Genomewide Association Studies of Stroke
Open accessAbstract
BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
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Low educational level has been reported to be associated with an increased risk for VaD.
“Low educational level has been reported to be associated with an increased risk for VaD.280”
From Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association (2011) · cites this paper as [280]
The Methods and Results sections examine genetic variants associated with incident stroke, not vascular dementia (VaD). Searches for low educational level, education, and dementia found no passage in our copy addressing the claimed association; page numbers were not available. (LLM, conf=0.75)
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Self-citation
- Authors
- Ikram, M. A., Seshadri, S., Bis, J. C., Fornage, M., DeStefano, A. L., Aulchenko, Y. S., Debette, S., Lumley, T., Folsom, A. R., van den Herik, E. G., Bos, M. J., Beiser, A., Cushman, M., Launer, L. J., Shahar, E., Struchalin, M., Du, Y., Glazer, N. L., Rosamond, W. D., Rivadeneira, F., Kelly-Hayes, M., Lopez, O. L., Coresh, J., Hofman, A., DeCarli, C., Heckbert, S. R., Koudstaal, P. J., Yang, Q., Smith, N. L., Kase, C. S., Rice, K., Haritunians, T., Roks, G., de Kort, P. L. M., Taylor, K. D., de Lau, L. M., Oostra, B. A., Uitterlinden, A. G., Rotter, J. I., Boerwinkle, E., Psaty, B. M., Mosley, T. H., van Duijn, C. M., Breteler, M. M. B., Longstreth, W. T., & Wolf, P. A.
- Affiliations
- Erasmus MC (NL)
- Boston University (US)
- University of Washington (US)
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- University of Minnesota (US)
- University of Vermont (US)
- National Institute on Aging (US)
- University of Arizona (US)
- University of North Carolina at Chapel Hill (US)
- Johns Hopkins University (US)
- Group Health Cooperative (US)
- Cedars-Sinai Medical Center (US)
- Elisabeth-TweeSteden Ziekenhuis (NL)
- University of Mississippi Medical Center (US)
- ORCID
- Ikram, M. Arfan
- Seshadri, Sudha
- Bis, Joshua C.
- Fornage, Myriam
- DeStefano, Anita L.
- Aulchenko, Yurii S.
- Folsom, Aaron R.
- Beiser, Alexa
- Cushman, Mary
- Launer, Lenore J.
- Shahar, Eyal
- Struchalin, Maksim
- Glazer, Nicole L.
- Rosamond, Wayne D.
- Rivadeneira, Fernando
- Coresh, Josef
- DeCarli, Charles
- Heckbert, Susan R.
- Koudstaal, Peter J.
- Yang, Qiong
- Smith, Nicholas L.
- Kase, Carlos S.
- Rice, Kenneth
- Haritunians, Talin
- Roks, Gerwin
- Taylor, Kent D.
- Rotter, Jerome I.
- Boerwinkle, Eric
- Psaty, Bruce M.
- Mosley, Thomas H.
- Breteler, Monique M.B.
- Wolf, Philip A.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-04-23
- Volume
- 360
- Issue
- 17
- Pages
- 1718-1728
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2768348
- OpenAlex
- W2011877873
- Cited by
- 458
- References
- 44
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 10 · 2021: 15 · 2020: 12 · 2019: 21 · 2018: 16 · 2017: 23 · 2016: 28 · 2015: 39 · 2014: 34 · 2013: 36 · 2012: 61
- FWCI
- 39.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (n01hc085082-026, n01hc085081-021, n01hc045133-001, n01hc085079-024, n01hc015103-009, n01hc085084-005, n01hc55021-47-0-1, n01hc085085-011, n01hc085083-027, n01hc55020-39-0-0, n01hc085080-026, n01hc55016-37-0-0, n01hc055022-024, n01hc085086-022, n01hc55019-35-0-1, n01hc55018-38-0-1, n01hc25195-41-0-1, n01hc55222-0-0-0, n01hc075150-004, n01hc035129-010, n01hc55015-48-0-1)
- U.S. Public Health Service (HHSN 268200625226C)
- National Institute on Aging (P30AG010129, AG-16495, AG08122, AG033193, R01AG016495, R01AG033193, R01AG008122)
- National Heart, Lung, and Blood Institute (N01-HC-85081, N01-HC55022, N01 HC085086, N01HC-85083, N01 HC055016, N01-HC-55018, N01 HC 55020, N01 HC085079, N01 HC085083, N01‐HC25195, N01 HC 55019, N01HC85082, N01HC‐75150, N01 HC85086, N01 HC085080, R01HL087652, N01 HC055020, N01 HC035129, N01HC85080, N02- HL-64278, N01 HC055018, N01 HC015103, N01 HC55222, N01 HC085085, N01-HC-025195, N01-HC55016, R01HL087641, N01 HC055022, R01HL059367, N01HC085082, U01HL080295, N01 HC055019, N01 HC055222, N01 HC085081, N01‐HC‐55015, N01-HC55021, N01 HC075150, N01 HC055021, N01 HC085084, N01 HC055015, N01 HC045133, R01HL086694, N01-HC85079)
- National Human Genome Research Institute (U01HG004402)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, P30DK063491)
- National Institute of Neurological Disorders and Stroke (NS17950, R01NS017950)
- National Center for Research Resources (UL1RR025005, M01RR000069)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Keywords
- stroke, ischemic stroke, genetic susceptibility, NINJ2, chromosome 12p13, single nucleotide polymorphisms, intergenic variants, genetic association, Black population, Caucasian population, Dutch population, population attributable risk, replication cohort
- MeSH terms
- Aged, Chromosomes, Human, Pair 12, Female, Genetic Markers, Genotype, Humans, Male, Middle Aged, Risk Factors, Cohort Studies, Proportional Hazards Models, Genetic Predisposition to Disease, Stroke, Polymorphism, Single Nucleotide, Black People, White People, Genome-Wide Association Study
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