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  • Review Article
  • Published:

Genome-wide association studies: progress and potential for drug discovery and development

Nature Reviews Drug Discovery volume 7, pages 221–230 (2008)Cite this article

Key Points

  • Genetic factors are the cause of most common human diseases.

  • Common human diseases are genetically complex.

  • Genome-wide association (GWA) studies represent a new approach to identify common genetic variants that are associated with complex diseases.

  • GWA studies seek statistically significant associations between a disease phenotype and genotypes of hundreds of thousands of common, single nucleotide variants that are distributed throughout the genome in hundreds or thousands of affected individuals and matched controls.

  • During the past year and a half, GWA studies have had considerable success in identifying genetic risk factors for common diseases such as diabetes mellitus, inflammatory bowel disease and cancer.

  • Independent replication of the findings of GWA studies is essential.

  • GWA studies are anticipated to have a broad impact on drug discovery and development by providing a molecular understanding of common diseases and tools for molecular stratification of patients.

  • The applicability of GWA studies is being increased by examination of copy-number variants, large scale resequencing of genes and genomic regions in populations and establishment of new, very large population genetics studies.

Abstract

Although genetic studies have been critically important for the identification of therapeutic targets in Mendelian disorders, genetic approaches aiming to identify targets for common, complex diseases have traditionally had much more limited success. However, during the past year, a novel genetic approach — genome-wide association (GWA) — has demonstrated its potential to identify common genetic variants associated with complex diseases such as diabetes, inflammatory bowel disease and cancer. Here, we highlight some of these recent successes, and discuss the potential for GWA studies to identify novel therapeutic targets and genetic biomarkers that will be useful for drug discovery, patient selection and stratification in common diseases.

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Figure 1: Overview of the general design and workflow of a genome-wide association (GWA) study.
Figure 2: Schematic view of genetic linkage, GWA results, fine mapping and linkage disequilibrium structure in a region of chromosome 8q24.21 that demonstrates an association of rs1447295 and rs16901979 with prostate cancer.

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References

  1. Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nature Genet. 33 (Suppl.), 228–237 (2003).

    CAS  PubMed  Google Scholar 

  2. Freimer, N. & Sabatti, C. The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology. Nature Genet. 36, 1045–1051 (2004).

    CAS  PubMed  Google Scholar 

  3. Goring, H. H., Terwilliger, J. D. & Blangero, J. Large upward bias in estimation of locus-specific effects from genomewide scans. Am. J. Hum. Genet. 69, 1357–1369 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).

    CAS  PubMed  Google Scholar 

  5. Chakravarti, A. Population genetics — making sense out of sequence. Nature Genet. 21, 56–60 (1999).

    CAS  PubMed  Google Scholar 

  6. Reich, D. E. & Lander, E. S. On the allelic spectrum of human disease. Trends Genet. 17, 502–510 (2001).

    CAS  PubMed  Google Scholar 

  7. The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  8. Sherry, S. T. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29, 308–311 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hirschhorn, J. N., Lohmueller, K., Byrne, E. & Hirschhorn, K. A comprehensive review of genetic association studies. Genet. Med. 4, 45–61 (2002).

    CAS  PubMed  Google Scholar 

  10. Ioannidis, J. P., Ntzani, E. E., Trikalinos, T. A. & Contopoulos-Ioannidis, D. G. Replication validity of genetic association studies. Nature Genet. 29, 306–309 (2001).

    CAS  PubMed  Google Scholar 

  11. Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. Nature Rev. Genet. 2, 91–99 (2001).

    CAS  PubMed  Google Scholar 

  12. Cardon, L. R. & Palmer, L. J. Population stratification and spurious allelic association. Lancet 361, 598–604 (2003).

    PubMed  Google Scholar 

  13. Redden, D. T. & Allison, D. B. Nonreplication in genetic association studies of obesity and diabetes research. J. Nutr. 133, 3323–3326 (2003).

    CAS  PubMed  Google Scholar 

  14. Sillanpaa, M. J. & Auranen, K. Replication in genetic studies of complex traits. Ann. Hum. Genet. 68, 646–657 (2004).

    CAS  PubMed  Google Scholar 

  15. Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S. & Hirschhorn, J. N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nature Genet. 33, 177–182 (2003).

    CAS  PubMed  Google Scholar 

  16. Risch, N. J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000).

    CAS  PubMed  Google Scholar 

  17. Chanock, S. J. et al. Replicating genotype–phenotype associations. Nature 447, 655–660 (2007).

    CAS  PubMed  Google Scholar 

  18. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007). The largest GWA study undertaken to date.

  19. Hunter, D. J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nature Genet. 39, 870–874 (2007).

    CAS  PubMed  Google Scholar 

  20. Ozaki, K. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nature Genet. 32, 650–654 (2002). The first large scale association study of a complex human disorder.

    CAS  PubMed  Google Scholar 

  21. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    CAS  PubMed  Google Scholar 

  22. Clark, A. G. & Li, J. Conjuring SNPs to detect associations. Nature Genet. 39, 815–816 (2007).

    CAS  PubMed  Google Scholar 

  23. Grupe, A. et al. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Hum. Mol. Genet. 16, 865–873 (2007).

    CAS  PubMed  Google Scholar 

  24. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007).

    CAS  PubMed  Google Scholar 

  25. Huang, H. et al. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C. Gastroenterology 130, 1679–1687 (2006).

    CAS  PubMed  Google Scholar 

  26. Luke, M. M. et al. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 27, 2030–2036 (2007).

    CAS  PubMed  Google Scholar 

  27. Shiffman, D. et al. Identification of four gene variants associated with myocardial infarction. Am. J. Hum. Genet. 77, 596–605 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Smyth, D. J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genet. 38, 617–619 (2006).

    CAS  PubMed  Google Scholar 

  29. Clarke, R. et al. Lymphotoxin-α gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study. PLoS Genet. 2, e107 (2006).

    PubMed  PubMed Central  Google Scholar 

  30. Kimura, A. et al. Lack of association between LTA and LGALS2 polymorphisms and myocardial infarction in Japanese and Korean populations. Tissue Antigens 69, 265–269 (2007).

    CAS  PubMed  Google Scholar 

  31. Koch, W. et al. Association of variants in the BAT1–NFKBIL1–LTA genomic region with protection against myocardial infarction in Europeans. Hum. Mol. Genet. 16, 1821–1827 (2007).

    CAS  PubMed  Google Scholar 

  32. Laxton, R., Pearce, E., Kyriakou, T. & Ye, S. Association of the lymphotoxin-α gene Thr26Asn polymorphism with severity of coronary atherosclerosis. Genes Immun. 6, 539–541 (2005).

    CAS  PubMed  Google Scholar 

  33. Mizuno, H. et al. Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction. Atherosclerosis 185, 400–405 (2006).

    CAS  PubMed  Google Scholar 

  34. Sedlacek, K. et al. Lymphotoxin-α and galectin-2 SNPs are not associated with myocardial infarction in two different German populations. J. Mol. Med. 85, 997–1004 (2007).

    CAS  PubMed  Google Scholar 

  35. Yamada, A. et al. Lack of association of polymorphisms of the lymphotoxin α gene with myocardial infarction in Japanese. J. Mol. Med. 82, 477–483 (2004).

    CAS  PubMed  Google Scholar 

  36. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005). Discovery of a single variant that explains a large component of the genetic variance in a common human disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl Acad. Sci. USA 102, 7227–7232 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Magnusson, K. P. et al. CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS Med. 3, e5 (2006).

    PubMed  Google Scholar 

  39. Souied, E. H. et al. Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol. Vis. 11, 1135–1140 (2005).

    CAS  PubMed  Google Scholar 

  40. Zareparsi, S. et al. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am. J. Hum. Genet. 77, 149–153 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature Genet. 38, 458–462 (2006).

    CAS  PubMed  Google Scholar 

  42. Yates, J. R. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 357, 553–561 (2007).

    CAS  PubMed  Google Scholar 

  43. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Libioulle, C. et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).

    PubMed  PubMed Central  Google Scholar 

  45. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007).

    CAS  PubMed  Google Scholar 

  46. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genet. 39, 830–832 (2007).

    CAS  PubMed  Google Scholar 

  47. Yamazaki, K. et al. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. J. Hum. Genet. 52, 575–583 (2007).

    CAS  PubMed  Google Scholar 

  48. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    CAS  PubMed  Google Scholar 

  49. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    CAS  PubMed  Google Scholar 

  50. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    CAS  PubMed  Google Scholar 

  51. Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).

    CAS  PubMed  Google Scholar 

  52. Raelson, J. V. et al. Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci. Proc. Natl Acad. Sci. USA 104, 14747–14752 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nature Genet. 39, 631–637 (2007).

    CAS  PubMed  Google Scholar 

  54. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

    CAS  PubMed  Google Scholar 

  55. Scott, L. J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

    CAS  PubMed  Google Scholar 

  57. Steinthorsdottir, V. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genet. 39, 770–775 (2007).

    CAS  PubMed  Google Scholar 

  58. Liu, P. Y. et al. A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases. J. Med. Genet. 42, 221–227 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Morris, R. W. & Kaplan, N. L. On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles. Genet. Epidemiol. 23, 221–233 (2002).

    PubMed  Google Scholar 

  60. Zhang, K., Calabrese, P., Nordborg, M. & Sun, F. Haplotype block structure and its applications to association studies: power and study designs. Am. J. Hum. Genet. 71, 1386–1394 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang, K. & Sun, F. Assessing the power of tag SNPs in the mapping of quantitative trait loci (QTL) with extremal and random samples. BMC Genet. 6, 51 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Drysdale, C. M. et al. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc. Natl Acad. Sci. USA 97, 10483–10488 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320–323 (2006).

    CAS  PubMed  Google Scholar 

  65. Yi, F., Brubaker, P. L. & Jin, T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by β-catenin and glycogen synthase kinase-3β. J. Biol. Chem. 280, 1457–1464 (2005).

    CAS  PubMed  Google Scholar 

  66. Pearson, E. R. et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 56, 2178–2182 (2007).

    CAS  PubMed  Google Scholar 

  67. Florez, J. C. et al. Haplotype structure and genotype–phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53, 1360–1368 (2004).

    CAS  PubMed  Google Scholar 

  68. Helgason, A. et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nature Genet. 39, 218–225 (2007).

    CAS  PubMed  Google Scholar 

  69. Weedon, M. N. et al. Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med. 3, e374 (2006).

    PubMed  PubMed Central  Google Scholar 

  70. Stephens, J. C. et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493 (2001).

    CAS  PubMed  Google Scholar 

  71. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724–726 (2007).

    CAS  PubMed  Google Scholar 

  73. Rich, S. S. et al. The Type 1 Diabetes Genetics Consortium. Ann. NY Acad. Sci. 1079, 1–8 (2006).

    CAS  PubMed  Google Scholar 

  74. Ahmad, T., Marshall, S. E. & Jewell, D. Genetics of inflammatory bowel disease: the role of the HLA complex. World J. Gastroenterol. 12, 3628–3635 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Orozco, G., Rueda, B. & Martin, J. Genetic basis of rheumatoid arthritis. Biomed. Pharmacother. 60, 656–662 (2006).

    CAS  PubMed  Google Scholar 

  76. Sia, C. & Weinem, M. The role of HLA class I gene variation in autoimmune diabetes. Rev. Diabet. Stud. 2, 97–109 (2005).

    PubMed  PubMed Central  Google Scholar 

  77. Criswell, L. A. et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–571 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nature Genet. 39, 977–983 (2007).

    CAS  PubMed  Google Scholar 

  79. Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nature Genet. 39, 645–649 (2007).

    CAS  PubMed  Google Scholar 

  80. Amundadottir, L. T. et al. A common variant associated with prostate cancer in European and African populations. Nature Genet. 38, 652–658 (2006).

    CAS  PubMed  Google Scholar 

  81. Haiman, C. A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nature Genet. 39, 638–644 (2007).

    CAS  PubMed  Google Scholar 

  82. Rodriguez, C. et al. Diabetes and risk of prostate cancer in a prospective cohort of US men. Am. J. Epidemiol. 161, 147–152 (2005).

    PubMed  Google Scholar 

  83. Knight, J. C. Regulatory polymorphisms underlying complex disease traits. J. Mol. Med. 83, 97–109 (2005).

    CAS  Google Scholar 

  84. Thomas, P. D. & Kejariwal, A. Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. Proc. Natl Acad. Sci. USA 101, 15398–15403 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Stacey, S. N. et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nature Genet. 39, 865–869 (2007).

    CAS  PubMed  Google Scholar 

  87. Papassotiropoulos, A. et al. Common Kibra alleles are associated with human memory performance. Science 314, 475–478 (2006).

    CAS  PubMed  Google Scholar 

  88. Rodriguez-Rodriguez, E. et al. Age-dependent association of KIBRA genetic variation and Alzheimer's disease risk. Neurobiol. Aging 16 Aug 2007 (doi:10.1016/j.neurobiolaging.2007.07.003).

    PubMed  Google Scholar 

  89. Schaper, K., Kolsch, H., Popp, J., Wagner, M. & Jessen, F. KIBRA gene variants are associated with episodic memory in healthy elderly. Neurobiol. Aging 10 Mar 2007 (doi:10.1016/j.neurobiolaging.2007.02.001).

    CAS  PubMed  Google Scholar 

  90. Coon, K. D. et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J. Clin. Psychiatry 68, 613–618 (2007).

    CAS  PubMed  Google Scholar 

  91. Baum, A. E. et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol. Psychiatry 8 May 2007 (doi:10.1038/sj.mp.4002012).

    PubMed  PubMed Central  Google Scholar 

  92. Moffatt, M. F. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007).

    CAS  PubMed  Google Scholar 

  93. Bierut, L. J. et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum. Mol. Genet. 16, 24–35 (2007).

    CAS  PubMed  Google Scholar 

  94. Gudbjartsson, D. F. et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448, 353–357 (2007).

    CAS  PubMed  Google Scholar 

  95. Aarnoudse, A. J. et al. Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study. Circulation 116, 10–16 (2007).

    PubMed  Google Scholar 

  96. Arking, D. E. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nature Genet. 38, 644–651 (2006).

    CAS  PubMed  Google Scholar 

  97. van Heel, D. A. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genet. 39, 827–829 (2007).

    CAS  PubMed  Google Scholar 

  98. Spinola, M. et al. Genome-wide single nucleotide polymorphism analysis of lung cancer risk detects the KLF6 gene. Cancer Lett. 251, 311–316 (2007).

    CAS  PubMed  Google Scholar 

  99. Olds, L. C. & Sibley, E. Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Hum. Mol. Genet. 12, 2333–2340 (2003).

    CAS  PubMed  Google Scholar 

  100. Stefansson, H. et al. A genetic risk factor for periodic limb movements in sleep. N. Engl. J. Med. 357, 639–647 (2007).

    CAS  PubMed  Google Scholar 

  101. Winkelmann, J. et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nature Genet. 39, 1000–1006 (2007).

    CAS  PubMed  Google Scholar 

  102. Altshuler, D. & Daly, M. Guilt beyond a reasonable doubt. Nature Genet. 39, 813–815 (2007).

    CAS  PubMed  Google Scholar 

  103. Hunter, D. J. & Kraft, P. Drinking from the fire hose — statistical issues in genomewide association studies. N. Engl. J. Med. 357, 436–439 (2007).

    CAS  PubMed  Google Scholar 

  104. Ahituv, N. et al. Medical sequencing at the extremes of human body mass. Am. J. Hum. Genet. 80, 779–791 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Cohen, J. C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004). An example of a phenotype that fits the common disorder: rare alleles hypothesis.

    CAS  PubMed  Google Scholar 

  106. Fanous, A. H. & Kendler, K. S. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol. Psychiatry 10, 6–13 (2005).

    CAS  PubMed  Google Scholar 

  107. McClellan, J. M., Susser, E. & King, M. C. Schizophrenia: a common disease caused by multiple rare alleles. Br. J. Psychiatry 190, 194–199 (2007).

    PubMed  Google Scholar 

  108. Pritchard, J. K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Pritchard, J. K. & Cox, N. J. The allelic architecture of human disease genes: common disease–common variant...or not? Hum. Mol. Genet. 11, 2417–2423 (2002).

    CAS  PubMed  Google Scholar 

  110. Kryukov, G. V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nature Genet. 39, 984–988 (2007).

    CAS  PubMed  Google Scholar 

  112. Zanke, B. W. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nature Genet. 39, 989–994 (2007).

    CAS  PubMed  Google Scholar 

  113. Haiman, C. A. et al. A common genetic risk factor for colorectal and prostate cancer. Nature Genet. 39, 954–956 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

A Deo lumen, ab amicis auxilium. This work was partially supported by National Institutes of Health grants N01A000,064 and U01AI066,569, and by National Science Foundation grant 0524,775. The authors thank the reviewers for their helpful suggestions.

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Authors and Affiliations

  1. National Center for Genome Resources, 2935 Rodeo Park Drive East, Santa Fe, 87505, New Mexico, USA

    Stephen F. Kingsmore, Ingrid E. Lindquist, Joann Mudge, Damian D. Gessler & William D. Beavis

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  1. Stephen F. Kingsmore
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Correspondence to Stephen F. Kingsmore.

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DATABASES

OMIM

age-related macular degeneration

acute myocardial infarction

Alzheimer's disease

anterior uveitis/ankylosing spondylitis

breast cancer

colorectal cancer

Crohn's disease

prostate cancer

restless leg syndrome

type 1 diabetes mellitus

type 2 diabetes mellitus

ulcerative colitis

FURTHER INFORMATION

Stephen Kingsmore's homepage

Glossary

Genetic linkage

Co-segregation (reduced recombination) of a trait and an allele in related subjects (pedigrees) more often than explicable by chance.

Dominant

An allele that confers a trait even when it is heterozygous (present as a single copy in a genome).

Recessive

An allele that confers a trait only when it is homozygous (present in two copies in a genome, one from each parent).

Endophenotype

A measurable component of a phenotype.

Multifactorial

Inheritance of a trait that is attributable to two or more genes and their interaction with the environment (also known as polygenic inheritance).

Allele

The DNA code at a given locus (position) on a chromosome.

Genome-wide association study

A comprehensive search of the human genome for genetic risk factors for a trait by a case-control association study involving comparisons of hundreds of thousands of alleles between unrelated subjects with and without a trait.

Haplotype

A combination of alleles at linked loci (on a single chromatid) that are transmitted together more often than explicable by chance.

Linkage disequilibrium

(LD). Combinations of alleles in a population that differ in frequency from that expected from random formation of haplotypes from alleles based on their frequencies.

Minor-allele frequency

The allele frequency of the less frequently occurring allele of a polymorphism.

Case–control association study

Comparison of the frequency of an allele between unrelated subjects with and without a trait. A difference in allele frequency between the two groups indicates that the allele might change the likelihood of the trait.

Genetic association

Correlation of a trait and an allele in a population more often than explicable by chance.

Genocopy

A genotype at a locus that produces a phenotype that is indistinguishable from that produced by a genotype at another locus.

Phenocopy

An environmentally produced phenotype that simulates the effect of a particular genotype.

Non-synonymous SNP

(nsSNP). A SNP that leads to a change in the amino-acid sequence of the gene's resulting protein and that might therefore affect its function.

Odds ratio

A measure of risk that compares the probability of occurrence of a disease in a group with a risk allele with the probability in a control group.

Pleiotropy

A single gene that influences multiple phenotypic traits.

Epistasis

Modification of the action of a gene by another gene.

Family-based association study

Evaluation of the frequency of co-transmission of an allele and a trait from parents to offspring. Co-transmission of an allele and trait to offspring more often than expected by chance indicates that the allele might change the likelihood of the trait.

Antagonistic pleiotropy

A single gene that influences multiple competing phenotypes such that beneficial effects of a trait created by the gene are offset by losses in other traits.

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Kingsmore, S., Lindquist, I., Mudge, J. et al. Genome-wide association studies: progress and potential for drug discovery and development. Nat Rev Drug Discov 7, 221–230 (2008). https://doi.org/10.1038/nrd2519

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