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Jan 05

1. trans-eQTL and complex disease in eQTLGen, Võsa, Franke et al

Question: are there any trans-eQTLs that are GWAS hits?

Observations from the paper:

  • Meta-analysis using up to 31,684 blood samples from 37 eQTLGen Consortium cohorts.

  • For trans, they focused on 10,317 trait-associated SNPs.

The paper linked trans-eQTLs with traits in two ways to find the potential driver genes for traits.

  1. trans-eQTL analysis
  • One-third of trait-associated variants have distal effects.

    Identified 59,786 trans-eQTL, representing 3,853 SNPs (37% of tested GWAS SNPs) and 6,298 genes (32% of tested genes).

    The largest previous trans-eQTL meta-analysis in blood (N = 5,311) identified trans-eQTL for 8% of tested SNPs.

  • Identify genes that are coordinately affected by multiple independent trait-associated SNPs.

    Identified 47 GWAS traits for which at least four independent variants affected the same gene in trans (Supplementary Tables 10). Examples genes affected by at least three SLE-associated genetic variants.

But, Individual trans-eQTL effects too weak to detect. Another way to look for the potential driver genes for traits and the “core” genes:

  1. eQTSs (associations between PGSs and gene expression, Fig. 6a, 6b)
  • Individual trait-associated SNPs are combined into a PGS that is associated with gene expression.

  • when the PGS for a trait correlates with the expression of a gene, trans-eQTL effects of individual risk variants converge on that gene, and it can be prioritized as a putative driver of the disease.

  • 1,263 traits in total. 18,210 eQTSs representing 689 unique traits (55% of tested traits) and 2,568 genes (13% of tested genes).

  • Of these genes, 719 (28%) were not identified in the trans-eQTL analysis.

Therefore, all 3,853 trans-eQTLs eQTLGen identified are GWAS hits.

Question: if so, can we replicate them?

Among 10,317 trait-associated SNPs, 9,056 (~89%) are included in DGN SNPs. Among 3,853 eQTLGen trans- eQTLs, 27 (~0.7%) are replicated in DGN signals (1,863, \(p<1e-8\)).

In the paper, another trans- study was mentioned,

The largest previous trans-eQTL meta-analysis in blood (N = 5,311) identified trans-eQTL for 8% of tested SNPs.

2. gene SENP7

the cross mappability of SENP7 and the genes in the trans modules

As noted in earlier section, we observed,

  • SENP7 is the neasrest gene of the lead SNPs of coloc regions.
  • Gene ZNF90P1 is located within SENP7.
  • Modules 25, 51, 153, 156 have coloc regions with immune traits and consist of many zinc finger genes.

Therefore, we wanted to know,

  1. Does gene ZNF90P1 have expression data?

I looked at the expression matrix of 13634 genes. ZNF90P1 doesn’t have expression data in this matrix.

  1. What is the cross mappability between SENP7 and the zinc finger genes in the modules?

See files for the cross mappability for module 25, module 51, module 153, module 156.

The columns include: “score” for cross mappability score, “score_map1” for mappability score of gene1, “score_map2” for mappability score of gene2.

  1. For the genes in the trans modules,

See a previous file here.

highlighting SENP7 as a trans-meQTL

https://www-nature-com.proxy.uchicago.edu/articles/s41588-021-00969-x Another paper highlighting SENP7 as a trans-meQTL.

3. pQTL resource


R version 4.1.0 (2021-05-18)
Platform: x86_64-apple-darwin17.0 (64-bit)
Running under: macOS Catalina 10.15.7

Matrix products: default
BLAS:   /Library/Frameworks/R.framework/Versions/4.1/Resources/lib/libRblas.dylib
LAPACK: /Library/Frameworks/R.framework/Versions/4.1/Resources/lib/libRlapack.dylib

locale:
[1] en_US.UTF-8/en_US.UTF-8/en_US.UTF-8/C/en_US.UTF-8/en_US.UTF-8

attached base packages:
[1] stats     graphics  grDevices utils     datasets  methods   base     

other attached packages:
[1] workflowr_1.6.2

loaded via a namespace (and not attached):
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[13] git2r_0.28.0     jquerylib_0.1.4  htmltools_0.5.2  ellipsis_0.3.2  
[17] rprojroot_2.0.2  yaml_2.2.1       digest_0.6.29    tibble_3.1.6    
[21] lifecycle_1.0.1  crayon_1.4.2     later_1.3.0      sass_0.4.0      
[25] vctrs_0.3.8      promises_1.2.0.1 fs_1.5.2         glue_1.6.0      
[29] evaluate_0.14    rmarkdown_2.10   stringi_1.7.6    bslib_0.3.1     
[33] compiler_4.1.0   pillar_1.6.4     jsonlite_1.7.2   httpuv_1.6.4    
[37] pkgconfig_2.0.3