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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.
Wednesday,2015-03-04 11:57 America/Los_Angeles — zdrager
| Title | Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Bis, JC, DeStefano, A, Liu, X, Brody, JA, Choi, SHoan, Verhaaren, BFJ, Debette, S, Ikram, AM, 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 |
| Journal | PLoS One |
| Volume | 9 |
| Issue | 6 |
| Pagination | e99798 |
| Date Published | 2014 |
| ISSN | 1932-6203 |
| Keywords | Cell Adhesion Molecules, Neuronal, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Heterogeneity, Humans, Introns, Ischemia, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS AND RESULTS: </b>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).</p><p><b>CONCLUSION: </b>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.</p> |
| DOI | 10.1371/journal.pone.0099798 |
| Alternate Journal | PLoS ONE |
| PubMed ID | 24959832 |
| PubMed Central ID | PMC4069013 |
| Grant List | N01HC55222 / HC / NHLBI NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01 HC085086 / HC / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States AG027058 / AG / NIA NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States AG15928 / AG / NIA NIH HHS / United States 5RC2HL102419 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States N01HC85080 / HC / NHLBI NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States HHSN268201100005C / / PHS HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States HHSN268201100009C / / PHS HHS / United States HL087652 / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States HL120393 / HL / NHLBI NIH HHS / United States HHSN268201100010C / / PHS HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States N01 HC085082 / HC / NHLBI NIH HHS / United States N01HC85081 / HC / NHLBI NIH HHS / United States N01 HC085080 / HC / NHLBI NIH HHS / United States N01HC85079 / HC / NHLBI NIH HHS / United States HHSN268201100008C / / PHS HHS / United States HHSN268201100012C / / PHS HHS / United States N01HC85086 / HC / NHLBI NIH HHS / United States N01HC85082 / HC / NHLBI NIH HHS / United States HHSN268201100007C / / PHS HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States HHSN268200800007C / / PHS HHS / United States HHSN268201100011C / / PHS HHS / United States HHSN268201200036C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States N01HC85083 / HC / NHLBI NIH HHS / United States AG20098 / AG / NIA NIH HHS / United States HHSN268201100006C / / PHS HHS / United States HL103612 / HL / NHLBI NIH HHS / United States R01 AG027058 / AG / NIA NIH HHS / United States AG023629 / AG / NIA NIH HHS / United States |