Biostatistics Advance Access published online on October 12, 2009
Biostatistics, doi:10.1093/biostatistics/kxp043
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A hidden Markov random field model for genome-wide association studies
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA hongzhe{at}upenn.edu
Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USA
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
* To whom correspondence should be addressed.
Genome-wide association studies (GWAS) are increasingly utilized for identifying novel susceptible genetic variants for complex traits, but there is little consensus on analysis methods for such data. Most commonly used methods include single single nucleotide polymorphism (SNP) analysis or haplotype analysis with Bonferroni correction for multiple comparisons. Since the SNPs in typical GWAS are often in linkage disequilibrium (LD), at least locally, Bonferroni correction of multiple comparisons often leads to conservative error control and therefore lower statistical power. In this paper, we propose a hidden Markov random field model (HMRF) for GWAS analysis based on a weighted LD graph built from the prior LD information among the SNPs and an efficient iterative conditional mode algorithm for estimating the model parameters. This model effectively utilizes the LD information in calculating the posterior probability that an SNP is associated with the disease. These posterior probabilities can then be used to define a false discovery controlling procedure in order to select the disease-associated SNPs. Simulation studies demonstrated the potential gain in power over single SNP analysis. The proposed method is especially effective in identifying SNPs with borderline significance at the single-marker level that nonetheless are in high LD with significant SNPs. In addition, by simultaneously considering the SNPs in LD, the proposed method can also help to reduce the number of false identifications of disease-associated SNPs. We demonstrate the application of the proposed HMRF model using data from a case–control GWAS of neuroblastoma and identify 1 new SNP that is potentially associated with neuroblastoma.
Keywords: Empirical Bayes; False discovery; Iterative conditional model; Linkage disequilibrium
Received December 10, 2008; revised June 29, 2009; accepted for publication September 15, 2009.