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S-LDSC

I applied Stratified Linkage Disequilibrium Score Regression1 (S-LDSC) to summary statistics from Willer et al.'s GWAS of triglycerides2 to identify possible key tissue and cell types affecting triglyceride levels.

Reference Data Sources

I used the reference datasets recommended and preprocessed by the authors of the S-LSDC method1. These reference datasets are ultimately drawn from the following data sources:

Results

GTEx and Franke lab tissue expression data

I first applied S-LDSC to Willer et al.'s triglyceride GWAS using the Franke lab and GTEx datasets as a reference. This produced two hits, both in liver cells, which is consistent with the liver's known role as a hub of lipid metabolism. The results are shown below:

Results of application of S-LDSC to Willer et al.'s triglyceride GWAS using the Franke lab/ GTEx dataset. Points are colored according to broad tissue category. Large points correspond to cell/tissue types deemed significant by an application of the Benjamini-Hochberg procedure at an FDR of 0.01.

Roadmap Chromatin data

Next, I applied S-LDSC using the roadmap epigenetics dataset as a reference. This produced no hits.

ImmGen data

The next step is to use the S-LDSC reference data derived from the ImmGen project. There were no significant cell types with this dataset.

Corces ATAC-seq data

The next step is the use the Corces ATAC-seq data as a reference. Surprisingly, this produced a single strong hit in the monocyte cell type.

Name Coefficient Coefficient_P_value Reject Null
Mono 4.402e-07 3.48457e-05 True
MEP 4.63353e-08 0.241071 False
GMP 2.94016e-08 0.312954 False
CMP 2.42517e-08 0.3478 False
Erythro 4.58955e-08 0.351669 False
Bcell 1.96021e-08 0.379962 False
CLP 2.03106e-08 0.396499 False
MPP -1.89262e-08 0.617103 False
HSC -2.88261e-08 0.669921 False
NK -2.96967e-08 0.69354 False
LMPP -4.90885e-08 0.752546 False
CD4 -7.21404e-08 0.895904 False
CD8 -1.08379e-07 0.958275 False

The meaning of this hit is unclear. It could be a proxy for a transcriptional program that is actually causal in another cell type, or it could reflect the fact that monocytes are macrophage precursors, and macrophages consume lipids to become foam cells when lipid levels are high3.

Cahoy and GTEx-Brain data

The remaining two datasets pertain to the central nervous system. There are no significant cell types with either of these datasets. This is consistent with triglyceride levels being a largely non-neurological trait.

  1. Hilary K Finucane, Yakir A Reshef, Verneri Anttila, Kamil Slowikowski, Alexander Gusev, Andrea Byrnes, Steven Gazal, Po-Ru Loh, Caleb Lareau, Noam Shoresh, and others. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nature Genetics, 50(4):621–629, 2018. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5896795/. ↩↩

  2. Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nature Genetics, 45(11):1274–1283, 2013. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC3838666/. ↩

  3. Daniel Steinberg. The cholesterol wars: the skeptics vs the preponderance of evidence. Elsevier, 2011. URL: https://www.amazon.com/dp/B0085TMWZ4. ↩