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; 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

doi:10.1056/NEJMoa0900094

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 RivadeneiraMargaret 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

Epidemiology

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

400 Scopus citations

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<5×10^-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 language	English (US)
Pages (from-to)	1718-1728
Number of pages	11
Journal	New England Journal of Medicine
Volume	360
Issue number	17
DOIs	https://doi.org/10.1056/NEJMoa0900094
State	Published - Apr 23 2009

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Ikram, M. A., Seshadri, S., Bis, J. C., Fornage, M., DeStefano, A. L., Aulchenko, Y. S., Debette, S., Lumley, T., Folsom, A. R., Van Den Herik, E. G., Bos, M. J., Beiser, A., Cushman, M., Launer, L. J., Shahar, E., Struchalin, M., Du, Y., Glazer, N. L., Rosamond, W. D., ... Wolf, P. A. (2009). Genomewide association studies of stroke. New England Journal of Medicine, 360(17), 1718-1728. https://doi.org/10.1056/NEJMoa0900094

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

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title = "Genomewide association studies of stroke",

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<5×10-8). 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.",

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

year = "2009",

month = apr,

day = "23",

doi = "10.1056/NEJMoa0900094",

language = "English (US)",

volume = "360",

pages = "1718--1728",

journal = "New England Journal of Medicine",

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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<5×10-8). 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<5×10-8). 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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Genomewide association studies of stroke

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