Journal
STROKE
Volume 41, Issue 2, Pages 210-217Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.109.569194
Keywords
brain infarction; cohort study; genome-wide association study; meta-analysis
Categories
Funding
- NIA [N01-AG-12100]
- NEI
- NIDCD
- NHLBI
- NIA Intramural Research Program, Hjartavernd
- National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL093029, N01-HC-85079, N01-HC- 85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C, UL1RR025005]
- NIH Roadmap for Medical Research
- Austrian Science Fond (FWF) [P20545-P05, P13180]
- National Institute of Neurological Disorders and Stroke
- National Center for Research Resources [M01RR00425]
- Cedars-Sinai General Clinical Research Center Genotyping core
- National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- National Institute of Neurological Disorders and Stroke [NS17950]
- National Institute of Aging [AG08122, AG16495, AG033193]
- Netherlands Organization of Scientific Research Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [01493- 015
- RIDE2]
- Netherlands Genomics Initiative (NGI)/ Netherlands Organization for Scientific Research [050-060810]
- NWO [918-46-615, 948-00-010]
- Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands
- Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture, and Science
- Ministry for Health, Welfare, and Sports
- European Commission
- Municipality of Rotterdam
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN)
- Institut de la Longevite
- Conseils Regionaux of Aquitaine and Bourgogne
- Fondation de France
- Ministry of Research-INSERM
- Austrian Science Fund (FWF) [P 20545] Funding Source: researchfish
- Austrian Science Fund (FWF) [P13180] Funding Source: Austrian Science Fund (FWF)
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Background and Purpose-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. Methods-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 >= 1 MRI infarct). Results-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 = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-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. Conclusions-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. (Stroke. 2010; 41: 210-217.)
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