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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
Authors: Bis J.C.
DeStefano A.
Liu X.
Brody J.A.
Choi S.H.
Verhaaren B.F.J.
Debette S.
Ikram M.A. 
Shahar E.
Butler Jr. K.R.
Gottesman R.F.
Muzny D.
Kovar C.L.
Psaty B.M.
Hofman A.
Lumley T.
Gupta M.
Wolf P.A.
Van Duijn C.
Gibbs R.A.
Mosley T.H.
Longstreth Jr. W.T.
Boerwinkle E.
Seshadri S.
Fornage M.
Keywords: adult
brain ischemia
cardiovascular disease
controlled study
gene frequency
gene function
gene locus
gene mapping
gene sequence
genetic association
genetic heterogeneity
genetic variability
major clinical study
medical research
middle aged
NINJ2 gene
risk assessment
DNA sequence
genetic association study
meta analysis
Myocardial Infarction
prospective study
single nucleotide polymorphism
nerve cell adhesion molecule
NINJ2 protein, human
Cell Adhesion Molecules, Neuronal
European Continental Ancestry Group
Genetic Association Studies
Genetic Heterogeneity
Myocardial Infarction
Polymorphism, Single Nucleotide
Prospective Studies
Sequence Analysis, DNA
Issue Date: 2014
Citation: Bis J.C., DeStefano A., Liu X., Brody J.A., Choi S.H., Verhaaren B.F.J., Debette S., Ikram M.A., Shahar E., Butler Jr. K.R., Gottesman R.F., Muzny D., Kovar C.L., Psaty B.M., Hofman A., Lumley T., Gupta M., Wolf P.A., Van Duijn C., Gibbs R.A., Mosley T.H., Longstreth Jr. W.T., 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 9 (6) : e99798. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2014 Bis et al.
Source Title: PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0099798
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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