Abstract
This chapter describes the strategy of association studies that can be used to characterize the genetics of stroke. It explains advantages and disadvantages of the method and discusses current evidence of the genes that have been associated with stroke.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ. A navigator for human genome epidemiology. Nat Genet. 2008;40(2):124–5.
Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22.
Bersano A, Ballabio E, Bresolin N, Candelise L. Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat. 2008;29(6):776–95.
Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004;61(11):1652–61.
Stankovi S, Majki-Singh N. Advances in the genetic basis of ischemic stroke. J Med Biochem. 2008;27(2):123–34.
Laird NM, Lange C. Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet. 2006;7(5):385–94.
Laird NM, Lange C. Family-based methods for linkage and association analysis. Adv Genet. 2008;60:219–52.
Meschia JF, Kissela BM, Brott TG, Brown Jr RD, Worrall BB, Beck J, et al. The siblings with ischemic stroke study (SWISS): a progress report. Clin Med Res. 2006;4(1):12–21.
Meschia JF, Nalls M, Matarin M, Brott TG, Brown Jr RD, Hardy J, et al. Siblings with ischemic stroke study: results of a genome-wide scan for stroke loci. Stroke. 2011;42(10):2726–32.
Attia J, Ioannidis JPA, Thakkinstian A, McEvoy M, Scott RJ, Minelli C, et al. How to use an article about genetic association: A: background concepts. JAMA. 2009;301:74–81.
Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet. 2003;361(9360):865–72.
Dichgans M, Markus HS. Genetic association studies in stroke: methodological issues and proposed standard criteria. Stroke. 2005;36(9):2027–31.
Pruissen DM, Kappelle LJ, Rosendaal FR, Algra A. Genetic association studies in ischaemic stroke: replication failure and prospects. Cerebrovasc Dis. 2009;27(3):290–4.
Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association studies (STREGA)–an extension of the STROBE statement. Eur J Clin Invest. 2009;39(4):247–66.
Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet. 2006;7(10):781–91.
Pompanon F, Bonin A, Bellemain E, Taberlet P. Genotyping errors: causes, consequences and solutions. Nat Rev Genet. 2005;6(11):847–59.
Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet. 2005;37(11):1243–6.
Leek JT, Scharpf RB, Bravo HC, Simcha D, Langmead B, Johnson WE, et al. Tackling the widespread and critical impact of batch effects in high-throughput data. Nat Rev Genet. 2010;11(10):733–9.
Thomas DC, Witte JS. Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev. 2002;11(6):505–12.
Wacholder S, Rothman N, Caporaso N. Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev. 2002;11(6):513–20.
Khlat M, Cazes MH, Genin E, Guiguet M. Robustness of case-control studies of genetic factors to population stratification: magnitude of bias and type I error. Cancer Epidemiol Biomarkers Prev. 2004;13(10):1660–4.
Wacholder S, Rothman N, Caporaso N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst. 2000;92(14):1151–8.
Pritchard JK, Stephens M, Rosenberg NA, Donnelly P. Association mapping in structured populations. Am J Hum Genet. 2000;67(1):170–81.
Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55(4):997–1004.
Bacanu SA, Devlin B, Roeder K. Association studies for quantitative traits in structured populations. Genet Epidemiol. 2002;22(1):78–93.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904–9.
Bardoczy Z, Gyorffy B, Kocsis I, Vasarhelyi B. Re-calculated Hardy-Weinberg values in papers published in atherosclerosis between 1995 and 2003. Atherosclerosis. 2004;173(1):141–3.
Sen S, Burmeister M. Hardy-Weinberg analysis of a large set of published association studies reveals genotyping error and a deficit of heterozygotes across multiple loci. Hum Genomics. 2008;3(1):36–52.
Attia J, Thakkinstian A, McElduff P, Milne E, Dawson S, Scott RJ, et al. Detecting genotyping error using measures of degree of Hardy-Weinberg disequilibrium. Stat Appl Genet Mol Biol. 2010;9(1):Article 5.
Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP. Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol. 2006;163(4):300–9.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–94.
Meschia JF. Addressing the heterogeneity of the ischemic stroke phenotype in human genetics research. Stroke. 2002;33(12):2770–4.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet. 2001;29(3):306–9.
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33(2):177–82.
Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G, et al. Replicating genotype-phenotype associations. Nature. 2007;447(7145):655–60.
Lin E, Hsu SY. A Bayesian approach to gene-gene and gene-environment interactions in chronic fatigue syndrome. Pharmacogenomics. 2009;10(1):35–42.
Smith JG, Melander O, Lovkvist H, Hedblad B, Engstrom G, Nilsson P, et al. Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study. Circ Cardiovasc Genet. 2009;2(2):159–64.
Gschwendtner A, Bevan S, Cole JW, Plourde A, Matarin M, Ross-Adams H, et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 2009;65(5):531–9.
Anderson CD, Biffi A, Rost NS, Cortellini L, Furie KL, Rosand J. Chromosome 9p21 in ischemic stroke: population structure and meta-analysis. Stroke. 2010;41(6):1123–31.
On beyond GWAS. Nat Genet. 2010;42(7):551.
Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet. 1986;1(8479):507–8.
Gray R, Wheatley K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant. 1991;7 Suppl 3:9–12.
Capon F, Allen MH, Ameen M, Burden AD, Tillman D, Barker JN, et al. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet. 2004;13(20):2361–8.
Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Stat Med. 2005;24(9):1291–306.
Trikalinos TA, Salanti G, Zintzaras E, Ioannidis JP. Meta-analysis methods. Adv Genet. 2008;60:311–34.
Zintzaras E, Lau J. Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol. 2008;61(7):634–45.
Thakkinstian A, Thompson JR, Minelli C, Attia J. Choosing between per-genotype, per-allele, and trend approaches for initial detection of gene-disease association. J Appl Stat. 2009;36(6):633–46.
Minelli C, Thompson JR, Abrams KR, Thakkinstian A, Attia J. The choice of a genetic model in the meta-analysis of molecular association studies. Int J Epidemiol. 2005;34(6):1319–28.
Salanti G, Southam L, Altshuler D, Ardlie K, Barroso I, Boehnke M, et al. Underlying genetic models of inheritance in established type 2 diabetes associations. Am J Epidemiol. 2009;170(5):537–45.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.
Greene CS, Penrod NM, Williams SM, Moore JH. Failure to replicate a genetic association may provide important clues about genetic architecture. PLoS One. 2009;4(6):e5639.
Ioannidis JP, Ntzani EE, Trikalinos TA. ‘Racial’ differences in genetic effects for complex diseases. Nat Genet. 2004;36(12):1312–8.
Moonesinghe R, Khoury MJ, Liu T, Ioannidis JP. Required sample size and nonreplicability thresholds for heterogeneous genetic associations. Proc Natl Acad Sci USA. 2008;105(2):617–22.
Pereira TV, Patsopoulos NA, Salanti G, Ioannidis JP. Discovery properties of genome-wide association signals from cumulatively combined data sets. Am J Epidemiol. 2009;170(10):1197–206.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.
Chapter 7: publication bias. In: Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F, editors. Methods for meta-analysis in medical research. West Sussex: Wiley; 2000.
Sterne JAC, Egger M, Smith GD. Investigating and dealing with publication and other biases. In: Egger M, Smith GD, Altman DG, editors. Systematic reviews in health care. 2nd ed. London: BMJ Books; 2001.
Maguire J, Sturm J, Levi C, Thakkinstian A, Whyte S, Attia J. Polymorphisms in platelet glycoprotein 1bα and factor VII and risk of ischemic stroke. A meta-analysis. Stroke. 2008;39:1710–6.
Lin PI, Vance JM, Pericak-Vance MA, Martin ER. No gene is an island: the flip-flop phenomenon. Am J Hum Genet. 2007;80(3):531–8.
Clarke GM, Cardon LR. Aspects of observing and claiming allele flips in association studies. Genet Epidemiol. 2010;34(3):266–74.
Maguire JM, Thakkinstian A, Sturm J, Levi C, Lincz L, Parsons M, et al. Polymorphisms in platelet glycoprotein 1balpha and factor VII and risk of ischemic stroke: a meta-analysis. Stroke. 2008;39(6):1710–6.
Minelli C, Thompson JR, Abrams KR, Thakkinstian A, Attia J. The quality of meta-analyses of genetic association studies: a review with recommendations. Am J Epidemiol. 2009;170(11):1333–43.
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9.
Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38(4):458–62.
Thakkinstian A, McKay GJ, McEvoy M, Chakravarthy U, Chakrabarti S, Silvestri G, et al. Systematic review and meta-analysis of the association between complement component 3 and age-related macular degeneration: a HUGE review and meta-analysis. Am J Epidemiol. 2011;173:1365–79.
Thanassoulis G, O’Donnell CJ. Mendelian randomisation. UptoDate. Wolters Kluwer Health.
Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010;303(24):2486–94.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag London
About this chapter
Cite this chapter
Holliday, E.G., Oldmeadow, C.J., Maguire, J.M., Attia, J. (2013). Candidate Gene Association Studies in Stroke. In: Sharma, P., Meschia, J. (eds) Stroke Genetics. Springer, London. https://doi.org/10.1007/978-0-85729-209-4_2
Download citation
DOI: https://doi.org/10.1007/978-0-85729-209-4_2
Published:
Publisher Name: Springer, London
Print ISBN: 978-0-85729-208-7
Online ISBN: 978-0-85729-209-4
eBook Packages: MedicineMedicine (R0)