Genetic Variation at 16q24.2 is associated with small vessel stroke. / Traylor, Matthew; Malik, Rainer ; Nalls, Mike; Cotlarciuc, Ioana; Radmanesh, Farid ; Thorleifsson, Gudmar ; Hanscombe, Ken; Langefeld, Carl ; Saleheen, Danish ; Rost, Natalia ; Yet, Idil ; Spector, Tim ; Bell, Jordana; Hannon, Eilis ; Mill, Jonathan ; Chauhan, Ganesh ; Debette, Stephanie ; Bis, Joshua ; Longstreth , WT ; Ikram, Arfan ; Launer, Lenore ; Seshadri, Sudha ; Hamilton Bruce, Monica Anne ; Jimenez-Conde, Jordi ; Cole, John ; Schmidt, Reinhold ; Słowik, Agnieszka; Lemmens, Robin ; Lindgren, Arne; Melander, Olle ; Grewal, Raji ; Sacco, Ralph; Rundek, Tatjana ; Rexrode, Kathryn ; Arnett, Donna; Johnson, Julie ; Benavente, Oscar; Wasssertheil-Smoller, Sylvia ; Lee, Jin-Moo ; Pulit, Sara ; Wong, Quenna ; Rich, Stephen; de Bakker, Paul ; McArdle, Patrick ; Woo, Daniel ; Anderson, Christopher; Xu, Huichun; Heitsch, Laura ; Fornage, Myriam ; Jern, Christina; Stefansson, Kari; Thorsteinsdottir, Unnur; Gretarsdottir, Solveig; Lewis, Cathryn ; Sharma, Pankaj; Sudlow, Cathie ; Rothwell, Peter ; Boncoraglio, Giorgio; Thijs, Vincent; Levi, Chris; Meschia, James ; Rosand, Jonathan; Kittner, Steven ; Mitchell, Braxton ; Dichgans, Martin ; Worrall, Bradford; Markus, Hugh.

In: Annals of Neurology, Vol. 81, No. 3, 25.03.2017, p. 383–394.

Research output: Contribution to journalArticle

Published

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Genetic Variation at 16q24.2 is associated with small vessel stroke. / Traylor, Matthew; Malik, Rainer ; Nalls, Mike; Cotlarciuc, Ioana; Radmanesh, Farid ; Thorleifsson, Gudmar ; Hanscombe, Ken; Langefeld, Carl ; Saleheen, Danish ; Rost, Natalia ; Yet, Idil ; Spector, Tim ; Bell, Jordana; Hannon, Eilis ; Mill, Jonathan ; Chauhan, Ganesh ; Debette, Stephanie ; Bis, Joshua ; Longstreth , WT ; Ikram, Arfan ; Launer, Lenore ; Seshadri, Sudha ; Hamilton Bruce, Monica Anne ; Jimenez-Conde, Jordi ; Cole, John ; Schmidt, Reinhold ; Słowik, Agnieszka; Lemmens, Robin ; Lindgren, Arne; Melander, Olle ; Grewal, Raji ; Sacco, Ralph; Rundek, Tatjana ; Rexrode, Kathryn ; Arnett, Donna; Johnson, Julie ; Benavente, Oscar; Wasssertheil-Smoller, Sylvia ; Lee, Jin-Moo ; Pulit, Sara ; Wong, Quenna ; Rich, Stephen; de Bakker, Paul ; McArdle, Patrick ; Woo, Daniel ; Anderson, Christopher; Xu, Huichun; Heitsch, Laura ; Fornage, Myriam ; Jern, Christina; Stefansson, Kari; Thorsteinsdottir, Unnur; Gretarsdottir, Solveig; Lewis, Cathryn ; Sharma, Pankaj; Sudlow, Cathie ; Rothwell, Peter ; Boncoraglio, Giorgio; Thijs, Vincent; Levi, Chris; Meschia, James ; Rosand, Jonathan; Kittner, Steven ; Mitchell, Braxton ; Dichgans, Martin ; Worrall, Bradford; Markus, Hugh.

In: Annals of Neurology, Vol. 81, No. 3, 25.03.2017, p. 383–394.

Research output: Contribution to journalArticle

Harvard

Traylor, M, Malik, R, Nalls, M, Cotlarciuc, I, Radmanesh, F, Thorleifsson, G, Hanscombe, K, Langefeld, C, Saleheen, D, Rost, N, Yet, I, Spector, T, Bell, J, Hannon, E, Mill, J, Chauhan, G, Debette, S, Bis, J, Longstreth , WT, Ikram, A, Launer, L, Seshadri, S, Hamilton Bruce, MA, Jimenez-Conde, J, Cole, J, Schmidt, R, Słowik, A, Lemmens, R, Lindgren, A, Melander, O, Grewal, R, Sacco, R, Rundek, T, Rexrode, K, Arnett, D, Johnson, J, Benavente, O, Wasssertheil-Smoller, S, Lee, J-M, Pulit, S, Wong, Q, Rich, S, de Bakker, P, McArdle, P, Woo, D, Anderson, C, Xu, H, Heitsch, L, Fornage, M, Jern, C, Stefansson, K, Thorsteinsdottir, U, Gretarsdottir, S, Lewis, C, Sharma, P, Sudlow, C, Rothwell, P, Boncoraglio, G, Thijs, V, Levi, C, Meschia, J, Rosand, J, Kittner, S, Mitchell, B, Dichgans, M, Worrall, B & Markus, H 2017, 'Genetic Variation at 16q24.2 is associated with small vessel stroke', Annals of Neurology, vol. 81, no. 3, pp. 383–394. https://doi.org/10.1002/ana.24840

APA

Traylor, M., Malik, R., Nalls, M., Cotlarciuc, I., Radmanesh, F., Thorleifsson, G., ... Markus, H. (2017). Genetic Variation at 16q24.2 is associated with small vessel stroke. Annals of Neurology, 81(3), 383–394. https://doi.org/10.1002/ana.24840

Vancouver

Traylor M, Malik R, Nalls M, Cotlarciuc I, Radmanesh F, Thorleifsson G et al. Genetic Variation at 16q24.2 is associated with small vessel stroke. Annals of Neurology. 2017 Mar 25;81(3):383–394. https://doi.org/10.1002/ana.24840

Author

Traylor, Matthew ; Malik, Rainer ; Nalls, Mike ; Cotlarciuc, Ioana ; Radmanesh, Farid ; Thorleifsson, Gudmar ; Hanscombe, Ken ; Langefeld, Carl ; Saleheen, Danish ; Rost, Natalia ; Yet, Idil ; Spector, Tim ; Bell, Jordana ; Hannon, Eilis ; Mill, Jonathan ; Chauhan, Ganesh ; Debette, Stephanie ; Bis, Joshua ; Longstreth , WT ; Ikram, Arfan ; Launer, Lenore ; Seshadri, Sudha ; Hamilton Bruce, Monica Anne ; Jimenez-Conde, Jordi ; Cole, John ; Schmidt, Reinhold ; Słowik, Agnieszka ; Lemmens, Robin ; Lindgren, Arne ; Melander, Olle ; Grewal, Raji ; Sacco, Ralph ; Rundek, Tatjana ; Rexrode, Kathryn ; Arnett, Donna ; Johnson, Julie ; Benavente, Oscar ; Wasssertheil-Smoller, Sylvia ; Lee, Jin-Moo ; Pulit, Sara ; Wong, Quenna ; Rich, Stephen ; de Bakker, Paul ; McArdle, Patrick ; Woo, Daniel ; Anderson, Christopher ; Xu, Huichun ; Heitsch, Laura ; Fornage, Myriam ; Jern, Christina ; Stefansson, Kari ; Thorsteinsdottir, Unnur ; Gretarsdottir, Solveig ; Lewis, Cathryn ; Sharma, Pankaj ; Sudlow, Cathie ; Rothwell, Peter ; Boncoraglio, Giorgio ; Thijs, Vincent ; Levi, Chris ; Meschia, James ; Rosand, Jonathan ; Kittner, Steven ; Mitchell, Braxton ; Dichgans, Martin ; Worrall, Bradford ; Markus, Hugh. / Genetic Variation at 16q24.2 is associated with small vessel stroke. In: Annals of Neurology. 2017 ; Vol. 81, No. 3. pp. 383–394.

BibTeX

@article{978a37abf36a4a48b7752202621df2cb,
title = "Genetic Variation at 16q24.2 is associated with small vessel stroke",
abstract = "ObjectiveGenome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke.MethodsWe used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.ResultsWe identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95{\%} confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95{\%} CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95{\%} CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6).Interpretation16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394",
author = "Matthew Traylor and Rainer Malik and Mike Nalls and Ioana Cotlarciuc and Farid Radmanesh and Gudmar Thorleifsson and Ken Hanscombe and Carl Langefeld and Danish Saleheen and Natalia Rost and Idil Yet and Tim Spector and Jordana Bell and Eilis Hannon and Jonathan Mill and Ganesh Chauhan and Stephanie Debette and Joshua Bis and WT Longstreth and Arfan Ikram and Lenore Launer and Sudha Seshadri and {Hamilton Bruce}, {Monica Anne} and Jordi Jimenez-Conde and John Cole and Reinhold Schmidt and Agnieszka Słowik and Robin Lemmens and Arne Lindgren and Olle Melander and Raji Grewal and Ralph Sacco and Tatjana Rundek and Kathryn Rexrode and Donna Arnett and Julie Johnson and Oscar Benavente and Sylvia Wasssertheil-Smoller and Jin-Moo Lee and Sara Pulit and Quenna Wong and Stephen Rich and {de Bakker}, Paul and Patrick McArdle and Daniel Woo and Christopher Anderson and Huichun Xu and Laura Heitsch and Myriam Fornage and Christina Jern and Kari Stefansson and Unnur Thorsteinsdottir and Solveig Gretarsdottir and Cathryn Lewis and Pankaj Sharma and Cathie Sudlow and Peter Rothwell and Giorgio Boncoraglio and Vincent Thijs and Chris Levi and James Meschia and Jonathan Rosand and Steven Kittner and Braxton Mitchell and Martin Dichgans and Bradford Worrall and Hugh Markus",
year = "2017",
month = "3",
day = "25",
doi = "10.1002/ana.24840",
language = "English",
volume = "81",
pages = "383–394",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - Genetic Variation at 16q24.2 is associated with small vessel stroke

AU - Traylor, Matthew

AU - Malik, Rainer

AU - Nalls, Mike

AU - Cotlarciuc, Ioana

AU - Radmanesh, Farid

AU - Thorleifsson, Gudmar

AU - Hanscombe, Ken

AU - Langefeld, Carl

AU - Saleheen, Danish

AU - Rost, Natalia

AU - Yet, Idil

AU - Spector, Tim

AU - Bell, Jordana

AU - Hannon, Eilis

AU - Mill, Jonathan

AU - Chauhan, Ganesh

AU - Debette, Stephanie

AU - Bis, Joshua

AU - Longstreth , WT

AU - Ikram, Arfan

AU - Launer, Lenore

AU - Seshadri, Sudha

AU - Hamilton Bruce, Monica Anne

AU - Jimenez-Conde, Jordi

AU - Cole, John

AU - Schmidt, Reinhold

AU - Słowik, Agnieszka

AU - Lemmens, Robin

AU - Lindgren, Arne

AU - Melander, Olle

AU - Grewal, Raji

AU - Sacco, Ralph

AU - Rundek, Tatjana

AU - Rexrode, Kathryn

AU - Arnett, Donna

AU - Johnson, Julie

AU - Benavente, Oscar

AU - Wasssertheil-Smoller, Sylvia

AU - Lee, Jin-Moo

AU - Pulit, Sara

AU - Wong, Quenna

AU - Rich, Stephen

AU - de Bakker, Paul

AU - McArdle, Patrick

AU - Woo, Daniel

AU - Anderson, Christopher

AU - Xu, Huichun

AU - Heitsch, Laura

AU - Fornage, Myriam

AU - Jern, Christina

AU - Stefansson, Kari

AU - Thorsteinsdottir, Unnur

AU - Gretarsdottir, Solveig

AU - Lewis, Cathryn

AU - Sharma, Pankaj

AU - Sudlow, Cathie

AU - Rothwell, Peter

AU - Boncoraglio, Giorgio

AU - Thijs, Vincent

AU - Levi, Chris

AU - Meschia, James

AU - Rosand, Jonathan

AU - Kittner, Steven

AU - Mitchell, Braxton

AU - Dichgans, Martin

AU - Worrall, Bradford

AU - Markus, Hugh

PY - 2017/3/25

Y1 - 2017/3/25

N2 - ObjectiveGenome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke.MethodsWe used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.ResultsWe identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6).Interpretation16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394

AB - ObjectiveGenome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke.MethodsWe used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.ResultsWe identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6).Interpretation16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394

U2 - 10.1002/ana.24840

DO - 10.1002/ana.24840

M3 - Article

VL - 81

SP - 383

EP - 394

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 3

ER -