Heritability Analysis of individual-level pathway scores in GTEx samples Pubblico
Dai, Anqi (Spring 2021)
Abstract
Background: QTL analysis plays an important role in exploring the functional impact of genetic variants, and further providing opportunities to understand complex diseases. Most QTL analyses are conducted one feature at a time due to computational cost and the need for controlling false positives, which omits the pleiotropic effect. Studies based on the aggregation of genetic variants, especially the pathway-based method can provide a more stable and effective way for assessing the biological impact of genetic variants. To ensure the feasibility of pathway-based QTL, heritability analysis for individual-level pathway expression scores is needed.
Method: After obtaining pathway expression scores from gene expression data using four methods, namely GSVA, Z-score, PLAGE, and ssGSEA, we used mixed model analysis to quantify the heritability of individual-level pathway scores for 186 KEGG Pathways, 196 PID Pathways, and 289 BIOCARTA Pathways across 49 tissues in the GTEx data via GCTA software. Based on the estimated heritability, analyses of value and significance of the heritability of pathway scores across tissues or pathways were conducted. A list of pathway/tissue combinations with the highest heritability was also identified.
Results: We found that in most tissues or pathways, regardless of scoring algorithms and pathway types, the genetic relationship matrix contributed significantly to explain the differences in individual-level pathway scores in at least one pair of tissue/pathway, and Whole Blood had the greatest number of pathways with significant heritability. Heritability estimates for different score methods were consistent with each other. We identified that KEGG Leishmania Infection, PID Aurora-A Pathway, and BIOCARTA CSK Pathway have the highest mean heritability. Brain Amygdala, Brain Spinal cord cervical c-1, Brain Frontal Cortex BA9, Small Intestine Terminal Ileum, and Whole Blood have higher mean heritability of GSVA scores, and this finding was consistent among three different types of pathways.
Conclusion: This heritability analysis strongly proved that the individual-level pathway expression scores are heritable. The findings from this study also provided a theoretical basis for future studies using pathway expression and QTL analysis based on pathway level.
Table of Contents
1. Introduction ..................................................................................................................... 1
2. Method ............................................................................................................................ 3
2.1 Genetic and transcriptomic data....................................................................................... 3
2.2 Calculation of pathway scores .......................................................................................... 3
2.3 Heritability of individual-level pathway scores .................................................................. 4
3. Results ............................................................................................................................. 5
3.1 Heritability Analysis for KEGG Pathways ........................................................................... 5
3.1.1 Correlation among different pathway score methods ....................................................... 6
3.1.2 Relationship between heritability and sample size .......................................................... 8
3.1.3 Summary of heritability across tissues ........................................................................... 9
3.1.4 Summary of heritability across KEGG pathways ............................................................. 11
3.1.5 Summary of heritability for KEGG pathway/tissue combination....................................... 12
3.2 Heritability Analysis for PID Pathways and BIOCARTA Pathways ....................................... 14
3.2.1 Relationship between heritability and sample size ......................................................... 15
3.2.2 Summary of heritability across tissues .......................................................................... 17
3.2.3 Summary of heritability across pathways ...................................................................... 20
3.2.4 Summary of heritability for pathway/tissue combination ............................................... 23
4. Discussion ..................................................................................................................... 26
Reference .......................................................................................................................... 28
Appendix ........................................................................................................................... 29
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