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. 74, No. 3-4, 2012
Issue release date: April 2013
Section title: Editorial
Free Access
Hum Hered 2012;74:113-117

Some Surprising Twists on the Road to Discovering the Contribution of Rare Variants to Complex Diseases

Thomas D.C.
University of Southern California, Los Angeles, Calif., USA
email Corresponding Author

Duncan C. Thomas

Division of Biostatistics, Keck School of Medicine

University of Southern California

Los Angeles, CA 90089 (USA)

E-Mail dthomas@usc.edu


  1. Luo L, Boerwinkle E, Xiong M: Association studies for next-generation sequencing. Genome Res 2011;21:1099-1108.
  2. Kim W, Londono D, Zhou L, Xing J, Nato AQ, Musolf A, Matise TC, Finch SJ, Gordon D: Single-variant and multi-variant trend tests for genetic association with next-generation sequencing that are robust to sequencing error. Hum Hered 2012;74:172-183.
    External Resources
  3. Feng T, Zhu X: Detecting rare variants. Methods Mol Biol 2012;850:453-464.
  4. Gibson G: Rare and common variants: twenty arguments. Nat Rev Genet 2011;13:135-145.
  5. Basu S, Pan W: Comparison of statistical tests for disease association with rare variants. Genet Epidemiol 2011;35:606-619.
  6. Asimit J, Zeggini E: Rare variant association analysis methods for complex traits. Annu Rev Genet 2010;44:293-308.
  7. Lee S, Wu MC, Lin X: Optimal tests for rare variant effects in sequencing association studies. Biostatistics 2012;13:762-775.
  8. 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.
  9. Madsen BE, Browning SR: A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genetics 2009;5:e1000384.
  10. Maher MC, Uricchio LH, Torgerson DG, Hernandez RD: Population genetics of rare variants and complex diseases. Hum Hered 2012;74:118-128.
  11. Hoffmann TJ, Marini NJ, Witte JS: Comprehensive approach to analyzing rare genetic variants. PLoS One 2010;5:e13584.
  12. Tachmazidou I, Morris A, Zeggini E: Rare variant association testing for next-generation sequencing data via hierarchical clustering. Hum Hered 2012;74:165-171.
    External Resources
  13. 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 Genetics 2011;7:e1001322.
  14. Neyman J, Scott E: On the use of c(alpha) optimal tests of composite hypotheses. Bull Internat Statist Inst 1966;41:477-497.
  15. Kocherlakota S, Kocherlakota K: Neyman's c(alpha) test and Rao's efficient score test for composite hypotheses. Statist Prob Lett 1991;11:499-493.
  16. 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.
  17. Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, Christiani DC, Wurfel MM, Lin X: Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet 2012;91:224-237.
  18. Beckmann L, Thomas DC, Fischer C, Chang-Claude J: Haplotype sharing analysis using mantel statistics. Hum Hered 2005;59:67-78.
  19. Tzeng JY, Zhang D: Haplotype-based association analysis via variance-components score test. Am J Hum Genet 2007;81:927-938.
  20. Allen AS, Satten GA: A novel haplotype-sharing approach for genome-wide case-control association studies implicates the calpastatin gene in Parkinson's disease. Genet Epidemiol 2009;33:657-667.
  21. Schaid DJ: Genomic similarity and kernel methods ii: methods for genomic information. Hum Hered 2010;70:132-140.
  22. Schaid DJ: Genomic similarity and kernel methods i: advancements by building on mathematical and statistical foundations. Hum Hered 2010;70:109-131.
  23. Hoeffding: A class of statistics with asymptotically normal distributions. Ann Math Stat 1948;19:293-325.
    External Resources
  24. 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.
  25. Capanu M, Concannon P, Haile RW, Bernstein L, Malone KE, Lynch CF, Liang X, Teraoka SN, Diep AT, Thomas DC, Bernstein JL, Begg CB: Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. Genet Epidemiol 2011;35:389-397.
  26. Quintana MA, Berstein JL, Thomas DC, Conti DV: Incorporating model uncertainty in detecting rare variants: the Bayesian risk index. Genet Epidemiol 2011;35:638-649.
  27. Raftery AE, Madigan D, Hoeting JA: Bayesian model averaging for linear regression models. J Am Statist Assoc 1997;92:179-191.
    External Resources
  28. Quintana MA, Schumacher FR, Casey G, Bernstein JL, Li L, Conti DV: Incorporating prior biologic information for high-dimensional rare variant association studies. Hum Hered 2012;74:184-195.
    External Resources
  29. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG: Replication validity of genetic association studies. Nat Genet 2001;29:306-309.
  30. 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 USA 2009;106:9362-9367.
  31. 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.
  32. Wang K, Li M, Hakonarson H: Analysing biological pathways in genome-wide association studies. Nat Rev Genet 2010;11:843-854.
  33. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005;102:15545-15550.
  34. Bailey-Wilson JE, Wilson AF: Linkage analysis in the next-generation sequencing era. Hum Hered 2011;72:228-236.
  35. Wijsman EM: The role of large pedigrees in an era of high-throughput sequencing. Hum Genet 2012;131:1555-1563.
  36. Ionita-Laza I, Ottman R: Study designs for identification of rare disease variants in complex diseases: the utility of family-based designs. Genetics 2011;189:1061-1068.
  37. Shi G, Rao DC: Optimum designs for next-generation sequencing to discover rare variants for common complex disease. Genet Epidemiol 2011;35:572-579.
  38. Zhu X, Feng T, Li Y, Lu Q, Elston RC: Detecting rare variants for complex traits using family and unrelated data. Genet Epidemiol 2010;34:171-187.
  39. Zhu Y, Xiong M: Family-based association studies for next-generation sequencing. Am J Hum Genet 2012;90:1028-1045.
  40. Perdry H, Müller-Myhsok B, Clerget-Darpoux F: Using affected sib-pairs to uncover rare disease variants. Hum Hered 2012;74: 129-141.
    External Resources
  41. Marchani EE, Chapman NH, Cheung CYK, Ankenman K, Stanaway IB, Coon HH, Nickerson D, Bernier R, Brkanac Z, Wijsman EM: Identification of rare variants from exome sequence in a large pedigree with autism. Hum Hered 2012;74:153-164.
    External Resources
  42. Génin E, Sahbatou M, Gazal S, Babron MC, Perdry H, Leutenegger AL: Could inbred cases identified in GWAS data succeed in detecting rare recessive variants where affected sib-pairs have failed? Hum Hered 2012;74: 142-152.
    External Resources
  43. Jouan L, Gauthier J, Dion PA, Rouleau GA: Rare variants in complex traits: novel identification strategies and the role of de novo mutations. Hum Hered 2012;74:215-225.
    External Resources
  44. Schifano ED, Epstein MP, Bielak LF, Jhun MA, Kardia SLR, Peyser PA, Lin X: SNP set association analysis for familial data. Genet Epidemiol 2012:797-810.
  45. Chen H, Meigs JB, Dupuis J: Sequence kernel association test for quantitative traits in family samples. Genet Epidemiol 2013;37:196-204.
  46. Asimit JL, Zeggini E: Imputation of rare variants in next-generation association studies. Hum Hered 2012;74:196-204.
    External Resources
  47. Burdick JT, Chen WM, Abecasis GR, Cheung VG: In silico method for inferring genotypes in pedigrees. Nat Genet 2006;38:1002-1004.
  48. Li Y, Willer C, Sanna S, Abecasis G: Genotype imputation. Annu Rev Genomics Hum Genet 2009;10:387-406.
  49. Van Steen K, McQueen MB, Herbert A, Raby B, Lyon H, DeMeo DL, Murphy A, Su J, Datta S, Rosenow C, Christman M, Silverman EK, Laird NM, Weiss ST, Lange C: Genomic screening and replication using the same data set in family-based association testing. Nat Genet 2005;37:683-691.
  50. Wason JMS, Dudbridge F: A general framework for two-stage analysis of genome-wide association studies and its application to case-control studies. Am J Hum Genet 2012;90:760-773.
  51. Gauderman WJ, Thomas DC, Murcray C, Conti DV, Li D, Lewinger JP: Efficient genome-wide association testing of gene-environment interaction in case-parent trios. Am J Epidemiol 2010;172:116-122.
  52. Kazma R, Cardin NJ, Witte JS: Does accounting for gene-environment interactions help uncover association between rare variants and complex diseases? Hum Hered 2012;74: 205-214.
    External Resources
  53. Tzeng JY, Zhang D, Pongpanich M, Smith C, McCarthy MI, Sale MM, Worrall BB, Hsu FC, Thomas DC, Sullivan PF: Studying gene and gene-environment effects of uncommon and common variants on continuous traits: a marker-set approach using gene-trait similarity regression. Am J Hum Genet 2011;89:277-288.
  54. Thomas DC, Casey G, Conti DV, Haile RW, Lewinger JP, Stram DO: Methodological issues in multistage genome-wide association studies. Stat Sci 2009;24:414-429.
  55. Cirulli ET, Goldstein DB: Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 2010;11:415-425.
  56. Mechanic LE, Chen HS, Amos CI, Chatterjee N, Cox NJ, Divi RL, Fan R, Harris EL, Jacobs K, Kraft P, Leal SM, McAllister K, Moore JH, Paltoo DN, Province MA, Ramos EM, Ritchie MD, Roeder K, Schaid DJ, Stephens M, Thomas DC, Weinberg CR, Witte JS, Zhang S, Zollner S, Feuer EJ, Gillanders EM: Next generation analytic tools for large scale genetic epidemiology studies of complex diseases. Genet Epidemiol 2012;36:22-35.