Associations of NINJ2 Sequence Variants with Incident Ischemic Stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) Consortium

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 tha...

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Vydané v:PloS one Ročník 9; číslo 6; s. e99798
Hlavní autori: 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
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Public Library of Science 24.06.2014
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ISSN:1932-6203, 1932-6203
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Abstract 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. 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). 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.
AbstractList 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.
BackgroundStroke, 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 resultsWe 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).ConclusionCommon 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.
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.BACKGROUNDStroke, 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.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).METHODS AND RESULTSWe 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).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.CONCLUSIONCommon 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.
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. 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). 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.
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.
Author Hofman, Albert
Psaty, Bruce M.
DeStefano, Anita
Gupta, Mayetri
Verhaaren, Benjamin F. J.
Boerwinkle, Eric
Mosley, Thomas H.
Fornage, Myriam
Debette, Stéphanie
Liu, Xiaoming
Brody, Jennifer A.
Gottesman, Rebecca F.
Gibbs, Richard A.
Bis, Joshua C.
Ikram, M. Arfan
Seshadri, Sudha
Muzny, Donna
Choi, Seung Hoan
Longstreth, W. T.
Kovar, Christie L.
van Duijn, Cornelia
Shahar, Eyal
Butler, Kenneth R.
Wolf, Philip A.
Lumley, Thomas
AuthorAffiliation 7 Department of Epidemiology, University of Versailles Saint-Quentin-en-Yvelines, Paris, France
4 Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
18 Department of Neurology, University of Washington, Seattle, Washington, United States of America
19 Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Texas, United States of America
8 Department of Neurology, Erasmus MC, Rotterdam, The Netherlands (M.A.I.); Netherlands
9 Consortium for Healthy Aging, Leiden, The Netherlands
12 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
10 Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, United States of America
2 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
3 Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United Stat
AuthorAffiliation_xml – name: 1 Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/24959832$$D View this record in MEDLINE/PubMed
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2014 Bis et al 2014 Bis et al
Copyright_xml – notice: 2014 Bis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: 2014 Bis et al 2014 Bis et al
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Competing Interests: Bruce M.Psaty serves on the DSMB of a clinical trial of a device funded by Zoll LifeCor. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6-4278). This study did not receive support from Affymetrix. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Conceived and designed the experiments: JCB AD BMP RAG THM WTL EB SS MF. Performed the experiments: DM CLK. Analyzed the data: JCB AD JAB XL SHC MG MF. Contributed reagents/materials/analysis tools: JAB MG TL XL. Wrote the paper: JCB AD SS BMP WTL THM EB BFJV SD MAI ES KRB RFG PAW CvD AH MF.
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Snippet Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study...
Background Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association...
BackgroundStroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association...
Background Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association...
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StartPage e99798
SubjectTerms Aging
Arteriosclerosis
Atherosclerosis
Bioinformatics
Cardiovascular diseases
Cell Adhesion Molecules, Neuronal - genetics
Chromosome 12
Consortia
Epidemiology
Female
Gene expression
Gene frequency
Genetic Association Studies - methods
Genetic Heterogeneity
Genetics
Genome-wide association studies
Genomes
Geriatrics
Health risks
Heart
Heterogeneity
Humans
Introns
Ischemia
Ischemia - genetics
Loci
Male
Medical research
Medicine
Medicine and Health Sciences
Meta-analysis
Myocardial Infarction - etiology
Myocardial Infarction - genetics
Neurology
Polymorphism, Single Nucleotide
Prospective Studies
Public health
Replication
Risk
Science
Sequence Analysis, DNA
Statistical analysis
Stroke
Studies
White People - genetics
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Title Associations of NINJ2 Sequence Variants with Incident Ischemic Stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) Consortium
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