Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Sara L. Pulit; Lu-Chen Weng; Patrick F. McArdle; Ludovic Trinquart; Seung Hoan Choi; Braxton D. Mitchell; Jonathan Rosand; Paul I. W. de Bakker; Emelia J. Benjamin; Patrick T. Ellinor; Steven J. Kittner; Steven A. Lubitz; Christopher D. Anderson; Ingrid E. Christophersen; Michiel Rienstra; Carolina Roselli; Xiaoyan Yin; Bastiaan Geelhoed; John Barnard; Honghuang Lin; Dan E. Arking; Albert Smith; Christine M. Albert; Mark Chaffin; Nathan R. Tucker; Molong Li; Derek Klarin; Nathan A. Bihlmeyer; Siew-Kee Low; Peter E. Weeke; Martina Muller-Nurasyid; J. Gustav Smith; Jennifer A. Brody; Maartje N. Niemeijer; Marcus Dorr; Stella Trompet; Jennifer Huffman; Stefan Gustafsson; Claudia Schurmann; Marcus E. Kleber; Leo-Pekka Lyytikainen; Ilkka Seppala; Rainer Malik; Andrea R. V. R. Horimoto; Marco Perez; Juha Sinisalo; Stefanie Aeschbacher; Sebastien Theriault; Lin Y. Chen; Julie Staals; Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium

doi:10.1212/NXG.0000000000000293

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Sara L. Pulit, Lu-Chen Weng, Patrick F. McArdle, Ludovic Trinquart, Seung Hoan Choi, Braxton D. Mitchell, Jonathan Rosand, Paul I. W. de Bakker, Emelia J. Benjamin, Patrick T. Ellinor, Steven J. Kittner, Steven A. Lubitz^*, Christopher D. Anderson^*, Ingrid E. Christophersen, Michiel Rienstra, Carolina Roselli, Xiaoyan Yin, Bastiaan Geelhoed, John Barnard, Honghuang LinDan E. Arking, Albert Smith, Christine M. Albert, Mark Chaffin, Nathan R. Tucker, Molong Li, Derek Klarin, Nathan A. Bihlmeyer, Siew-Kee Low, Peter E. Weeke, Martina Muller-Nurasyid, J. Gustav Smith, Jennifer A. Brody, Maartje N. Niemeijer, Marcus Dorr, Stella Trompet, Jennifer Huffman, Stefan Gustafsson, Claudia Schurmann, Marcus E. Kleber, Leo-Pekka Lyytikainen, Ilkka Seppala, Rainer Malik, Andrea R. V. R. Horimoto, Marco Perez, Juha Sinisalo, Stefanie Aeschbacher, Sebastien Theriault, Lin Y. Chen, Julie Staals, Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium

^*Corresponding author for this work

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

Abstract

Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

Original language	English
Article number	293
Number of pages	8
Journal	Neurology. Genetics
Volume	4
Issue number	6
DOIs	https://doi.org/10.1212/NXG.0000000000000293
Publication status	Published - 1 Dec 2018

Keywords

ISCHEMIC-STROKE
CAUSATIVE CLASSIFICATION
LIFETIME RISK
EPIDEMIOLOGY
ASSOCIATION
PREVENTION
VARIANTS
ASPIRIN
BURDEN

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Pulit, S. L., Weng, L.-C., McArdle, P. F., Trinquart, L., Choi, S. H., Mitchell, B. D., Rosand, J., de Bakker, P. I. W., Benjamin, E. J., Ellinor, P. T., Kittner, S. J., Lubitz, S. A., Anderson, C. D., Christophersen, I. E., Rienstra, M., Roselli, C., Yin, X., Geelhoed, B., Barnard, J., ... Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium (2018). Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes. Neurology. Genetics, 4(6), Article 293. https://doi.org/10.1212/NXG.0000000000000293

@article{08af6d61916b4bc396be08d685f2f95f,

title = "Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes",

abstract = "Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.",

keywords = "ISCHEMIC-STROKE, CAUSATIVE CLASSIFICATION, LIFETIME RISK, EPIDEMIOLOGY, ASSOCIATION, PREVENTION, VARIANTS, ASPIRIN, BURDEN",

author = "Pulit, {Sara L.} and Lu-Chen Weng and McArdle, {Patrick F.} and Ludovic Trinquart and Choi, {Seung Hoan} and Mitchell, {Braxton D.} and Jonathan Rosand and {de Bakker}, {Paul I. W.} and Benjamin, {Emelia J.} and Ellinor, {Patrick T.} and Kittner, {Steven J.} and Lubitz, {Steven A.} and Anderson, {Christopher D.} and Christophersen, {Ingrid E.} and Michiel Rienstra and Carolina Roselli and Xiaoyan Yin and Bastiaan Geelhoed and John Barnard and Honghuang Lin and Arking, {Dan E.} and Albert Smith and Albert, {Christine M.} and Mark Chaffin and Tucker, {Nathan R.} and Molong Li and Derek Klarin and Bihlmeyer, {Nathan A.} and Siew-Kee Low and Weeke, {Peter E.} and Martina Muller-Nurasyid and Smith, {J. Gustav} and Brody, {Jennifer A.} and Niemeijer, {Maartje N.} and Marcus Dorr and Stella Trompet and Jennifer Huffman and Stefan Gustafsson and Claudia Schurmann and Kleber, {Marcus E.} and Leo-Pekka Lyytikainen and Ilkka Seppala and Rainer Malik and Horimoto, {Andrea R. V. R.} and Marco Perez and Juha Sinisalo and Stefanie Aeschbacher and Sebastien Theriault and Chen, {Lin Y.} and Julie Staals and {Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium}",

year = "2018",

month = dec,

day = "1",

doi = "10.1212/NXG.0000000000000293",

language = "English",

volume = "4",

journal = "Neurology. Genetics",

issn = "2376-7839",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "6",

}

Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Muller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Dorr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Chen, LY, Staals, J & Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium 2018, 'Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes', Neurology. Genetics, vol. 4, no. 6, 293. https://doi.org/10.1212/NXG.0000000000000293

TY - JOUR

T1 - Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AU - Pulit, Sara L.

AU - Weng, Lu-Chen

AU - McArdle, Patrick F.

AU - Trinquart, Ludovic

AU - Choi, Seung Hoan

AU - Mitchell, Braxton D.

AU - Rosand, Jonathan

AU - de Bakker, Paul I. W.

AU - Benjamin, Emelia J.

AU - Ellinor, Patrick T.

AU - Kittner, Steven J.

AU - Lubitz, Steven A.

AU - Anderson, Christopher D.

AU - Christophersen, Ingrid E.

AU - Rienstra, Michiel

AU - Roselli, Carolina

AU - Yin, Xiaoyan

AU - Geelhoed, Bastiaan

AU - Barnard, John

AU - Lin, Honghuang

AU - Arking, Dan E.

AU - Smith, Albert

AU - Albert, Christine M.

AU - Chaffin, Mark

AU - Tucker, Nathan R.

AU - Li, Molong

AU - Klarin, Derek

AU - Bihlmeyer, Nathan A.

AU - Low, Siew-Kee

AU - Weeke, Peter E.

AU - Muller-Nurasyid, Martina

AU - Smith, J. Gustav

AU - Brody, Jennifer A.

AU - Niemeijer, Maartje N.

AU - Dorr, Marcus

AU - Trompet, Stella

AU - Huffman, Jennifer

AU - Gustafsson, Stefan

AU - Schurmann, Claudia

AU - Kleber, Marcus E.

AU - Lyytikainen, Leo-Pekka

AU - Seppala, Ilkka

AU - Malik, Rainer

AU - Horimoto, Andrea R. V. R.

AU - Perez, Marco

AU - Sinisalo, Juha

AU - Aeschbacher, Stefanie

AU - Theriault, Sebastien

AU - Chen, Lin Y.

AU - Staals, Julie

AU - Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

AB - Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

KW - ISCHEMIC-STROKE

KW - CAUSATIVE CLASSIFICATION

KW - LIFETIME RISK

KW - EPIDEMIOLOGY

KW - ASSOCIATION

KW - PREVENTION

KW - VARIANTS

KW - ASPIRIN

KW - BURDEN

U2 - 10.1212/NXG.0000000000000293

DO - 10.1212/NXG.0000000000000293

M3 - Article

SN - 2376-7839

VL - 4

JO - Neurology. Genetics

JF - Neurology. Genetics

IS - 6

M1 - 293

ER -