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Accounting for linkage disequilibrium in genome-wide association studies: A penalized regression method.

ABSTRACT: Penalized regression methods are becoming increasingly popular in genome-wide association studies (GWAS) for identifying genetic markers associated with disease. However, standard penalized methods such as LASSO do not take into account the possible linkage disequilibrium between adjacent markers. We propose a novel penalized approach for GWAS using a dense set of single nucleotide polymorphisms (SNPs). The proposed method uses the minimax concave penalty (MCP) for marker selection and incorporates linkage disequilibrium (LD) information by penalizing the difference of the genetic effects at adjacent SNPs with high correlation. A coordinate descent algorithm is derived to implement the proposed method. This algorithm is efficient in dealing with a large number of SNPs. A multi-split method is used to calculate the p-values of the selected SNPs for assessing their significance. We refer to the proposed penalty function as the smoothed MCP and the proposed approach as the SMCP method. Performance of the proposed SMCP method and its comparison with LASSO and MCP approaches are evaluated through simulation studies, which demonstrate that the proposed method is more accurate in selecting associated SNPs. Its applicability to real data is illustrated using heterogeneous stock mice data and a rheumatoid arthritis.

SUBMITTER: Liu J

PROVIDER: S-EPMC4172344 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Accounting for linkage disequilibrium in genome-wide association studies: A penalized regression method.

Liu Jin J Wang Kai K Ma Shuangge S Huang Jian J

Statistics and its interface 20130101 1

Penalized regression methods are becoming increasingly popular in genome-wide association studies (GWAS) for identifying genetic markers associated with disease. However, standard penalized methods such as LASSO do not take into account the possible linkage disequilibrium between adjacent markers. We propose a novel penalized approach for GWAS using a dense set of single nucleotide polymorphisms (SNPs). The proposed method uses the minimax concave penalty (MCP) for marker selection and incorpora ...[more]

PMID: 25258655

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Project description:BackgroundGenome-wide association studies (GWASs) have been widely used to discover the genetic basis of complex phenotypes. However, standard single-SNP GWASs suffer from lack of power. In particular, they do not directly account for linkage disequilibrium, that is the dependences between SNPs (Single Nucleotide Polymorphisms).ResultsWe present the comparative study of two multilocus GWAS strategies, in the random forest-based framework. The first method, T-Trees, was designed by Botta and collaborators (Botta et al., PLoS ONE 9(4):e93379, 2014). We designed the other method, which is an innovative hybrid method combining T-Trees with the modeling of linkage disequilibrium. Linkage disequilibrium is modeled through a collection of tree-shaped Bayesian networks with latent variables, following our former works (Mourad et al., BMC Bioinformatics 12(1):16, 2011). We compared the two methods, both on simulated and real data. For dominant and additive genetic models, in either of the conditions simulated, the hybrid approach always slightly performs better than T-Trees. We assessed predictive powers through the standard ROC technique on 14 real datasets. For 10 of the 14 datasets analyzed, the already high predicted power observed for T-Trees (0.910-0.946) can still be increased by up to 0.030. We also assessed whether the distributions of SNPs' scores obtained from T-Trees and the hybrid approach differed. Finally, we thoroughly analyzed the intersections of top 100 SNPs output by any two or the three methods amongst T-Trees, the hybrid approach, and the single-SNP method.ConclusionsThe sophistication of T-Trees through finer linkage disequilibrium modeling is shown beneficial. The distributions of SNPs' scores generated by T-Trees and the hybrid approach are shown statistically different, which suggests complementary of the methods. In particular, for 12 of the 14 real datasets, the distribution tail of highest SNPs' scores shows larger values for the hybrid approach. Thus are pinpointed more interesting SNPs than by T-Trees, to be provided as a short list of prioritized SNPs, for a further analysis by biologists. Finally, among the 211 top 100 SNPs jointly detected by the single-SNP method, T-Trees and the hybrid approach over the 14 datasets, we identified 72 and 38 SNPs respectively present in the top25s and top10s for each method.

Dataset Information

Accounting for linkage disequilibrium in genome-wide association studies: A penalized regression method.

Publications

Accounting for linkage disequilibrium in genome-wide association studies: A penalized regression method.

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