Chen, Y. C., Carter, H., Parla, J., Kramer, M., Goes, F. S., Pirooznia, M., Zandi, P. P., McCombie, W. R., Potash, J. B., Karchin, R. (January 2013) A Hybrid Likelihood Model for Sequence-Based Disease Association Studies. PLoS Genetics, 9 (1). ISSN 15537390 (ISSN)
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Abstract
In the past few years, case-control studies of common diseases have shifted their focus from single genes to whole exomes. New sequencing technologies now routinely detect hundreds of thousands of sequence variants in a single study, many of which are rare or even novel. The limitation of classical single-marker association analysis for rare variants has been a challenge in such studies. A new generation of statistical methods for case-control association studies has been developed to meet this challenge. A common approach to association analysis of rare variants is the burden-style collapsing methods to combine rare variant data within individuals across or within genes. Here, we propose a new hybrid likelihood model that combines a burden test with a test of the position distribution of variants. In extensive simulations and on empirical data from the Dallas Heart Study, the new model demonstrates consistently good power, in particular when applied to a gene set (e.g., multiple candidate genes with shared biological function or pathway), when rare variants cluster in key functional regions of a gene, and when protective variants are present. When applied to data from an ongoing sequencing study of bipolar disorder (191 cases, 107 controls), the model identifies seven gene sets with nominal p-values<0.05, of which one MAPK signaling pathway (KEGG) reaches trend-level significance after correcting for multiple testing. © 2013 Chen et al.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > mental disorders > impulse control disorders diseases & disorders > mental disorders diseases & disorders > mental disorders > mood disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants |
| CSHL Authors: | |
| Communities: | CSHL labs > McCombie lab CSHL Post Doctoral Fellows |
| Depositing User: | Matt Covey |
| Date: | January 2013 |
| Date Deposited: | 29 Mar 2013 19:34 |
| Last Modified: | 19 Jul 2021 13:31 |
| PMCID: | PMC3554549 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/28049 |
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