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Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.
Tuesday,2012-11-06 12:19 America/Los_Angeles — eenright
| Title | Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Debette, S, Bis, JC, Fornage, M, Schmidt, H, Ikram, AM, Sigurdsson, S, Heiss, G, Struchalin, M, Smith, AV, van der Lugt, A, DeCarli, C, Lumley, T, Knopman, DS, Enzinger, C, Eiriksdottir, G, Koudstaal, PJ, DeStefano, AL, Psaty, BM, Dufouil, C, Catellier, DJ, Fazekas, F, Aspelund, T, Aulchenko, YS, Beiser, A, Rotter, JI, Tzourio, C, Shibata, DK, Tscherner, M, Harris, TB, Rivadeneira, F, Atwood, LD, Rice, K, Gottesman, RF, van Buchem, MA, Uitterlinden, AG, Kelly-Hayes, M, Cushman, M, Zhu, Y, Boerwinkle, E, Gudnason, V, Hofman, A, Romero, JR, Lopez, O, van Duijn, CM, Au, R, Heckbert, SR, Wolf, PA, Mosley, TH, Seshadri, S, Breteler, MMB, Schmidt, R, Launer, LJ, Longstreth, WT |
| Journal | Stroke |
| Volume | 41 |
| Issue | 2 |
| Pagination | 210-7 |
| Date Published | 2010 Feb |
| ISSN | 1524-4628 |
| Keywords | African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies |
| Abstract | <p><b>BACKGROUND AND PURPOSE: </b>Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.</p><p><b>METHODS: </b>Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).</p><p><b>RESULTS: </b>The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.</p><p><b>CONCLUSIONS: </b>This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.</p> |
| DOI | 10.1161/STROKEAHA.109.569194 |
| Alternate Journal | Stroke |
| PubMed ID | 20044523 |
| PubMed Central ID | PMC2923092 |
| Grant List | N01HC55020 / HL / NHLBI NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States RC2 HL102419-02 / RC / CCR NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States P30 DK063491-05 / DK / NIDDK NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States N01AG12100 / AG / NIA NIH HHS / United States N01HC55018 / HL / NHLBI NIH HHS / United States R01 AG016495 / AG / NIA NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States R01HL093029 / HL / NHLBI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States ZIA AG007380-04 / / Intramural NIH HHS / United States N01 HC055018 / HC / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States HHSN268200625226C / / PHS HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States N01HC55022 / HL / NHLBI NIH HHS / United States R01 HL080295-07 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States N01HC55015 / HL / NHLBI NIH HHS / United States R01 HL093029 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States P 20545 / / Austrian Science Fund FWF / Austria P30 DK063491-039004 / DK / NIDDK NIH HHS / United States P30 AG010129-18 / AG / NIA NIH HHS / United States N01 HC055019 / HC / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States M01RR00425 / RR / NCRR NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States N01-HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01HC55016 / HL / NHLBI NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States P30 DK063491-029004 / DK / NIDDK NIH HHS / United States M01 RR000425 / RR / NCRR NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC55019 / HL / NHLBI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States P30 DK063491-019004 / DK / NIDDK NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States RC2 HL102419-02 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States K23 AG038444 / AG / NIA NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States P30 DK063491-049004 / DK / NIDDK NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States N01HC55021 / HL / NHLBI NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States |