Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Joshua C. Bis, Anita DeStefano, Xiaoming Liu, Jennifer A. Brody, Seung Hoan Choi, Benjamin F J Verhaaren, Stéphanie Debette, M. Arfan Ikram, Eyal Shahar, Kenneth R. Butler, Rebecca F Gottesman, Donna Muzny, Christie L. Kovar, Bruce M. Psaty, Albert Hofman, Thomas Lumley, Mayetri Gupta, Philip A. Wolf, Cornelia Van Duijn, Richard A. GibbsThomas H. Mosley, W. T. Longstreth, Eric Boerwinkle, Sudha Seshadri, Myriam Fornage

Research output: Contribution to journalArticle

Abstract

Background: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. Methods and Results: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). Conclusion: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

Original languageEnglish (US)
Article numbere99798
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 24 2014

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Epidemiology
stroke
epidemiology
Genes
Aging of materials
Stroke
heart
genomics
Genome-Wide Association Study
Gene Frequency
gene frequency
Chromosomes
Health
Statistics
loci
atherosclerosis
prospective studies
nervous system
Nervous System
Meta-Analysis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. / Bis, Joshua C.; DeStefano, Anita; Liu, Xiaoming; Brody, Jennifer A.; Choi, Seung Hoan; Verhaaren, Benjamin F J; Debette, Stéphanie; Ikram, M. Arfan; Shahar, Eyal; Butler, Kenneth R.; Gottesman, Rebecca F; Muzny, Donna; Kovar, Christie L.; Psaty, Bruce M.; Hofman, Albert; Lumley, Thomas; Gupta, Mayetri; Wolf, Philip A.; Van Duijn, Cornelia; Gibbs, Richard A.; Mosley, Thomas H.; Longstreth, W. T.; Boerwinkle, Eric; Seshadri, Sudha; Fornage, Myriam.

In: PLoS One, Vol. 9, No. 6, e99798, 24.06.2014.

Research output: Contribution to journalArticle

Bis, JC, DeStefano, A, Liu, X, Brody, JA, Choi, SH, Verhaaren, BFJ, Debette, S, Ikram, MA, Shahar, E, Butler, KR, Gottesman, RF, Muzny, D, Kovar, CL, Psaty, BM, Hofman, A, Lumley, T, Gupta, M, Wolf, PA, Van Duijn, C, Gibbs, RA, Mosley, TH, Longstreth, WT, Boerwinkle, E, Seshadri, S & Fornage, M 2014, 'Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium', PLoS One, vol. 9, no. 6, e99798. https://doi.org/10.1371/journal.pone.0099798
Bis, Joshua C. ; DeStefano, Anita ; Liu, Xiaoming ; Brody, Jennifer A. ; Choi, Seung Hoan ; Verhaaren, Benjamin F J ; Debette, Stéphanie ; Ikram, M. Arfan ; Shahar, Eyal ; Butler, Kenneth R. ; Gottesman, Rebecca F ; Muzny, Donna ; Kovar, Christie L. ; Psaty, Bruce M. ; Hofman, Albert ; Lumley, Thomas ; Gupta, Mayetri ; Wolf, Philip A. ; Van Duijn, Cornelia ; Gibbs, Richard A. ; Mosley, Thomas H. ; Longstreth, W. T. ; Boerwinkle, Eric ; Seshadri, Sudha ; Fornage, Myriam. / Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. In: PLoS One. 2014 ; Vol. 9, No. 6.
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abstract = "Background: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. Methods and Results: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1{\%}) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1{\%} using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). Conclusion: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.",
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T1 - Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

AU - Bis, Joshua C.

AU - DeStefano, Anita

AU - Liu, Xiaoming

AU - Brody, Jennifer A.

AU - Choi, Seung Hoan

AU - Verhaaren, Benjamin F J

AU - Debette, Stéphanie

AU - Ikram, M. Arfan

AU - Shahar, Eyal

AU - Butler, Kenneth R.

AU - Gottesman, Rebecca F

AU - Muzny, Donna

AU - Kovar, Christie L.

AU - Psaty, Bruce M.

AU - Hofman, Albert

AU - Lumley, Thomas

AU - Gupta, Mayetri

AU - Wolf, Philip A.

AU - Van Duijn, Cornelia

AU - Gibbs, Richard A.

AU - Mosley, Thomas H.

AU - Longstreth, W. T.

AU - Boerwinkle, Eric

AU - Seshadri, Sudha

AU - Fornage, Myriam

PY - 2014/6/24

Y1 - 2014/6/24

N2 - Background: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. Methods and Results: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). Conclusion: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

AB - Background: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. Methods and Results: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). Conclusion: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

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