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Method Paper

Explore the Multiple QTL Model Identification Procedure and apply Clustering Methods to clinical trait data in islet Model Identification. Learn how to identify main effects, interactions, and enrichments in QTL Archive Studies.

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Method Paper

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  1. Method Paper

  2. Outline • Methods • Multiple QTL model identification procedure • Adjacency Measurement • Clustering Methods • QTL Archive Studies • Application to F2 data: clinical trait data + expression data in islet

  3. Model Identification Procedure • Apply a single QTL mapping method. Pick several markers with relatively high LOD scores from each chromosome as candidate marker effects. • Identify baseline model, the best model with main effects only using stepwise regression and BIC (or pLOD) criterion. Allowed main effects are those cadidate marker effects identified in Step 1 and other covariates such as sex. • Identify the best model allowing first order interactions using stepwise regression, and BIC (or pLOD) criterion, starting from the baseline model. Allowed interactions are between main effects in the baseline model and all candidate marker effects.

  4. QTL archive studies (25 traits in 12 studies)

  5. QTL Archive Studies (25 traits in 12 studies) 1: published method; 2: our method.

  6. QTL Archive Studies • GBV Malcolm A. Lyons et al. (2003) New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice. Physiological Genomics. 14: 225-239.

  7. QTL Archive Studies

  8. QTL Archive Studies • HDL Naoki Ishimori et al. (2004) Quantitative Trait Loci Analysis for Plasma HDL-Cholesterol Concentrations and Atherosclerosis Susceptibility Between Inbred Mouse Strains C57BL/6J and 129S1/SvImJ. Arterioscler. Thromb. Vasc. Biol. 24: 161-166.

  9. QTL Archive Studies Hdlq14: D1Mit159 Hdlq15: D1Mit406 Hdlq19: D2Mit285

  10. QTL Archive Studies • HDL: Malcolm A. Lyons et al. (2003) Quantitative trait loci that determine lipoprotein cholesterol levels in DBA/2J and CAST/Ei inbred mice. Journal of Lipid Research. 44: 953-967.

  11. QTL Archive Studies

  12. Insulin’s Weighted Model 1984 transcripts’ weighted models overlap with insulin’s weighted model

  13. Insulin’s Model Plots

  14. Weighted model vector: Weighted Model The rest of the vector are 0.

  15. Adjacency Measurement • Similarity between weighted models • Adjacency measurement

  16. Topological Overlap Matrix (TOM): defined as reflects the similarity with respect to relationships to all other nodes considered. When defined previously are used here, the relationship refers to co-regulation and co-expression. • TOM distance can be used as dissimilarity measurement in clustering. TOM Distance

  17. 1984 transcripts ordered by their adjacency with insulin decreasingly from top.

  18. 500 transcripts ordered by their adjacency with insulin decreasingly from top.

  19. 1984 transcripts clustered using 1-adjacency as distance

  20. Cluster Identification Using TOM Distance

  21. 1984 transcripts clustered using TOM distance

  22. Enrichment Test • Enrichment test for 1984 transcripts Polyunsaturated fatty acid biosynthesis Glutamate metabolism Regulation of autophagy Butanoate metabolism Methane metabolism Bile acid biosynthesis Fatty acid metabolism (p-value<0.05) • Enrichment test for modules e.g., transcripts in yellow module are enriched for Phosphatidylinositol signaling system Long-term depression N-Glycan biosynthesis Gap junction Inositol phosphate metabolism (p-value<0.01)

  23. Application Paper

  24. Adipose Paper 2: Result

  25. Paper 2: Result

  26. Paper 2: Result

  27. Insulin is red module

  28. Paper 2: Result • Enrichment tests on transcripts mapping to hot regions. • http://attie.wisc.edu/lab/tools/multiqtl_enrich.php • Enrichment tests on unique transcripts in each module. • Red module are enriched for Phosphatidylinositol signaling system Inositol phosphate metabolism Long-term depression N-Glycan biosynthesis (p-value<0.01) • Enrichment tests on transcripts in a specific tissue in each module.

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