Dataset Information

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

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.

SUBMITTER: Bis JC

PROVIDER: S-EPMC4069013 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

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

Bis Joshua C JC DeStefano Anita A Liu Xiaoming X Brody Jennifer A JA Choi Seung Hoan SH Verhaaren Benjamin F J BF Debette Stéphanie S Ikram M Arfan MA Shahar Eyal E Butler Kenneth R KR Gottesman Rebecca F RF Muzny Donna D Kovar Christie L CL Psaty Bruce M BM Hofman Albert A Lumley Thomas T Gupta Mayetri M Wolf Philip A PA van Duijn Cornelia C Gibbs Richard A RA Mosley Thomas H TH Longstreth W T WT Boerwinkle Eric E Seshadri Sudha S Fornage Myriam M

PloS one 20140624 6

<h4>Background</h4>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 ...[more]

PMID: 24959832

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Project description:BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.Methods and resultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.ConclusionThis study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

Project description:Background and objectivesBoth genetic and environmental factors contribute to stroke risk. We sought to identify novel metabolites associated with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and determine whether they reflected genetic or environmental variation.MethodsThis was a stroke case-cohort observational study nested in REGARDS. Cases were defined as incident stroke and metabolomic profiles were compared to a randomly selected control cohort. In baseline plasma samples, 162 metabolites were measured using liquid chromatography-tandem mass spectrometry. Cox proportional hazards models were adjusted for age, sex, race, and age by race in the base model. Fully adjusted models included traditional stroke risk factors. Mediation analyses conducted for these stroke risk factors used the metabolite as mediator. Genome-wide associations with the leading candidate metabolites were calculated using array data. Replication analyses in the Jackson Heart Study (JHS) were conducted using random effects meta-analysis.ResultsThere were 2,043 participants who were followed over an average period of 7.1 years, including 1,075 stroke cases and 968 random controls. Nine metabolites were associated with stroke in the base model, 8 of which were measured and remained significant in meta-analysis with JHS. In the fully adjusted model in REGARDS, guanosine (hazard ratio [HR] 1.34, 95% CI 1.18-1.53; p = 7.26 × 10-6) and pseudouridine (HR 1.28, 95% CI 1.13-1.45; p = 1.03 × 10-4) were associated with incident ischemic stroke following Bonferroni adjustment. Guanosine also partially mediated the relationship between hypertension and stroke (17.6%) and pseudouridine did not mediate any risk factor. Genome-wide association analysis identified loci rs34631560 and rs34631560 associated with pseudouridine, but these did not explain the association of pseudouridine with stroke.DiscussionGuanosine and pseudouridine are nucleosides associated with incident ischemic stroke independently of other risk factors. Genetic and mediation analyses suggest that environmental exposures rather than genetic variation link nucleoside levels to stroke risk.Classification of evidenceThis study provides Class II evidence that guanosine and pseudouridine are associated with incident stroke.

Dataset Information

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

Background

Methods and results

Conclusion

Publications

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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