Home LiteratureArticle Details
PMID: 19733727 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Epistasis and its implications for personal genetics.

American journal of human genetics ·Vol. 85 ·No. 3 ·2009-09-00 ·Pages 309-20

Moore JH, Williams SM

Abstract

The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.

MeSH Terms
Epistasis, Genetic Genetic Predisposition to Disease Genetics, Medical Genome-Wide Association Study Humans Models, Genetic Models, Statistical
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Moore Jason H
Computational Genetics Laboratory, Department of Genetics and Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA. jason.h.moore@dartmouth.edu
Williams Scott M
References (95)
95 references, click to expand
  1. Interpretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers.
    PLoS Genet. 2009 Feb;5(2):e1000337 PMID: 19197355
  2. Epistasis, complex traits, and mapping genes.
    Genetica. 2001;112-113:59-69 PMID: 11838787
  3. Evaporative cooling feature selection for genotypic data involving interactions.
    Bioinformatics. 2007 Aug 15;23(16):2113-20 PMID: 17586549
  4. Bioinformatics.
    J Cell Physiol. 2007 Nov;213(2):365-9 PMID: 17654500
  5. Replicating genotype-phenotype associations.
    Nature. 2007 Jun 7;447(7145):655-60 PMID: 17554299
  6. Systems genetics of complex traits in Drosophila melanogaster.
    Nat Genet. 2009 Mar;41(3):299-307 PMID: 19234471
  7. A complete enumeration and classification of two-locus disease models.
    Hum Hered. 2000 Nov-Dec;50(6):334-49 PMID: 10899752
  8. Family-centered approaches to understanding and preventing coronary heart disease.
    Am J Prev Med. 2003 Feb;24(2):143-51 PMID: 12568820
  9. Problems with genome-wide association studies.
    Science. 2007 Jun 29;316(5833):1840-2 PMID: 17605173
  10. Complex adaptive system models and the genetic analysis of plasma HDL-cholesterol concentration.
    Perspect Biol Med. 2006 Autumn;49(4):490-503 PMID: 17146134
  11. Old and new pathways in human genetics.
    Am J Hum Genet. 1951 Mar;3(1):1-16 PMID: 13171371
  12. The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics.
    Mamm Genome. 2008 Jun;19(6):382-9 PMID: 18716833
  13. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer.
    Am J Hum Genet. 2001 Jul;69(1):138-47 PMID: 11404819
  14. Odds ratio based multifactor-dimensionality reduction method for detecting gene-gene interactions.
    Bioinformatics. 2007 Jan 1;23(1):71-6 PMID: 17092990
  15. Identification of gene-gene interactions in the presence of missing data using the multifactor dimensionality reduction method.
    Genet Epidemiol. 2009 Nov;33(7):646-56 PMID: 19241410
  16. Multifactor dimensionality reduction-phenomics: a novel method to capture genetic heterogeneity with use of phenotypic variables.
    Am J Hum Genet. 2007 Dec;81(6):1251-61 PMID: 17999363
  17. Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission.
    Hum Genet. 2009 Feb;125(1):63-79 PMID: 19052778
  18. Shadows of complexity: what biological networks reveal about epistasis and pleiotropy.
    Bioessays. 2009 Feb;31(2):220-7 PMID: 19204994
  19. Log-linear model-based multifactor dimensionality reduction method to detect gene gene interactions.
    Bioinformatics. 2007 Oct 1;23(19):2589-95 PMID: 17872915
  20. Detecting gene-gene interactions that underlie human diseases.
    Nat Rev Genet. 2009 Jun;10(6):392-404 PMID: 19434077
  21. On schemes of combinatorial transcription logic.
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5136-41 PMID: 12702751
  22. Beyond odds ratios--communicating disease risk based on genetic profiles.
    Nat Rev Genet. 2009 Apr;10(4):264-9 PMID: 19238176
  23. Alternative contingency table measures improve the power and detection of multifactor dimensionality reduction.
    BMC Bioinformatics. 2008 May 16;9:238 PMID: 18485205
  24. Epistasis and its contribution to genetic variance components.
    Genetics. 1995 Mar;139(3):1455-61 PMID: 7768453
  25. Detecting epistatic interactions contributing to quantitative traits.
    Genet Epidemiol. 2004 Sep;27(2):141-52 PMID: 15305330
  26. The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.
    J Natl Cancer Inst. 2008 Nov 5;100(21):1552-6 PMID: 18957677
  27. Novel methods for detecting epistasis in pharmacogenomics studies.
    Pharmacogenomics. 2007 Sep;8(9):1229-41 PMID: 17924838
  28. The Collaborative Cross, a community resource for the genetic analysis of complex traits.
    Nat Genet. 2004 Nov;36(11):1133-7 PMID: 15514660
  29. Accelerating epistasis analysis in human genetics with consumer graphics hardware.
    BMC Res Notes. 2009 Jul 24;2:149 PMID: 19630950
  30. A computationally efficient hypothesis testing method for epistasis analysis using multifactor dimensionality reduction.
    Genet Epidemiol. 2009 Jan;33(1):87-94 PMID: 18671250
  31. A global view of epistasis.
    Nat Genet. 2005 Jan;37(1):13-4 PMID: 15624016
  32. Screening large-scale association study data: exploiting interactions using random forests.
    BMC Genet. 2004 Dec 10;5:32 PMID: 15588316
  33. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans.
    Nat Genet. 1999 Feb;21(2):213-5 PMID: 9988276
  34. Failure to replicate a genetic association may provide important clues about genetic architecture.
    PLoS One. 2009 Jun 02;4(6):e5639 PMID: 19503614
  35. Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility.
    Carcinogenesis. 2006 May;27(5):1030-7 PMID: 16311243
  36. Breast cancer susceptibility: current knowledge and implications for genetic counselling.
    Eur J Hum Genet. 2009 Jun;17(6):722-31 PMID: 19092773
  37. A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation.
    Genome Res. 2001 Mar;11(3):458-70 PMID: 11230170
  38. Studying complex biological systems using multifactorial perturbation.
    Nat Rev Genet. 2003 Feb;4(2):145-51 PMID: 12560811
  39. From genotypes to genometypes: putting the genome back in genome-wide association studies.
    Eur J Hum Genet. 2009 Oct;17(10):1205-6 PMID: 19277066
  40. The regulation of direct-to-consumer genetic tests.
    Hum Mol Genet. 2008 Oct 15;17(R2):R180-3 PMID: 18852208
  41. Genetics, statistics and human disease: analytical retooling for complexity.
    Trends Genet. 2004 Dec;20(12):640-7 PMID: 15522460
  42. Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics.
    Mol Genet Metab. 2005 Feb;84(2):104-11 PMID: 15670716
  43. The Pathway Less Traveled: Moving from Candidate Genes to Candidate Pathways in the Analysis of Genome-Wide Data from Large Scale Pharmacogenetic Association Studies.
    Curr Pharmacogenomics Person Med. 2008;6(3):150-159 PMID: 19421424
  44. Exploiting the proteome to improve the genome-wide genetic analysis of epistasis in common human diseases.
    Hum Genet. 2008 Aug;124(1):19-29 PMID: 18551320
  45. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans.
    Hum Mol Genet. 2002 Oct 1;11(20):2463-8 PMID: 12351582
  46. STUDENTJAMA. The challenges of whole-genome approaches to common diseases.
    JAMA. 2004 Apr 7;291(13):1642-3 PMID: 15069055
  47. New strategies for identifying gene-gene interactions in hypertension.
    Ann Med. 2002;34(2):88-95 PMID: 12108579
  48. Genome-wide association study identifies novel breast cancer susceptibility loci.
    Nature. 2007 Jun 28;447(7148):1087-93 PMID: 17529967
  49. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence.
    Am J Hum Genet. 2007 Jun;80(6):1125-37 PMID: 17503330
  50. "Are we there yet?": Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits.
    Am J Hum Genet. 2003 Oct;73(4):711-9 PMID: 13680525
  51. Ideal discrimination of discrete clinical endpoints using multilocus genotypes.
    In Silico Biol. 2004;4(2):183-94 PMID: 15107022
  52. Biofilter: a knowledge-integration system for the multi-locus analysis of genome-wide association studies.
    Pac Symp Biocomput. 2009;:368-79 PMID: 19209715
  53. Machine learning for detecting gene-gene interactions: a review.
    Appl Bioinformatics. 2006;5(2):77-88 PMID: 16722772
  54. Decanalization and the origin of complex disease.
    Nat Rev Genet. 2009 Feb;10(2):134-40 PMID: 19119265
  55. The language of gene interaction.
    Genetics. 1998 Jul;149(3):1167-71 PMID: 9649511
  56. Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis.
    Bioessays. 2005 Jun;27(6):637-46 PMID: 15892116
  57. A testing framework for identifying susceptibility genes in the presence of epistasis.
    Am J Hum Genet. 2006 Jan;78(1):15-27 PMID: 16385446
  58. Identifying interacting SNPs using Monte Carlo logic regression.
    Genet Epidemiol. 2005 Feb;28(2):157-70 PMID: 15532037
  59. Commentary: statistical analysis or biological analysis as tools for understanding biological causes.
    Int J Epidemiol. 2006 Jun;35(3):536-7 PMID: 16672311
  60. Genome-wide association studies in cancer.
    Hum Mol Genet. 2008 Oct 15;17(R2):R109-15 PMID: 18852198
  61. Annotation: the analysis of variance and the analysis of causes.
    Am J Hum Genet. 1974 May;26(3):400-11 PMID: 4827368
  62. A novel method to identify gene-gene effects in nuclear families: the MDR-PDT.
    Genet Epidemiol. 2006 Feb;30(2):111-23 PMID: 16374833
  63. Genome-wide association studies: theoretical and practical concerns.
    Nat Rev Genet. 2005 Feb;6(2):109-18 PMID: 15716907
  64. Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes.
    Am J Hum Genet. 1995 Oct;57(4):920-34 PMID: 7573054
  65. Parallel multifactor dimensionality reduction: a tool for the large-scale analysis of gene-gene interactions.
    Bioinformatics. 2006 Sep 1;22(17):2173-4 PMID: 16809395
  66. Predictive behavior within microbial genetic networks.
    Science. 2008 Jun 6;320(5881):1313-7 PMID: 18467556
  67. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility.
    J Theor Biol. 2006 Jul 21;241(2):252-61 PMID: 16457852
  68. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.
    Nat Genet. 2009 May;41(5):585-90 PMID: 19330027
  69. Genome-wide association studies for common diseases and complex traits.
    Nat Rev Genet. 2005 Feb;6(2):95-108 PMID: 15716906
  70. Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions.
    Bioinformatics. 2003 Feb 12;19(3):376-82 PMID: 12584123
  71. Sequence analysis using logic regression.
    Genet Epidemiol. 2001;21 Suppl 1:S626-31 PMID: 11793751
  72. Statistical modeling of interlocus interactions in a complex disease: rejection of the multiplicative model of epistasis in type 1 diabetes.
    Genetics. 2001 May;158(1):357-67 PMID: 11333244
  73. Systematic biological prioritization after a genome-wide association study: an application to nicotine dependence.
    Bioinformatics. 2008 Aug 15;24(16):1805-11 PMID: 18565990
  74. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer.
    Cancer Res. 2009 Sep 1;69(17):6857-64 PMID: 19706757
  75. William Bateson: a biologist ahead of his time.
    J Genet. 2002 Aug;81(2):49-58 PMID: 12532036
  76. Combinatorial pharmacogenetics.
    Nat Rev Drug Discov. 2005 Nov;4(11):911-8 PMID: 16264434
  77. Genes, environment, and cardiovascular disease.
    Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1190-6 PMID: 12730090
  78. New evaluation measures for multifactor dimensionality reduction classifiers in gene-gene interaction analysis.
    Bioinformatics. 2009 Feb 1;25(3):338-45 PMID: 19164302
  79. Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder.
    Am J Hum Genet. 2009 Jul;85(1):13-24 PMID: 19539887
  80. A balanced accuracy function for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction.
    Genet Epidemiol. 2007 May;31(4):306-15 PMID: 17323372
  81. A new approach to decoding life: systems biology.
    Annu Rev Genomics Hum Genet. 2001;2:343-72 PMID: 11701654
  82. Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity.
    Genet Epidemiol. 2003 Feb;24(2):150-7 PMID: 12548676
  83. The ubiquitous nature of epistasis in determining susceptibility to common human diseases.
    Hum Hered. 2003;56(1-3):73-82 PMID: 14614241
  84. Sensible Initialization Using Expert Knowledge for Genome-Wide Analysis of Epistasis Using Genetic Programming.
    Genet Evol Comput Conf. 2009 May 18;2009:1289-1296 PMID: 21197156
  85. Pathway analysis by adaptive combination of P-values.
    Genet Epidemiol. 2009 Dec;33(8):700-9 PMID: 19333968
  86. BRCA1 and BRCA2: 1994 and beyond.
    Nat Rev Cancer. 2004 Sep;4(9):665-76 PMID: 15343273
  87. Linkage of calpain 10 to type 2 diabetes: the biological rationale.
    Diabetes. 2004 Feb;53 Suppl 1:S19-25 PMID: 14749261
  88. Spatially uniform relieff (SURF) for computationally-efficient filtering of gene-gene interactions.
    BioData Min. 2009 Sep 22;2(1):5 PMID: 19772641
  89. Genotype-based association test for general pedigrees: the genotype-PDT.
    Genet Epidemiol. 2003 Nov;25(3):203-13 PMID: 14557988
  90. Determinants of the success of whole-genome association testing.
    Genome Res. 2005 Nov;15(11):1463-7 PMID: 16251455
  91. Identifying SNPs predictive of phenotype using random forests.
    Genet Epidemiol. 2005 Feb;28(2):171-82 PMID: 15593090
  92. A test for linkage and association in general pedigrees: the pedigree disequilibrium test.
    Am J Hum Genet. 2000 Jul;67(1):146-54 PMID: 10825280
  93. A perspective on epistasis: limits of models displaying no main effect.
    Am J Hum Genet. 2002 Feb;70(2):461-71 PMID: 11791213
  94. Computational analysis of gene-gene interactions using multifactor dimensionality reduction.
    Expert Rev Mol Diagn. 2004 Nov;4(6):795-803 PMID: 15525222
  95. Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems.
    Nat Rev Genet. 2008 Nov;9(11):855-67 PMID: 18852697
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2009.08.006
Email
jason.h.moore@dartmouth.edu
Published
2009-09-00
Pages
309-20
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC2771593
Subset
IM
Grants
NLM NIH HHS · R01 LM010098 · United States
NICHD NIH HHS · HD047447 · United States
NICHD NIH HHS · R01 HD047447 · United States
NLM NIH HHS · LM010098 · United States
NLM NIH HHS · LM009012 · United States
NIAID NIH HHS · AI59694 · United States
NIAID NIH HHS · R01 AI059694 · United States
NLM NIH HHS · R01 LM009012 · United States
External Links
PubMed source DOI: 10.1016/j.ajhg.2009.08.006 PMC Full Text View journal details
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