Genomewide association studies of stroke

M. Arfan Ikram, Sudha Seshadri, Joshua C. Bis, Myriam Fornage, Anita L. DeStefano, Yurii S. Aulchenko, Stephanie Debette, Thomas Lumley, Aaron R. Folsom, Evita G. Van Den Herik, Michiel J. Bos, Alexa Beiser, Mary Cushman, Lenore J. Launer, Eyal Shahar, Maksim Struchalin, Yangchun Du, Nicole L. Glazer, Wayne D. Rosamond, Fernando Rivadeneira & 26 others Margaret Kelly-Hayes, Oscar L. Lopez, Josef Coresh, Albert Hofman, Charles DeCarli, Susan R. Heckbert, Peter J. Koudstaal, Qiong Yang, Nicholas L. Smith, Carlos S. Kase, Kenneth Rice, Talin Haritunians, Gerwin Roks, Paul L M De Kort, Kent D. Taylor, Lonneke M. De Lau, Ben A. Oostra, Andre G. Uitterlinden, Jerome I. Rotter, Eric Boerwinkle, Bruce M. Psaty, Thomas H. Mosley, Cornelia M. Van Duijn, Monique M B Breteler, W. T. Longstreth, Philip A. Wolf

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P-8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Original languageEnglish (US)
Pages (from-to)1718-1728
Number of pages11
JournalNew England Journal of Medicine
Volume360
Issue number17
DOIs
StatePublished - Apr 23 2009

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Stroke
Confidence Intervals
Chromosomes
Genetic Loci
Neuroglia
Population
Genes
Single Nucleotide Polymorphism
Epidemiology
Wounds and Injuries
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ikram, M. A., Seshadri, S., Bis, J. C., Fornage, M., DeStefano, A. L., Aulchenko, Y. S., ... Wolf, P. A. (2009). Genomewide association studies of stroke. New England Journal of Medicine, 360(17), 1718-1728. https://doi.org/10.1056/NEJMoa0900094

Genomewide association studies of stroke. / Ikram, M. Arfan; Seshadri, Sudha; Bis, Joshua C.; Fornage, Myriam; DeStefano, Anita L.; Aulchenko, Yurii S.; Debette, Stephanie; Lumley, Thomas; Folsom, Aaron R.; Van Den Herik, Evita G.; Bos, Michiel J.; Beiser, Alexa; Cushman, Mary; Launer, Lenore J.; Shahar, Eyal; Struchalin, Maksim; Du, Yangchun; Glazer, Nicole L.; Rosamond, Wayne D.; Rivadeneira, Fernando; Kelly-Hayes, Margaret; Lopez, Oscar L.; Coresh, Josef; Hofman, Albert; DeCarli, Charles; Heckbert, Susan R.; Koudstaal, Peter J.; Yang, Qiong; Smith, Nicholas L.; Kase, Carlos S.; Rice, Kenneth; Haritunians, Talin; Roks, Gerwin; De Kort, Paul L M; Taylor, Kent D.; De Lau, Lonneke M.; Oostra, Ben A.; Uitterlinden, Andre G.; Rotter, Jerome I.; Boerwinkle, Eric; Psaty, Bruce M.; Mosley, Thomas H.; Van Duijn, Cornelia M.; Breteler, Monique M B; Longstreth, W. T.; Wolf, Philip A.

In: New England Journal of Medicine, Vol. 360, No. 17, 23.04.2009, p. 1718-1728.

Research output: Contribution to journalArticle

Ikram, MA, Seshadri, S, Bis, JC, Fornage, M, DeStefano, AL, Aulchenko, YS, Debette, S, Lumley, T, Folsom, AR, Van Den Herik, EG, Bos, MJ, Beiser, A, Cushman, M, Launer, LJ, Shahar, E, Struchalin, M, Du, Y, Glazer, NL, Rosamond, WD, Rivadeneira, F, Kelly-Hayes, M, Lopez, OL, Coresh, J, Hofman, A, DeCarli, C, Heckbert, SR, Koudstaal, PJ, Yang, Q, Smith, NL, Kase, CS, Rice, K, Haritunians, T, Roks, G, De Kort, PLM, Taylor, KD, De Lau, LM, Oostra, BA, Uitterlinden, AG, Rotter, JI, Boerwinkle, E, Psaty, BM, Mosley, TH, Van Duijn, CM, Breteler, MMB, Longstreth, WT & Wolf, PA 2009, 'Genomewide association studies of stroke', New England Journal of Medicine, vol. 360, no. 17, pp. 1718-1728. https://doi.org/10.1056/NEJMoa0900094
Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS et al. Genomewide association studies of stroke. New England Journal of Medicine. 2009 Apr 23;360(17):1718-1728. https://doi.org/10.1056/NEJMoa0900094
Ikram, M. Arfan ; Seshadri, Sudha ; Bis, Joshua C. ; Fornage, Myriam ; DeStefano, Anita L. ; Aulchenko, Yurii S. ; Debette, Stephanie ; Lumley, Thomas ; Folsom, Aaron R. ; Van Den Herik, Evita G. ; Bos, Michiel J. ; Beiser, Alexa ; Cushman, Mary ; Launer, Lenore J. ; Shahar, Eyal ; Struchalin, Maksim ; Du, Yangchun ; Glazer, Nicole L. ; Rosamond, Wayne D. ; Rivadeneira, Fernando ; Kelly-Hayes, Margaret ; Lopez, Oscar L. ; Coresh, Josef ; Hofman, Albert ; DeCarli, Charles ; Heckbert, Susan R. ; Koudstaal, Peter J. ; Yang, Qiong ; Smith, Nicholas L. ; Kase, Carlos S. ; Rice, Kenneth ; Haritunians, Talin ; Roks, Gerwin ; De Kort, Paul L M ; Taylor, Kent D. ; De Lau, Lonneke M. ; Oostra, Ben A. ; Uitterlinden, Andre G. ; Rotter, Jerome I. ; Boerwinkle, Eric ; Psaty, Bruce M. ; Mosley, Thomas H. ; Van Duijn, Cornelia M. ; Breteler, Monique M B ; Longstreth, W. T. ; Wolf, Philip A. / Genomewide association studies of stroke. In: New England Journal of Medicine. 2009 ; Vol. 360, No. 17. pp. 1718-1728.
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abstract = "BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P-8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95{\%} confidence interval [CI], 1.19 to 1.42) and 1.33 (95{\%} CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11{\%} and 12{\%} in the discovery cohorts. Corresponding hazard ratios were 1.35 (95{\%} CI, 1.01 to 1.79; P = 0.04) and 1.42 (95{\%} CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95{\%} CI, 1.01 to 1.37; P = 0.03) and 1.19 (95{\%} CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.",
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TY - JOUR

T1 - Genomewide association studies of stroke

AU - Ikram, M. Arfan

AU - Seshadri, Sudha

AU - Bis, Joshua C.

AU - Fornage, Myriam

AU - DeStefano, Anita L.

AU - Aulchenko, Yurii S.

AU - Debette, Stephanie

AU - Lumley, Thomas

AU - Folsom, Aaron R.

AU - Van Den Herik, Evita G.

AU - Bos, Michiel J.

AU - Beiser, Alexa

AU - Cushman, Mary

AU - Launer, Lenore J.

AU - Shahar, Eyal

AU - Struchalin, Maksim

AU - Du, Yangchun

AU - Glazer, Nicole L.

AU - Rosamond, Wayne D.

AU - Rivadeneira, Fernando

AU - Kelly-Hayes, Margaret

AU - Lopez, Oscar L.

AU - Coresh, Josef

AU - Hofman, Albert

AU - DeCarli, Charles

AU - Heckbert, Susan R.

AU - Koudstaal, Peter J.

AU - Yang, Qiong

AU - Smith, Nicholas L.

AU - Kase, Carlos S.

AU - Rice, Kenneth

AU - Haritunians, Talin

AU - Roks, Gerwin

AU - De Kort, Paul L M

AU - Taylor, Kent D.

AU - De Lau, Lonneke M.

AU - Oostra, Ben A.

AU - Uitterlinden, Andre G.

AU - Rotter, Jerome I.

AU - Boerwinkle, Eric

AU - Psaty, Bruce M.

AU - Mosley, Thomas H.

AU - Van Duijn, Cornelia M.

AU - Breteler, Monique M B

AU - Longstreth, W. T.

AU - Wolf, Philip A.

PY - 2009/4/23

Y1 - 2009/4/23

N2 - BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P-8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

AB - BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P-8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

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