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Meta-Analysis
. 2014 Jun 24;9(6):e99798.
doi: 10.1371/journal.pone.0099798. eCollection 2014.

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

Joshua C Bis  1 , Anita DeStefano  2 , Xiaoming Liu  3 , Jennifer A Brody  1 , Seung Hoan Choi  2 , Benjamin F J Verhaaren  4 , Stéphanie Debette  5 , M Arfan Ikram  6 , Eyal Shahar  7 , Kenneth R Butler Jr  8 , Rebecca F Gottesman  9 , Donna Muzny  10 , Christie L Kovar  10 , Bruce M Psaty  11 , Albert Hofman  12 , Thomas Lumley  13 , Mayetri Gupta  2 , Philip A Wolf  14 , Cornelia van Duijn  12 , Richard A Gibbs  10 , Thomas H Mosley  8 , W T Longstreth Jr  15 , Eric Boerwinkle  16 , Sudha Seshadri  14 , Myriam Fornage  17
Affiliations
Meta-Analysis

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

Joshua C Bis et al. PLoS One. .

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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Conflict of interest statement

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.

Figures

Figure 1
Figure 1. Associations of common variants (MAF≥1%) with incident ischemic stroke in the CHARGE Targeted Sequencing Study.
Association p-values are plotted against their genomic position.
Figure 2
Figure 2. T1 test of association of rare variants with predicted functional impact on protein function or gene regulation in the 3 cohorts.
Shown are the hazard ratios (HR) and associated confidence intervals for each cohort and the summary measure (diamond) from the meta-analysis.
See this image and copyright information in PMC

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