The recent large genotyping studies have identified a new repertoire of disease susceptibility loci of unknown function, characterized by high allele frequencies and low relative risks, lending support to the common disease-common variant (CDCV) hypothesis. The variants explain a much larger proportion of the disease etiology, measured by the population attributable fraction, than of the familial risk. We show here that if the identified polymorphisms were markers of rarer functional alleles they would explain a much larger proportion of the familial risk. For example, in a plausible scenario where the marker is 10 times more common than the causative allele, the excess familial risk of the causative allele is over 10 times higher than that of the marker allele. However, the population attributable fractions of the two alleles are equal. The penetrance mode of the causative locus may be very difficult to deduce from the apparent penetrance mode of the marker locus.
References
[1]
Reich DE, Lander ES (2001) On the allelic spectrum of human disease. Trends Genet 17: 502–10.
[2]
Wang WY, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6: 109–18.
[3]
TheWellcomeTrustCaseControlConsortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661–83.
[4]
Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, et al. (2006) A common variant associated with prostate cancer in European and African populations. Nat Genet 38: 652–8.
[5]
Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, et al. (2007) Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39: 638–44.
[6]
Haiman CA, Le Marchand L, Yamamato J, Stram DO, Sheng X, Kolonel LN, et al. (2007) A common genetic risk factor for colorectal and prostate cancer. Nat Genet 39: 954–6.
[7]
Tomlinson I, Webb EL, Carvajal-Carmona L, Broderick J, Kemp Z, Span S, et al. (2007) A genome-wide association scan of tag SNPs identifies a susceptibility varaint for colorectal cancer at 8q24.21. Nat Genet 39: 984–8.
[8]
Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM, et al. (2007) Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39: 989–94.
[9]
Gudmundsson J, Sulem P, Rafnar T, Bergthorsson JT, Manolescu A, Gudbjartsson D, et al. (2008) Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer. Nat Genet 40: 281–3.
[10]
Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, et al. (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40: 310–5.
[11]
Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, et al. (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40: 316–21.
[12]
Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087–93.
[13]
Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, et al. (2007) Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39: 631–7.
[14]
Hemminki K, Lorenzo Bermejo J, F？rsti A (2006) The balance between heritable and environmental aetiology of human disease. Nature Reviews Genetics 7: 958–65.
[15]
Hemminki K, Forsti A, Lorenzo Bermejo J (2008) Surveying germline genomic landscape of breast cancer. Breast Cancer Res Treat e-publ.
[16]
Hemminki K, F？rsti A, Lorenzo Bermejo J (2008) Etiologic impact of known cancer susceptibility genes. Mut Res Rev 658: 42–54.
[17]
Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40: 17–22.
[18]
Hemminki K, Li X, Sundquist K, Sundquist J (2008) Familial risks for common diseases: Etiologic clues and guidance to gene identification. Mutat Res Rev e-pub.
[19]
Hemminki K, Lorenzo Bermejo J (2007) Constraints for genetic association studies imposed by attributable fraction and familial risk. Carcinogenesis 28: 648–56.
[20]
Chanock S, Hunter D (2008) When the smoke clears… Nature e-pub.
[21]
Xu S (2003) Theoretical basis of the Beavis effect. Genetics 165: 2259–68.
[22]
Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M (2005) Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat Rev Genet 6: 376–88.
[23]
Lewis CM, Whitwell SC, Forbes A, Sanderson J, Mathew CG, Marteau TM (2007) Estimating risks of common complex diseases across genetic and environmental factors: the example of Crohn disease. J Med Genet 44: 689–94.
[24]
Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP (2004) Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 99: 2393–404.
