Genetic variation at 16q24.2 is associated with small vessel stroke

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

doi:10.1002/ana.24840

Genetic variation at 16q24.2 is associated with small vessel stroke

Matthew Traylor
, Rainer Malik
, Mike A. Nalls
, Ioana Cotlarciuc
, Farid Radmanesh
, Gudmar Thorleifsson
, Ken B. Hanscombe
, Carl Langefeld
, Danish Saleheen
, Natalia S. Rost
, Idil Yet
, Tim D. Spector
, Jordana T. Bell
, Eilis Hannon
, Jonathan Mill
, Ganesh Chauhan
, Stephanie Debette
, Joshua C. Bis
, W. T. Longstreth
, M. Arfan Ikram

Lenore J. Launer, Sudha Seshadri, Monica Anne Hamilton-Bruce, Jordi Jimenez-Conde, John W. Cole, Reinhold Schmidt, Agnieszka Słowik, Robin Lemmens, Arne Lindgren, Olle Melander, Raji P. Grewal, Ralph L. Sacco, Tatjana Rundek, Kathryn Rexrode, Donna K. Arnett, Julie A. Johnson, Oscar R. Benavente, Sylvia Wasssertheil-Smoller, Jin Moo Lee, Sara L. Pulit, Quenna Wong, Stephen S. Rich, Paul I W de Bakker, Patrick F. McArdle, Daniel Woo, Christopher D. Anderson, Huichun Xu, Laura Heitsch, Myriam Fornage, Christina Jern, Kari Stefansson, Unnur Thorsteinsdottir, Solveig Gretarsdottir, Cathryn M. Lewis, Pankaj Sharma, Cathie L M Sudlow, Peter M. Rothwell, Giorgio B. Boncoraglio, Vincent Thijs, Chris Levi, James F. Meschia, Jonathan Rosand, Steven J. Kittner, Braxton D. Mitchell, Martin Dichgans, Bradford B. Worrall, Hugh S. Markus

King's College London
Klinikum Großhadern
National Institute on Aging
Royal Holloway, University of London
Massachusetts General Hospital
deCODE Genetics
Wake Forest University
University of Pennsylvania
University of Exeter
University of Bordeaux
University of Washington
Erasmus University Medical Center
Blood Institute's Framingham Heart Study
Royal Adelaide Hospital
Servicio de Medicina Interna y Enfermedades Infecciosas, Hospital del Mar-IMIM and RETICEF
University of Maryland
Medical University of Graz
Jagiellonian University
University Hospitals Leuven
Skåne University Hospital
Lund University
Seton Hall University
University of Miami
Harvard Medical School
University of Kentucky
University of Florida
Vancouver General Hospital, The Prostate Centre, University of British Columbia, Faculty of Medicine
Albert Einstein College of Medicine
Washington University in St Louis
UMC University Medical Center Utrecht
University of Virginia
University of Cincinnati
Broad Institute of MIT and Harvard
UTHealth University of Texas Health Science Center at Houston
University of Gothenburg
University of Iceland
University of Edinburgh
University of Oxford
Research Hospital of the Neurological Institute Carlo Besta
Austin Health
Hunter Medical Research Institute, Australia
Mayo Clinic, Jacksonville
Oklahoma City Veterans Affairs Medical Center
SyNergy
University of Cambridge

Research output: Contribution to journal › Article › peer-review

84 Citations (Scopus)

281 Downloads (Pure)

Abstract

Objective: Genome-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. Methods: We 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. Results: We 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). Interpretation: 16q24.2 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.

Original language	English
Pages (from-to)	383-394
Number of pages	12
Journal	Annals of Neurology
Volume	81
Issue number	3
Early online date	20 Dec 2016
DOIs	https://doi.org/10.1002/ana.24840
Publication status	Published - 1 Mar 2017

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10.1002/ana.24840

Genetic Variation at_TRAYLOR_Accepted3December2016_GOLD AAMAccepted author manuscript, 1.76 MB

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Traylor, M., Malik, R., Nalls, M. A., Cotlarciuc, I., Radmanesh, F., Thorleifsson, G., Hanscombe, K. B., Langefeld, C., Saleheen, D., Rost, N. S., Yet, I., Spector, T. D., Bell, J. T., Hannon, E., Mill, J., Chauhan, G., Debette, S., Bis, J. C., Longstreth, W. T., ... Markus, H. S. (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

@article{0c728c5cfd2b4940be6c18b83799209c,

title = "Genetic variation at 16q24.2 is associated with small vessel stroke",

abstract = "Objective: Genome-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. Methods: We 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. Results: We 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). Interpretation: 16q24.2 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 Nalls, \{Mike A.\} and Ioana Cotlarciuc and Farid Radmanesh and Gudmar Thorleifsson and Hanscombe, \{Ken B.\} and Carl Langefeld and Danish Saleheen and Rost, \{Natalia S.\} and Idil Yet and Spector, \{Tim D.\} and Bell, \{Jordana T.\} and Eilis Hannon and Jonathan Mill and Ganesh Chauhan and Stephanie Debette and Bis, \{Joshua C.\} and Longstreth, \{W. T.\} and Ikram, \{M. Arfan\} and Launer, \{Lenore J.\} and Sudha Seshadri and Hamilton-Bruce, \{Monica Anne\} and Jordi Jimenez-Conde and Cole, \{John W.\} and Reinhold Schmidt and Agnieszka S{\l}owik and Robin Lemmens and Arne Lindgren and Olle Melander and Grewal, \{Raji P.\} and Sacco, \{Ralph L.\} and Tatjana Rundek and Kathryn Rexrode and Arnett, \{Donna K.\} and Johnson, \{Julie A.\} and Benavente, \{Oscar R.\} and Sylvia Wasssertheil-Smoller and Lee, \{Jin Moo\} and Pulit, \{Sara L.\} and Quenna Wong and Rich, \{Stephen S.\} and \{de Bakker\}, \{Paul I W\} and McArdle, \{Patrick F.\} and Daniel Woo and Anderson, \{Christopher D.\} and Huichun Xu and Laura Heitsch and Myriam Fornage and Christina Jern and Kari Stefansson and Unnur Thorsteinsdottir and Solveig Gretarsdottir and Lewis, \{Cathryn M.\} and Pankaj Sharma and Sudlow, \{Cathie L M\} and Rothwell, \{Peter M.\} and Boncoraglio, \{Giorgio B.\} and Vincent Thijs and Chris Levi and Meschia, \{James F.\} and Jonathan Rosand and Kittner, \{Steven J.\} and Mitchell, \{Braxton D.\} and Martin Dichgans and Worrall, \{Bradford B.\} and Markus, \{Hugh S.\}",

year = "2017",

month = mar,

day = "1",

doi = "10.1002/ana.24840",

language = "English",

volume = "81",

pages = "383--394",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley \& Sons Inc.",

number = "3",

}

Traylor, M, Malik, R, Nalls, MA, Cotlarciuc, I, Radmanesh, F, Thorleifsson, G, Hanscombe, KB, Langefeld, C, Saleheen, D, Rost, NS, Yet, I , Spector, TD , Bell, JT, Hannon, E, Mill, J, Chauhan, G, Debette, S, Bis, JC, Longstreth, WT, Ikram, MA, Launer, LJ, Seshadri, S, Hamilton-Bruce, MA, Jimenez-Conde, J, Cole, JW, Schmidt, R, Słowik, A, Lemmens, R, Lindgren, A, Melander, O, Grewal, RP, Sacco, RL, Rundek, T, Rexrode, K, Arnett, DK, Johnson, JA, Benavente, OR, Wasssertheil-Smoller, S, Lee, JM, Pulit, SL, Wong, Q, Rich, SS, de Bakker, PIW, McArdle, PF, Woo, D, Anderson, CD, Xu, H, Heitsch, L, Fornage, M, Jern, C, Stefansson, K, Thorsteinsdottir, U, Gretarsdottir, S, Lewis, CM, Sharma, P, Sudlow, CLM, Rothwell, PM, Boncoraglio, GB, Thijs, V, Levi, C, Meschia, JF, Rosand, J, Kittner, SJ, Mitchell, BD, Dichgans, M, Worrall, BB & Markus, HS 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

TY - JOUR

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

AU - Traylor, Matthew

AU - Malik, Rainer

AU - Nalls, Mike A.

AU - Cotlarciuc, Ioana

AU - Radmanesh, Farid

AU - Thorleifsson, Gudmar

AU - Hanscombe, Ken B.

AU - Langefeld, Carl

AU - Saleheen, Danish

AU - Rost, Natalia S.

AU - Yet, Idil

AU - Spector, Tim D.

AU - Bell, Jordana T.

AU - Hannon, Eilis

AU - Mill, Jonathan

AU - Chauhan, Ganesh

AU - Debette, Stephanie

AU - Bis, Joshua C.

AU - Longstreth, W. T.

AU - Ikram, M. Arfan

AU - Launer, Lenore J.

AU - Seshadri, Sudha

AU - Hamilton-Bruce, Monica Anne

AU - Jimenez-Conde, Jordi

AU - Cole, John W.

AU - Schmidt, Reinhold

AU - Słowik, Agnieszka

AU - Lemmens, Robin

AU - Lindgren, Arne

AU - Melander, Olle

AU - Grewal, Raji P.

AU - Sacco, Ralph L.

AU - Rundek, Tatjana

AU - Rexrode, Kathryn

AU - Arnett, Donna K.

AU - Johnson, Julie A.

AU - Benavente, Oscar R.

AU - Wasssertheil-Smoller, Sylvia

AU - Lee, Jin Moo

AU - Pulit, Sara L.

AU - Wong, Quenna

AU - Rich, Stephen S.

AU - de Bakker, Paul I W

AU - McArdle, Patrick F.

AU - Woo, Daniel

AU - Anderson, Christopher D.

AU - Xu, Huichun

AU - Heitsch, Laura

AU - Fornage, Myriam

AU - Jern, Christina

AU - Stefansson, Kari

AU - Thorsteinsdottir, Unnur

AU - Gretarsdottir, Solveig

AU - Lewis, Cathryn M.

AU - Sharma, Pankaj

AU - Sudlow, Cathie L M

AU - Rothwell, Peter M.

AU - Boncoraglio, Giorgio B.

AU - Thijs, Vincent

AU - Levi, Chris

AU - Meschia, James F.

AU - Rosand, Jonathan

AU - Kittner, Steven J.

AU - Mitchell, Braxton D.

AU - Dichgans, Martin

AU - Worrall, Bradford B.

AU - Markus, Hugh S.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Objective: Genome-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. Methods: We 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. Results: We 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). Interpretation: 16q24.2 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 - Objective: Genome-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. Methods: We 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. Results: We 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). Interpretation: 16q24.2 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.

UR - https://www.scopus.com/pages/publications/85016118346

U2 - 10.1002/ana.24840

DO - 10.1002/ana.24840

M3 - Article

AN - SCOPUS:85016118346

SN - 0364-5134

VL - 81

SP - 383

EP - 394

JO - Annals of Neurology

JF - Annals of Neurology

IS - 3

ER -

Genetic variation at 16q24.2 is associated with small vessel stroke

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