Carcinogenesis Advance Access published online on September 28, 2006
Carcinogenesis, doi:10.1093/carcin/bgl182
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1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany; Center for Family Medicine, Karolinska Institute, 141 83 Huddinge, Sweden
* To whom correspondence should be addressed. Candidate gene studies have become very popular but some of their implicit constraints, such as the familial risk and the population attributable fraction (PAF) conferred by the gene under study, are poorly understood. We model here these parameters for susceptibility genes in terms of genotype relative risk (GRR), allele frequency and statistical power in simulated genetic association studies, assuming 500 or 2000 case-control pairs and different modes of inheritance. The results show that the common association studies on genes with minor allele frequency higher than 10% have sufficient power to detect disease-causing variants conferring PAFs higher than 10%, which can be compared to known genes, such as BRCA1 with a PAF of 1.8%. Yet, common low-risk variants confer low familial risks, typically less than 1.1. The models show that candidate gene studies may be able to identify genes conferring close to 100% of the PAF, but they may not explain the empirical familial risks. In order to explain familial risks, rare, high-penetrant genes or interacting combinations of common variants need to be uncovered. However, the candidate gene studies for common alleles do not target this class of genes. The results may challenge the common disease-common variant hypothesis, which posits common variants with low GRRs and large PAFs, however failing to accommodate the empirical familial risks.
Received July 26, 2006
Revised September 13, 2006
Accepted September 15, 2006
CANCER PREVENTION
Constraints for genetic association studies imposed by attributable fraction and familial risk
Kari Hemminki 1 * and Justo Lorenzo Bermejo 2
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
Kari Hemminki, E-mail: k.hemminki{at}dkfz.de
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