Although genome-wide association studies （GWAS） have successfully identified thousands of genomic loci associated with hun- dreds of complex traits in the past decade, the debate about such problems as missing herit...Although genome-wide association studies （GWAS） have successfully identified thousands of genomic loci associated with hun- dreds of complex traits in the past decade, the debate about such problems as missing heritabiUty and weak interpretability has been appealing for effective computational methods to facilitate the advanced analysis of the vast volume of existing and antici- pated genetic data. Towards this goal, gene-tevel integrative GWAS analysis with the assumption that genes associated with a phenotype tend to be enriched in biological gene sets or gene networks has recently attracted much attention, due to such advan- tages as straightforward interpretation, tess multiple testing burdens, and robustness across studies. However, existing methods in this category usually exploit non-tissue-specific gene networks and thus lack the ability to utilize informative tissue-specific characteristics. To overcome this limitation, we proposed a Bayesian approach called SIGNET （Simultaneously Inference of GeNEs and Tissues） to integrate GWAS data and multiple tissue-specific gene networks for the simultaneous inference of phenotype- associated genes and relevant tissues. Through extensive simulation studies, we showed the effectiveness of our method in find- ing both associated genes and relevant tissues for a phenotype. In applications to real GWAS data of 14 complex phenotypes, we demonstrated the power of our method in both deciphering genetic basis and discovering biological insights of a phenotype. With this understanding, we expect to see SIGNET as a valuable tool for integrative GWAS analysis, thereby boosting the preven- tion, diagnosis, and treatment of human inherited diseases and eventually facilitating precision medicine.展开更多
文摘Although genome-wide association studies （GWAS） have successfully identified thousands of genomic loci associated with hun- dreds of complex traits in the past decade, the debate about such problems as missing heritabiUty and weak interpretability has been appealing for effective computational methods to facilitate the advanced analysis of the vast volume of existing and antici- pated genetic data. Towards this goal, gene-tevel integrative GWAS analysis with the assumption that genes associated with a phenotype tend to be enriched in biological gene sets or gene networks has recently attracted much attention, due to such advan- tages as straightforward interpretation, tess multiple testing burdens, and robustness across studies. However, existing methods in this category usually exploit non-tissue-specific gene networks and thus lack the ability to utilize informative tissue-specific characteristics. To overcome this limitation, we proposed a Bayesian approach called SIGNET （Simultaneously Inference of GeNEs and Tissues） to integrate GWAS data and multiple tissue-specific gene networks for the simultaneous inference of phenotype- associated genes and relevant tissues. Through extensive simulation studies, we showed the effectiveness of our method in find- ing both associated genes and relevant tissues for a phenotype. In applications to real GWAS data of 14 complex phenotypes, we demonstrated the power of our method in both deciphering genetic basis and discovering biological insights of a phenotype. With this understanding, we expect to see SIGNET as a valuable tool for integrative GWAS analysis, thereby boosting the preven- tion, diagnosis, and treatment of human inherited diseases and eventually facilitating precision medicine.
