the ‘common disease-common variant’ hypothesis and familial risksu201c常见的身上常见变异u201d假说和家族性风险.pdfVIP

The ‘Common Disease-Common Variant’ Hypothesis and Familial Risks 1,2 ¨ 1,2 1 Kari Hemminki *, Asta Forsti , Justo Lorenzo Bermejo 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, 2 Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden Abstract 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. ¨ Citation: Hemminki K, Forsti A, Bermejo JL (2008) The ‘Common Disease-Common Variant’ Hypothesis and Familial Risks. PLoS ONE 3(6): e2504. doi:10.1371/ journal.pone.0002504 Editor: A. Cecile J. W. Janssens, Erasmus University Medical Center, Netherlands Received January 30, 2008; Accepted May 16, 2008; Published June 18, 2008 Copyright: 2008 Hemminki et al. This is an open-access article distributed under th