohammad A. ; Fornage, Myriam ; Launer, Lenore J. ; Seshadri, Sudha ; Longstreth, W. T. ; Debette, Stephanie. / Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting. In: Neurology. 2019 ; Vol. 92, No. 5. pp. E486-E503.
@article{aa160684b27d40dd94cbbb6864f4e703,
title = "Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting",
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.",
author = "Ganesh Chauhan and Adams, {Hieab H.H.} and Satizabal, {Claudia L.} and Bis, {Joshua C.} and Alexander Teumer and Muralidharan Sargurupremraj and Edith Hofer and Stella Trompet and Saima Hilal and Smith, {Albert Vernon} and Xueqiu Jian and Rainer Malik and Matthew Traylor and Pulit, {Sara L.} and Philippe Amouyel and Bernard Mazoyer and Zhu, {Yi Cheng} and Sara Kaffashian and Sabrina Schilling and Beecham, {Gary W.} and Montine, {Thomas J.} and Schellenberg, {Gerard D.} and Olafur Kjartansson and Vilmundur Guonason and Knopman, {David S.} and Griswold, {Michael E.} and Windham, {B. Gwen} and Gottesman, {Rebecca F} and Mosley, {Thomas H.} and Reinhold Schmidt and Yasaman Saba and Helena Schmidt and Fumihiko Takeuchi and Shuhei Yamaguchi and Toru Nabika and Norihiro Kato and Rajan, {Kumar B.} and Aggarwal, {Neelum T.} and {De Jager}, {Philip L.} and Evans, {Denis A.} and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Kenneth Rice and Lopez, {Oscar L.} and Jiemin Liao and Christopher Chen and Cheng, {Ching Yu} and Wong, {Tien Y.} and Ikram, {Mohammad K.} and {Van Der Lee}, {J. Sven} and Najaf Amin and Vincent Chouraki and DeStefano, {Anita L.} and Aparicio, {Hugo J.} and Romero, {Jose R.} and Pauline Maillard and Charles DeCarli and Wardlaw, {Joanna M.} and {Del Valdes Hernandez}, {Maria C.} and Michelle Luciano and David Liewald and Deary, {Ian J.} and Starr, {John M.} and Bastin, {Mark E.} and Maniega, {Susana Mu{\~n}oz} and Slagboom, {P. Eline} and Marian Beekman and Joris Deelen and Uh, {Hae Won} and Robin Lemmens and Henry Brodaty and Wright, {Margaret J.} and David Ames and Boncoraglio, {Giorgio B.} and Hopewell, {Jemma C.} and Beecham, {Ashley H.} and Blanton, {Susan H.} and Wright, {Clinton B.} and Sacco, {Ralph L.} and Wei Wen and Anbupalam Thalamuthu and Armstrong, {Nicola J.} and Elizabeth Chong and Schofield, {Peter R.} and Kwok, {John B.} and {Van der Grond}, Jeroen and Stott, {David J.} and Ian Ford and Jukema, {J. Wouter} and Vernooij, {Meike W.} and Albert Hofman and Uitterlinden, {Andre G.} and {Van der Lugt}, Aad and Katharina Wittfeld and Grabe, {Hans J.} and Norbert Hosten and {Von Sarnowski}, Bettina and Uwe Volker and Christopher Levi and Jordi Jimenez-Conde and Pankaj Sharma and Sudlow, {Cathie L.M.} and Jonathan Rosand and Daniel Woo and Cole, {John W.} and Meschia, {James F.} and Agnieszka Slowik and Vincent Thijs and Arne Lindgren and Olle Melander and Grewal, {Raji P.} and Tatjana Rundek and Kathy Rexrode and Rothwell, {Peter M.} and Arnett, {Donna K.} and Christina Jern and Johnson, {Julie A.} and Benavente, {Oscar R.} and Sylvia Wasssertheil-Smoller and Lee, {Jin Moo} and Quenna Wong and Mitchell, {Braxton D.} and Rich, {Stephen S.} and McArdle, {Patrick F.} and Geerlings, {Mirjam I.} and {Van der Graaf}, Yolanda and {De Bakker}, {Paul I.W.} and Asselbergs, {Folkert W.} and Velandai Srikanth and Russell Thomson and Rebekah McWhirter and Chris Moran and Michele Callisaya and Thanh Phan and Rutten-Jacobs, {Loes C.A.} and Steve Bevan and Christophe Tzourio and Mather, {Karen A.} and Sachdev, {Perminder S.} and {Van Duijn}, {Cornelia M.} and Worrall, {Bradford B.} and Martin Dichgans and Kittner, {Steven J.} and Markus, {Hugh S.} and Ikram, {Mohammad A.} and Myriam Fornage and Launer, {Lenore J.} and Sudha Seshadri and Longstreth, {W. T.} and Stephanie Debette",
year = "2019",
month = "1",
day = "29",
doi = "10.1212/WNL.0000000000006851",
language = "English (US)",
volume = "92",
pages = "E486--E503",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

AU - Chauhan, Ganesh

AU - Adams, Hieab H.H.

AU - Satizabal, Claudia L.

AU - Bis, Joshua C.

AU - Teumer, Alexander

AU - Sargurupremraj, Muralidharan

AU - Hofer, Edith

AU - Trompet, Stella

AU - Hilal, Saima

AU - Smith, Albert Vernon

AU - Jian, Xueqiu

AU - Malik, Rainer

AU - Traylor, Matthew

AU - Pulit, Sara L.

AU - Amouyel, Philippe

AU - Mazoyer, Bernard

AU - Zhu, Yi Cheng

AU - Kaffashian, Sara

AU - Schilling, Sabrina

AU - Beecham, Gary W.

AU - Montine, Thomas J.

AU - Schellenberg, Gerard D.

AU - Kjartansson, Olafur

AU - Guonason, Vilmundur

AU - Knopman, David S.

AU - Griswold, Michael E.

AU - Windham, B. Gwen

AU - Gottesman, Rebecca F

AU - Mosley, Thomas H.

AU - Schmidt, Reinhold

AU - Saba, Yasaman

AU - Schmidt, Helena

AU - Takeuchi, Fumihiko

AU - Yamaguchi, Shuhei

AU - Nabika, Toru

AU - Kato, Norihiro

AU - Rajan, Kumar B.

AU - Aggarwal, Neelum T.

AU - De Jager, Philip L.

AU - Evans, Denis A.

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Rice, Kenneth

AU - Lopez, Oscar L.

AU - Liao, Jiemin

AU - Chen, Christopher

AU - Cheng, Ching Yu

AU - Wong, Tien Y.

AU - Ikram, Mohammad K.

AU - Van Der Lee, J. Sven

AU - Amin, Najaf

AU - Chouraki, Vincent

AU - DeStefano, Anita L.

AU - Aparicio, Hugo J.

AU - Romero, Jose R.

AU - Maillard, Pauline

AU - DeCarli, Charles

AU - Wardlaw, Joanna M.

AU - Del Valdes Hernandez, Maria C.

AU - Luciano, Michelle

AU - Liewald, David

AU - Deary, Ian J.

AU - Starr, John M.

AU - Bastin, Mark E.

AU - Maniega, Susana Muñoz

AU - Slagboom, P. Eline

AU - Beekman, Marian

AU - Deelen, Joris

AU - Uh, Hae Won

AU - Lemmens, Robin

AU - Brodaty, Henry

AU - Wright, Margaret J.

AU - Ames, David

AU - Boncoraglio, Giorgio B.

AU - Hopewell, Jemma C.

AU - Beecham, Ashley H.

AU - Blanton, Susan H.

AU - Wright, Clinton B.

AU - Sacco, Ralph L.

AU - Wen, Wei

AU - Thalamuthu, Anbupalam

AU - Armstrong, Nicola J.

AU - Chong, Elizabeth

AU - Schofield, Peter R.

AU - Kwok, John B.

AU - Van der Grond, Jeroen

AU - Stott, David J.

AU - Ford, Ian

AU - Jukema, J. Wouter

AU - Vernooij, Meike W.

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Van der Lugt, Aad

AU - Wittfeld, Katharina

AU - Grabe, Hans J.

AU - Hosten, Norbert

AU - Von Sarnowski, Bettina

AU - Volker, Uwe

AU - Levi, Christopher

AU - Jimenez-Conde, Jordi

AU - Sharma, Pankaj

AU - Sudlow, Cathie L.M.

AU - Rosand, Jonathan

AU - Woo, Daniel

AU - Cole, John W.

AU - Meschia, James F.

AU - Slowik, Agnieszka

AU - Thijs, Vincent

AU - Lindgren, Arne

AU - Melander, Olle

AU - Grewal, Raji P.

AU - Rundek, Tatjana

AU - Rexrode, Kathy

AU - Rothwell, Peter M.

AU - Arnett, Donna K.

AU - Jern, Christina

AU - Johnson, Julie A.

AU - Benavente, Oscar R.

AU - Wasssertheil-Smoller, Sylvia

AU - Lee, Jin Moo

AU - Wong, Quenna

AU - Mitchell, Braxton D.

AU - Rich, Stephen S.

AU - McArdle, Patrick F.

AU - Geerlings, Mirjam I.

AU - Van der Graaf, Yolanda

AU - De Bakker, Paul I.W.

AU - Asselbergs, Folkert W.

AU - Srikanth, Velandai

AU - Thomson, Russell

AU - McWhirter, Rebekah

AU - Moran, Chris

AU - Callisaya, Michele

AU - Phan, Thanh

AU - Rutten-Jacobs, Loes C.A.

AU - Bevan, Steve

AU - Tzourio, Christophe

AU - Mather, Karen A.

AU - Sachdev, Perminder S.

AU - Van Duijn, Cornelia M.

AU - Worrall, Bradford B.

AU - Dichgans, Martin

AU - Kittner, Steven J.

AU - Markus, Hugh S.

AU - Ikram, Mohammad A.

AU - Fornage, Myriam

AU - Launer, Lenore J.

AU - Seshadri, Sudha

AU - Longstreth, W. T.

AU - Debette, Stephanie

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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.

AB - 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.

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U2 - 10.1212/WNL.0000000000006851

DO - 10.1212/WNL.0000000000006851

M3 - Article

VL - 92

SP - E486-E503

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 5

ER -