Behavior Genetics

, Volume 36, Issue 5, pp 678–686 | Cite as

The Effect of Assortative Mating upon Genetic Association Studies: Spurious Associations and Population Substructure in the Absence of Admixture

Article

Abstract

Spurious associations due to confounding factors are an often cited and intensely debated concern for genetic association studies. Great attention has been focused upon the specific threat of confounding due to population stratification. This emphasis has spurred the development of many statistical genetic methods to detect and correct for the potentially confounding effects of admixture. Unfortunately, this emphasis on admixture has led some authors to suggest that if ethnically homogenous populations are used, spurious associations are unlikely to occur. We show that under small and realistic degrees of assortative mating over time, spurious associations arise even in ethnically homogeneous populations. We demonstrate that structured association and genomic control tests can, under certain conditions, correct for these spurious associations. We conclude that investigators should not assume spurious associations will not occur in association studies using ethnically homogenous populations and recommend the use of genomic control methods and/or family-based association tests within genetic association studies.

KEY WORDS

Assortative mating genetic association studies population stratification spurious association 

References

  1. Adams G. T., Snieder H., McKie V. C., Clair B., Brambilla D., Adams R. J., Kutlar A. (2003). Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case–control association study and genomewide screen. BMC Med. Genet. 4:6CrossRefPubMedGoogle Scholar
  2. Ahern F. M., Johnson R. C., Wilson J. R., McClearn G. E., Vandenberg S. G. (1982). Family resemblances in personality. Behav. Genet. 12:261–280PubMedCrossRefGoogle Scholar
  3. Allison D. B. (1997). Transmission–disequilibrium tests for quantitative traits. Am. J. Hum. Genet. 60:676–690PubMedGoogle Scholar
  4. Allison D. B., Neale M. C. (2001). Joint tests of linkage and association for quantitative traits. Theor. Popul. Biol. 60:239–251PubMedCrossRefGoogle Scholar
  5. Allison D. B., Neale M. C., Kezis M. I., Alfonso V. C., Heshka S., Heymsfield S. B. (1996). Assortative mating for relative weight: genetic implications. Behav. Genet. 26:103–111PubMedCrossRefGoogle Scholar
  6. Ardlie K. G., Lunetta K. L., Seielstad M. (2002). Testing for population subdivision and association in four case–control studies. Am. J. Hum. Genet. 71:304–311PubMedCrossRefGoogle Scholar
  7. Cardon L. R., Palmer L. J. (2003). Population stratification and spurious allelic association. Lancet 361:598–604CrossRefPubMedGoogle Scholar
  8. Deng H. W. (2001). Population admixture may appear to mask, change or reverse genetic effects of genes underlying complex traits. Genetics 159:1319–1323PubMedGoogle Scholar
  9. Devlin B., Roeder K. (1999). Genomic control for association studies. Biometrics 55:155–166CrossRefGoogle Scholar
  10. Dufouil C., Alperovitch A. (2000). Couple similarities for cognitive functions and psychological health. J. Clin. Epidemiol. 53:589–593PubMedCrossRefGoogle Scholar
  11. Ewens W. J., Spielman R. S. (1995). The transmission/disequilibrium test: history, subdivision, and admixture. Am. J. Hum. Genet. 57:455–464PubMedGoogle Scholar
  12. Friedlander Y., Kark J. D., Stein Y. (1998). Family resemblance for serum uric acid in a Jerusalem sample of families. Hum. Genet. 79:58–63CrossRefGoogle Scholar
  13. Freedman M. L., Reich D., Penney K. L., McDonald G. L., Mignault A. A., Patterson N., Gabriel S. B., Topol E. J., Smoller J. W., Pato C. N., Pato M. T., Petryshen T. L., Kolonel L. N., Lander E. S., Sklar P., Henderson B., Hirschhorn J. N., Altshuler D. (2004). Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36:388–393PubMedCrossRefGoogle Scholar
  14. Garn S., Sullivan T. V., Hawthorne V. M. (1989). The education of one spouse and the fatness of the other spouse. Am. J. Hum. Biol. 1: 233–238CrossRefGoogle Scholar
  15. Hoggart C. J., Parra E. J., Shriver M. D., Bonilla C., Kittles R. A., Clayton D. G., McKeigue P. M. (2003). Control of confounding of genetic association in stratified populations. Am. J. Hum. Genet. 72:1492–1504PubMedCrossRefGoogle Scholar
  16. Hunt S. C., Dadone M. M., Williams R. R., Wu L. L., Smith J. B., Kuida H., Ash K. O. (1987). Familial correlations from genes and shared environment for urine, plasma, and intraerythrocytic sodium. Am. J. Med. Genet. 27: 249–255PubMedCrossRefGoogle Scholar
  17. Lynch M., Walsh B. (1998). Genetics and Analysis of Quantitative Traits. Vol 1, Sinauer Associates, INC, Sunderland, MAGoogle Scholar
  18. Morton N. E., Collins A. (1998). Tests and estimates of allelic association in complex inheritance. Proc. Natl. Acad. Sci. USA 95:11389–11393PubMedCrossRefGoogle Scholar
  19. Nadeau J. H., Frankel W. N. (2000). The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat. Genet. 25:381–384PubMedCrossRefGoogle Scholar
  20. Pérusse L., Bouchard C. (1994). Genetics of energy intake and food preferences. In: Bouchard C. (ed) The Genetics of Obesity. CRC Press, Boca Raton, pp. 125–134Google Scholar
  21. Pritchard J. K., Rosenberg N. A. (1999). Use of unlinked genetic markers to detect population stratificaton in association studies. Am. J. Hum. Genet. 65:220–228PubMedCrossRefGoogle Scholar
  22. Pritchard J. K., Stephens M., Rosenberg N. A., Donnelley P. (2001). Association mapping in structured populations. Am. J. Hum. Genet. 67:170–181CrossRefGoogle Scholar
  23. Risch N., Merikangas K. (1996). The future of genetic studies of complex human diseases. Science 273:1516–1517PubMedCrossRefGoogle Scholar
  24. Satten G. A., Flanders W. D., Yang Q. (2001). Accounting for unmeasured population substructure in case control studies of genetic association studies using a novel latent-class structure. Am. J. Hum. Genet. 68:466–477PubMedCrossRefGoogle Scholar
  25. Speers M. A., Kasl S. V., Freeman D. H. Jr., Ostfeld A. M. (1986). Blood pressure concordance between spouses. Am. J. Epidemiol. 123:818–829PubMedGoogle Scholar
  26. Spielman R. S., McGinnis R. E., Ewens W. J. (1993). Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52:506–516PubMedGoogle Scholar
  27. Thomas D. C., Witte J. S. (2002). Point: population Stratification – a problem for case–control studies of candidate–gene associations? Cancer Epidemiol. Biomarkers Prev. 11:505–512PubMedGoogle Scholar
  28. Wacholder S., Rothman N., Caporaso N. (2002). 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. 11:513–520PubMedGoogle Scholar
  29. Whittaker J. C., Morris A. P. (2001). Family-based tests of association and/or linkage. Ann. Hum. Genet. 65:407–419CrossRefPubMedGoogle Scholar
  30. Zhao H. (2000). Family-based association studies. Stat. Methods Med. Res. 9:563–587CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Biostatistics, Section on Statistical Genetics and Clinical Nutrition Research CenterUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.The University of Alabama at BirminghamBirminghamUSA

Personalised recommendations