Skip to main content
Log in

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis

  • Published:
AGE Aims and scope Submit manuscript

Abstract

An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Barnes DE, Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 10:819–828

    Article  PubMed Central  PubMed  Google Scholar 

  • Bath PMW, Anderton PR, Ankolekar S (2010) Hemostasis and vascular dementia. Arterioscler Thromb Vasc Biol 30:461–463

    Article  CAS  PubMed  Google Scholar 

  • Bots ML, Breteler MM, van Kooten F, Haverkate F, Meijer P, Koudstaal PJ, Grobbee DE, Kluft C (1998) Coagulation and fibrinolysis markers and risk of dementia the Dutch Vascular Factors in Dementia Study. Haemostasis 28:216–222

    CAS  PubMed  Google Scholar 

  • Campos M, Sun W, Yu F, Barbalic M, Tang W, Chambless LE, Wu KK, Ballantyne C, Folsom AR, Boerwinkle E, Dong J (2011) Genetic determinants of plasma von Willebrand factor antigen: a target gene SNP and haplotype analysis of ARIC cohort. Blood 117:5224–5230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Davey Smith G, Hemani G (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23:R89–R98

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dehghan A, Yang Q, Peters A, Basu S, Bis JC, Rudnicka AR, Kavousi M, Chen MH, Baumert J, Lowe GD, McKnight B, Tang W, de Maat M, Larson MG, Eyhermendy S, McArdle WL, Lumley T, Pankow JS, Hofman A, Massaro JM, et al. (2009) Association of novel genetic loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circulation: Cardiovascular Genetics 2:125–133

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fewell Z, Davey Smith G, Sterne JAC (2007) The impact of residual and unmeasured confounding in epidemiological studies: a simulation study. Am J Epidemiol 166:646–655

    Article  PubMed  Google Scholar 

  • Gallacher J, Bayer A, Lowe G, Fish M, Pickering J, Pedro S, Dunstan F, White J, Yarnell J, Ben-Shlomo Y (2010) Is sticky blood bad for the brain? Hemostatic and inflammatory systems and dementia in the Caerphilly prospective study. Arterioscler Thromb Vasc Biol 30:599–604

    Article  CAS  PubMed  Google Scholar 

  • Gow AJ, Bielak AAM, Gerstorf D (2012) Lifestyle factors and cognitive ageing: variation across ability and lifestyle domains. J Aging Res 2012:143595

    Article  PubMed Central  PubMed  Google Scholar 

  • Huang J, Sabater-Lleal M, Asselbergs FW, Tregouet D, Shin SY, Ding J, Baumert J, Oudot-Mellakh T, Folkersen L, Johnson AD, Smith NL, Williams SM, Ikram MA, Kleber ME, Becker DM, Truong V, Mychaleckyj JC, Tang W, Yang Q, Sennblad B, Moore JH, Williams FM, Dehghan A, Silbernagel G, Schrijvers EM, Smith S, Karakas M, Tofler GH, Silveira A, Navis GJ, Lohman K, Chen MH, Peters A, Goel A, Hopewell JC, Chambers JC, Saleheen D, Lundmark P, Psaty BM, Strawbridge RJ, Boehm BO, Carter AM, Meisinger C, Peden JF, Bis JC, McKnight B, Öhrvik J, Taylor K, Franzosi MG, Seedorf U, Collins R, Franco-Cereceda A, Syvänen AC, Goodall AH, Yanek LR, Cushman M, Müller-Nurasyid M, Folsom AR, Basu S, Matijevic N, van Gilst WH, Kooner JS, Hofman A, Danesh J, Clarke R (2012) Meigs JB; DIAGRAM Consortium, Kathiresan S, Reilly MP; CARDIoGRAM Consortium, Klopp N, Harris TB, Winkelmann BR, Grant PJ, Hillege HL, Watkins H; C4D Consortium, Spector TD, Becker LC, Tracy RP, März W, Uitterlinden AG, Eriksson P, Cambien F; CARDIOGENICS Consortium, Morange PE, Koenig W, Soranzo N, van der Harst P, Liu Y, O’Donnell CJ, Hamsten A. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood 120:4873–4881

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kathiresan S, Gabriel SB, Yang Q, Lochner AL, Larson MG, Levy D, Tofler GH, Hirschhorn JN, O’Donnell CJ (2005) Comprehensive survey of common genetic variation at the plasminogen activator inhibitor-1 locus and relationship to circulating plasminogen activator inhibitor-1 levels. Circulation 112:1728–1735

    Article  CAS  PubMed  Google Scholar 

  • Lezak MD (1995) Mill Hill Vocabulary Test. Neuropsychological testing 3rd edition. Oxford University Press, Oxford, UK

    Google Scholar 

  • Luciano M, Gow AJ, Harris SE, Hayward C, Allerhand M, Starr JM, Visscher PM, Deary IJ (2011) Cognitive ability at age 11 and 70 years, information processing speed, and APOE variation: the Lothian birth cohort 1936 study. Psychology and Aging. 24:129–138

  • Marioni RE, Deary IJ, Murray GD, Lowe GDO, Strachan MWJ, Luciano M, Houlihan LM, Gow AJ, Harris SE, Rumley A, Stewart MC, Fowkes FGR, Price JF (2011) Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts. Behav Genet 41:691–699

    Article  PubMed  Google Scholar 

  • National Statistics Scotland (2012) Scottish index of multiple deprivation. Scottish Government, Edinburgh

    Google Scholar 

  • Quinn TJ, Gallacher J, Deary IJ, Lowe GDO, Fenton C, Stott DJ (2011) Association between circulating hemostatic measures and dementia or cognitive impairment: systematic review and meta-analysis. J Thromb Haemostasis. 9:1475–1482

    Article  CAS  Google Scholar 

  • R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/.

  • Raven JC, Court JH, Raven J (1977) Verbal Fluency Test. Manual for Raven’s progressive matrices and vocabulary scales. London, UK, H. K. Lewis

    Google Scholar 

  • Ritchie CW, Terrera GM, Quinn TJ (2015) Dementia trials and dementia tribulations: methodological and analytical challenges in dementia research. Alz Res Therap. 7:1

    Article  Google Scholar 

  • Smith BH, Campbell C, Linksted P, Fitzpatrick B, Jackson C, Kerr SM, Deary IJ, Macintyre DJ, Campbell H, McGilchrist M, Hocking LJ, Wisely L, Ford I, Lindsay RS, Morton R, Palmer CN, Dominiczak AF, Porteous DJ, Morris AD (2012) Cohort profile: generation Scotland: Scottish Family Health Study. The study participants and the potential for genetic research on health and illness. Int J Epidemiol 42:689–700

    Article  PubMed  Google Scholar 

  • Smith NL, Chen MH, Dehghan A, Strachan DP, Basu S, Soranzo N, Hayward C, Rudan I, Sabater-Lleal M, Bis JC, de Maat MP, Rumley A, Kong X, Yang Q, Williams FM, Vitart V, Campbell H, Mälarstig A, Wiggins KL, Van Duijn CM, et al. (2010) Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor. Circulation 121:1382–1392

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith NL, Huffman JE, Strachan DP, Huang J, Dehghan A, Trompet S, Lopez LM, Shin SY, Baumert J, Vitart V, Bis JC, Wild SH, Rumley A, Yang Q, Uitterlinden AG, Stott DJ, Davies G, Carter AM, Thorand B, Polašek O, et al. (2011) Genetic predictors of fibrin D-dimer levels in healthy adults. Circulation 123:1864–1872

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stott DJ, Robertson MJ, Rumley A, Welsh P, Sattar N, Packard CJ, Shepherd J, Trompet S, Westendorp RG, de Craen AJ, Jukema JW, Buckley B, Ford I, Lowe GD (2010) Activation of haemostasis and decline in cognitive function in older people. Arterioscler Thromb Vasc Biol 30:605–611

    Article  CAS  PubMed  Google Scholar 

  • van Schie MC, de Maat MP, Isaacs A, van Duijn CM, Deckers JW, Dippel DW, Leebeek FW (2011) Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease. Blood 117:1393–1399

    Article  PubMed  Google Scholar 

  • Wechsler D (1998a) Logical Memory Tests. Wechsler memory scale III. Psychological Corporation, London, UK

    Google Scholar 

  • Wechsler D (1998b) Digit Symbol Tests. Wechsler adult intelligence scale III. Psychological Corporation, London, UK

    Google Scholar 

  • Welsh P, Sattar N (2014) Vitamin D genes and mortality. BMJ 349:g6599

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Dr. Quinn designed the research study, assisted with analysis and drafted the manuscript.

Dr. Alghamdi assisted with genotyping and drafting of the manuscript.

Prof Padmanabhan, Porteus, Smith and Hocking assisted with collection and processing of samples.

Prof Deary, Gallacher and Stott assisted with supervision, analysis of cognitive data, interpretation of data and drafting of the manuscript.

Dr. Messow performed the statistical analyses and assisted with drafting of the manuscript.

Sources of funding

This work was supported by the Academy of Medical Sciences, UK.

Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 and the Scottish Funding Council HR03006.

Dr. Quinn is supported by a joint Stroke Association / Chief Scientist Office Senior Clinical Lectureship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Terence J. Quinn.

Electronic supplementary material

ESM 1

(PDF 313 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quinn, T.J., Alghamdi, J., Padmanabhan, S. et al. Association between cognition and gene polymorphisms involved in thrombosis and haemostasis. AGE 37, 80 (2015). https://doi.org/10.1007/s11357-015-9820-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11357-015-9820-y

Keywords

Navigation