title: Polygenic modeling of genome-wide association studies: an application to prostate and breast cancer.
abstract: Genome-wide association studies (GWAS) have successfully detected and replicated associations with numerous diseases, including cancers of the prostate and breast. These findings are helping clarify the genomic basis of such diseases, but appear to explain little of disease heritability. This limitation might reflect the focus of conventional GWAS on a small set of the most statistically significant associations with disease. More information might be obtained by analyzing GWAS using a polygenic model, which allows for the possibility that thousands of genetic variants could impact disease. Furthermore, there may exist common polygenic effects between potentially related phenotypes (e.g., prostate and breast cancer). Here we present and apply a polygenic model to GWAS of prostate and breast cancer. Our results indicate that the polygenic model can explain an increasing--albeit low--amount of heritability for both of these cancers, even when excluding the most statistically significant associations. In addition, nonaggressive prostate cancer and breast cancer appear to share a common polygenic model, potentially reflecting a similar underlying biology. This supports the further development and application of polygenic models to genomic data.
authors.affiliation: Institute for Human Genetics, Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, California, USA. jwitte@ucsf.edu
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hoffmann
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics*; D003198:Computer Simulation; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*