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Table of Contents
Vol. 74, No. 3-4, 2012
Issue release date: April 2013
Section title: Paper
Hum Hered 2012;74:205-214

Does Accounting for Gene-Environment Interactions Help Uncover Association between Rare Variants and Complex Diseases?

Kazma R. · Cardin N.J. · Witte J.S.
Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California, San Francisco, Calif., USA
email Corresponding Author

John S. Witte, PhD

MC 3110, UCSF, Helen Diller Family Cancer Research Building

1450 3rd Street, PO Box 589001

San Francisco, CA 94158-9001 (USA)

E-Mail WitteJ@humgen.ucsf.edu


  1. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH: Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 2010;11:446-450.
  2. Manolio TA, Collins FS, Cox NJ, et al: Finding the missing heritability of complex diseases. Nature 2009;461:747-753.
  3. Mechanic LE, Chen HS, Amos CI, et al: Next generation analytic tools for large scale genetic epidemiology studies of complex diseases. Genet Epidemiol 2012;36:22-35.
  4. van Ijzendoorn MH, Bakermans-Kranenburg MJ, Belsky J, Beach S, Brody G, Dodge KA, Greenberg M, Posner M, Scott S: Gene-by-environment experiments: a new approach to finding the missing heritability. Nat Rev Genet 2011;12:881; author reply 881.
  5. Keinan A, Clark AG: Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 2012;336:740-743.
  6. Nelson MR, Wegmann D, Ehm MG, et al: An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science 2012;337:100-104.
  7. Tennessen JA, Bigham AW, O'Connor TD, et al: Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012;337:64-69.
  8. Gibson G: Rare and common variants: twenty arguments. Nat Rev Genet 2011;13:135-145.
  9. Basu S, Pan W: Comparison of statistical tests for disease association with rare variants. Genet Epidemiol 2011;35:606-619.
  10. Stitziel NO, Kiezun A, Sunyaev S: Computational and statistical approaches to analyzing variants identified by exome sequencing. Genome Biol 2011;12:227.
  11. Ladouceur M, Dastani Z, Aulchenko YS, Greenwood CM, Richards JB: The empirical power of rare variant association methods: results from sanger sequencing in 1,998 individuals. PLoS Genet 2012;8:e1002496.
  12. Hoffmann TJ, Marini NJ, Witte JS: Comprehensive approach to analyzing rare genetic variants. PLoS One 2010;5:e13584.
  13. Kazma R, Hoffmann TJ, Witte JS: Use of principal components to aggregate rare variants in case-control and family-based association studies in the presence of multiple covariates. BMC Proc 2011;5(suppl 9):S29.
  14. Li B, Leal SM: Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 2008;83:311-321.
  15. Madsen BE, Browning SR: A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 2009;5:e1000384.
  16. Morgenthaler S, Thilly WG: A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: a cohort allelic sums test (CAST). Mutat Res 2007;615:28-56.
  17. Morris AP, Zeggini E: An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet Epidemiol 2010;34:188-193.
  18. Neale BM, Rivas MA, Voight BF, Altshuler D, Devlin B, Orho-Melander M, Kathiresan S, Purcell SM, Roeder K, Daly MJ: Testing for an unusual distribution of rare variants. PLoS Genet 2011;7:e1001322.
  19. Price AL, Kryukov GV, de Bakker PI, Purcell SM, Staples J, Wei LJ, Sunyaev SR: Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet 2010;86:832-838.
  20. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X: Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 2011;89:82-93.
  21. Asimit J, Zeggini E: Rare variant association analysis methods for complex traits. Annu Rev Genet 2010;44:293-308.
  22. Kazma R, Babron MC, Genin E: Genetic association and gene-environment interaction: a new method for overcoming the lack of exposure information in controls. Am J Epidemiol 2011;173:225-235.
  23. Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ: Exploiting gene-environment interaction to detect genetic associations. Hum Hered 2007;63:111-119.
  24. Westfall P, Young S: On adjusting P-values for multiplicity. Biometrics 1993;49:941-945.
  25. Fisher R: On the interpretation of χ2 from contingency tables, and the calculation of P. J Royal Stat Soc 1922;85:87-94.
  26. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ, Hunter DJ, Lin X: Powerful SNP-set analysis for case-control genome-wide association studies. Am J Hum Genet 2010;86:929-942.
  27. Davies R: The distribution of a linear combination of chi-square random variables. J R Stat Soc Ser C Appl Stat 1980;29:323-333.
  28. Lee S, Wu MC, Lin X: Optimal tests for rare variant effects in sequencing association studies. Biostatistics 2012;13:762-775.
  29. Cardin NJ, Mefford JA, Witte JS: Joint association testing of common and rare genetic variants using hierarchical modeling. Genet Epidemiol 2012;36:642-651.
  30. Hernandez RD: A flexible forward simulator for populations subject to selection and demography. Bioinformatics 2008;24:2786-2787.
  31. R Development Core Team: R: a language and environment for statistical computing. Vienna, Austria, 2005. http://www.R-project.org.
  32. Hahn LW, Ritchie MD, Moore JH: Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 2003;19:376-382.
  33. Manuguerra M, Matullo G, Veglia F, et al: Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions. Carcinogenesis 2007;28:414-422.
  34. Ottman R: Gene-environment interaction: definitions and study designs. Prev Med 1996;25:764-770.