Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot Password? Reset your password

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login (Shibboleth)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Table of Contents
Vol. 71, No. 4, 2011
Issue release date: September 2011
Section title: Original Paper
Free Access
Hum Hered 2011;71:209–220

Two-Stage Design of Sequencing Studies for Testing Association with Rare Variants

Yang F. · Thomas D.C.
Department of Preventive Medicine, University of Southern California, Los Angeles, Calif., USA
email Corresponding Author

Duncan C. Thomas

Department of Preventive Medicine

University of Southern California

Los Angeles, CA 90089-9011 (USA)

Tel. +1 323 442 1218, E-Mail dthomas@usc.edu


  1. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA: Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci 2009;106:9362–9367.
  2. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM: Finding the missing heritability of complex diseases. Nature 2009;461:747–753.
  3. Maher B: Personal genomes: the case of the missing heritability. Nature 2008;456:18–21.
  4. Bodmer W, Bonilla C: Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 2008;40:695–701.
  5. Kryukov GV, Pennacchio LA, Sunyaev SR: Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet 2007;80:727–739.
  6. Iyengar SK, Elston RC: The genetic basis of complex traits: rare variants or ‘common gene, common disease’? Methods Mol Biol 2007;376:71–84.
  7. Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, Tomlinson IP, Mortensen NJ, Bodmer WF: Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci 2004;101:15992–15997.
  8. Hoggart CJ, Clark TG, De Iorio M, Whittaker JC, Balding DJ: Genome-wide significance for dense SNP and resequencing data. Genet Epidemiol 2008;32:179–185.
  9. Kryukov GV, Shpunt A, Stamatoyannopoulos JA, Sunyaev SR: Power of deep, all-exon resequencing for discovery of human trait genes. Proc Natl Acad Sci 2009;106:3871–3876.
  10. Droege M, Hill B: The Genome Sequencer FLX System – longer reads, more applications, straight forward bioinformatics and more complete data sets. J Biotechnol 2008;136:3–10.
  11. Bentley DR: Whole-genome re-sequencing. Curr Opin Genet Dev 2006;16:545–552.
  12. 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.
  13. 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.
  14. Johnson N, Fletcher O, Palles C, Rudd M, Webb E, Sellick G, Dos Santos Silva I, McCormack V, Gibson L, Fraser A, Leonard A, Gilham C, Tavtigian SV, Ashworth A, Houlston R, Peto J: Counting potentially functional variants in brca1, brca2 and atm predicts breast cancer susceptibility. Hum Mol Genet 2007;16:1051–1057.
  15. Madsen BE, Browning SR: A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 2009;5:e1000384.
  16. Li B, Leal SM: Discovery of rare variants via sequencing: implications for the design of complex trait association studies. PLoS Genet 2009;5:e1000481.
  17. Hudson RR: Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics 2002;18:337–338.
  18. Armitage P: Statistical Methods in Medical Research. Oxford, Blackwell Scientific Publications, 1971.
  19. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS Biol 2010;8:e1000294.
  20. Via M, Gignoux C, Burchard EG: The 1000 Genomes Project: new opportunities for research and social challenges. Genome Med 2010;2:3.
  21. Pritchard JK: Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001;69:124–137.
  22. Skol AD, Scott LJ, Abecasis GR, Boehnke M: Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006;38:209–213.
  23. Breslow NE, Lumley T, Ballantyne CM, Chambless LE, Kulich M: Using the whole cohort in the analysis of case-cohort data. Am J Epidemiol 2009;169:1398–1405.
  24. Breslow NE, Chatterjee N: Design and analysis of two-phase studies with binary outcome applied to Wilms tumour prognosis. Appl Statist 1999;48:457–468.
    External Resources
  25. Thomas DC, Casey G, Conti DV, Haile RW, Lewinger JP, Stram DO: Methodological issues in multistage genome-wide association studies. Statist Sci 2009;24:414–429.
  26. 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.
  27. Hoffmann T, Marini N, Witte J: Comprehensive approach to analyzing rare variants. PLoS One 2010;5:e13584.
  28. Han F, Pan W: A data-adaptive sum test for disease association with multiple common or rare variants. Hum Hered 2010;70:42–54.
  29. Lewinger JP, Conti DV, Baurley JW, Triche TJ, Thomas DC: Hierarchical Bayes prioritization of marker associations from a genome-wide association scan for further investigation. Genet Epidemiol 2007;31:871–882.
  30. Chen GK, Witte JS: Enriching the analysis of genomewide association studies with hierarchical modeling. Am J Hum Genet 2007;81:397–404.
  31. Conti D, Gauderman W: SNPs, haplotypes, and model selection in a candidate gene region: the simple analysis of multilocus data. Genet Epidemiol 2004;27:429–441.
  32. Ionita-Laza I, Laird NM: On the optimal design of genetic variant discovery studies. Stat Appl Genet and Mol Biol 2010;9:Article 33.
  33. Wang T, Lin CY, Rohan TE, Ye K: Resequencing of pooled DNA for detecting disease associations with rare variants. Genet Epidemiol 2010;34:492–501.
  34. Kim SY, Li Y, Guo Y, Li R, Holmkvist J, Hansen T, Pedersen O, Wang J, Nielsen R: Design of association studies with pooled or un-pooled next-generation sequencing data. Genet Epidemiol 2010;34:479–491.