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S-LDSC Asthma Analysis

I applied Stratified Linkage Disequilibrium Score Regression (S-LDSC) to summary statistics from Han et al.'s meta-GWAS of asthma1.

Reference Data Sources

I used the standard reference datasets recommended and preprocessed by the authors of the S-LDSC method.

Results

GTEx and Franke lab tissue expression data

The results are plotted below

s-ldsc-asthma-expression

The table below shows the tissue/cell types with the lowest p values.

Name Coefficient Coefficient_P_value Reject Null
A11.118.637.555.567.569.T.Lymphocytes 1.7136e-08 1.79629e-06 True
A15.145.229.637.555.567.569.200.CD4.Positive.T.Lymphocytes 1.09652e-08 3.90918e-05 True
A15.382.520.604.700.Spleen 1.19426e-08 0.00010796 True
A02.835.583.443.800.800.Synovial.Fluid 1.28336e-08 0.000122159 True
A15.145.229.Blood.Cells 1.17864e-08 0.000122277 True
A15.382.490.555.567.Lymphocytes 1.21767e-08 0.000125171 True
A11.118.637.555.567.569.200.700.T.Lymphocytes..Regulatory 1.01439e-08 0.000130168 True
A15.382.490.555.567.537.Killer.Cells..Natural 1.1958e-08 0.000343613 True
A15.145.Blood 1.10734e-08 0.000367411 True
Spleen 7.89811e-09 0.000682061 False
A10.549.Lymphoid.Tissue 1.19797e-08 0.000759795 False
A15.145.229.637.555.Leukocytes..Mononuclear 1.02734e-08 0.000826575 False
A15.382.490.555.567.622.Lymphocytes..Null 9.92795e-09 0.000963336 False
A11.118.637.Leukocytes 8.50474e-09 0.00106547 False
A10.549.400.Lymph.Nodes 9.3136e-09 0.00116527 False
A03.556.249.124.Ileum 1.06525e-08 0.00264645 False
A03.556.124.684.Intestine..Small 9.03662e-09 0.00267725 False
A15.378.316.580.Monocytes 6.43006e-09 0.00493671 False
A02.165.Cartilage 5.82729e-09 0.0057413 False
Esophagus_Muscularis 5.82619e-09 0.00759493 False
Whole_Blood 7.87232e-09 0.00966815 False

These results are consistent with the well-known immunological nature of asthma

Roadmap Chromatin data

I next applied S-LDSC to the asthma GWAS using reference data generated by Finucane et al.2 from the Roadmap Epigenetics Project.

The following graph and table show the results:

s-lsdc-chromatin-asthma

Name Coefficient Coefficient_P_value Reject Null
Primary_T_helper_17_cells_PMA-I_stimulated__H3K4me1 2.28473e-07 1.25164e-09 True
Primary_T_regulatory_cells_from_peripheral_blood__H3K4me1 1.65076e-07 1.77049e-09 True
Primary_T_helper_memory_cells_from_peripheral_blood_2__H3K4me1 1.52561e-07 9.40009e-08 True
Primary_T_helper_memory_cells_from_peripheral_blood_1__H3K4me1 1.78205e-07 1.5018e-07 True
Primary_T_helper_cells_from_peripheral_blood__H3K4me1 1.3524e-07 3.70906e-07 True
Primary_T_helper_cells_PMA-I_stimulated__H3K4me1 1.22911e-07 4.08701e-07 True
Primary_T_helper_17_cells_PMA-I_stimulated__H3K27ac 3.57399e-07 5.40299e-07 True
Spleen_ENTEX__H3K27ac 5.85499e-08 6.29279e-07 True
Primary_T_cells_effector_memory_enriched_from_peripheral_blood__H3K4me1 2.19465e-07 9.80666e-07 True
Primary_T_cells_from_peripheral_blood__H3K4me1 1.10633e-07 1.12969e-06 True
Primary_Natural_Killer_cells_from_peripheral_blood__DNase 2.87209e-07 1.27231e-06 True
Primary_T_helper_cells_PMA-I_stimulated__H3K27ac 1.62782e-07 1.43172e-06 True
Primary_T_cells_from_peripheral_blood__DNase 2.63651e-07 6.12566e-06 True
Primary_T_killer_memory_cells_from_peripheral_blood__H3K4me1 1.4703e-07 7.76036e-06 True
Primary_T_cells_from_peripheral_blood__H3K27ac 1.85166e-07 9.91999e-06 True
Primary_T_helper_17_cells_PMA-I_stimulated__H3K4me3 5.72705e-07 1.51429e-05 True
Primary_mononuclear_cells_from_peripheral_blood__H3K9ac 2.56674e-07 1.84474e-05 True
Primary_T_helper_naive_cells_from_peripheral_blood_1__H3K4me1 1.42012e-07 2.66904e-05 True
Primary_T_cells_from_cord_blood__DNase 2.76964e-07 4.84287e-05 True
Primary_T_regulatory_cells_from_peripheral_blood__H3K27ac 1.41208e-07 6.79159e-05 True
Primary_T_helper_cells_PMA-I_stimulated__H3K4me3 3.0952e-07 0.000146238 True
Primary_T_helper_memory_cells_from_peripheral_blood_1__H3K4me3 3.30703e-07 0.000190911 True
Primary_T_helper_memory_cells_from_peripheral_blood_1__H3K27ac 2.38795e-07 0.000191918 True
Primary_T_killer_naive_cells_from_peripheral_blood__H3K4me1 1.03862e-07 0.000234462 True
Colonic_Mucosa__H3K9ac 1.69975e-07 0.000258698 True
Primary_T_helper_17_cells_PMA-I_stimulated__H3K36me3 1.21335e-07 0.000361052 True
Primary_T_regulatory_cells_from_peripheral_blood__H3K4me3 2.56492e-07 0.000408582 True
Spleen_ENTEX__H3K36me3 2.85012e-08 0.000628698 False
Primary_Natural_Killer_cells_from_peripheral_blood__H3K4me1 1.02027e-07 0.000703613 False
Spleen_ENTEX__H3K4me1 1.71395e-07 0.00092961 False
Primary_T_cells_effector_memory_enriched_from_peripheral_blood__H3K27ac 2.5195e-07 0.00113583 False
Primary_T_helper_memory_cells_from_peripheral_blood_2__H3K4me3 2.28469e-07 0.00130371 False
Primary_T_helper_naive_cells_from_peripheral_blood__H3K9ac 3.11764e-07 0.00133795 False
Primary_Natural_Killer_cells_from_peripheral_blood__H3K27ac 1.54913e-07 0.00141558 False
Primary_T_helper_cells_PMA-I_stimulated__H3K36me3 7.10304e-08 0.00173045 False

Again the focus on immunological cell and tissue types is consistent with known biology.

The single significant intestinal cell type is of unclear importance. It may be noise and/or artifact, or it may reflect the presence of immune cells in the gut wall.

It is also interesting to observe that in both the GTEx and Roadmap analysis, T cells were the most significant, also consistent with known biology.

ImmGen data

I next applied S-LDSC to the asthma GWAS using ImmGen data as a reference.

The results are given in the plot and table below:

s-lsdc-asthma-immgen

Name Coefficient Coefficient_P_value Reject Null
T.4Mem.Sp 1.75441e-08 2.27642e-07 True
NKT.4+.Lv 1.45005e-08 5.31667e-07 True
NKT.4-.Sp 1.61158e-08 1.19597e-06 True
T.4Mem44h62l.Sp 1.51641e-08 1.68921e-06 True
LN.TR.14w.B6 1.4607e-08 3.05104e-06 True
ABD.TR.14w.B6 1.61976e-08 4.36389e-06 True
NKT.4-.Lv 1.31215e-08 6.96657e-06 True
T.4Mem44h62l.LN 1.37984e-08 1.28985e-05 True
CD4Control 1.36494e-08 5.34825e-05 True
T.4FP3+25+.Sp 1.10745e-08 0.00012789 True
T.8Eff.Sp.OT1.d10.LisOva 1.07401e-08 0.000175188 True
Tgd.vg2-.Sp 9.08137e-09 0.000236126 True
T.8Eff.Sp.OT1.d8.VSVOva 1.08524e-08 0.000238524 True
NKT.44+NK1.1+.Th 1.09896e-08 0.00030989 True
Tgd.vg2-.act.Sp 8.33486e-09 0.000323691 True
Tgd.vg2+.Sp 1.07736e-08 0.000392383 True
NKT.4+.Sp 1.1554e-08 0.000465112 True
NK.b2m-.Sp 8.96422e-09 0.000602208 True
T.4.Pa.BDC 1.00297e-08 0.000664139 False
T.4Mem.LN 9.51501e-09 0.00070779 False
T.8Eff.Sp.OT1.d8.LisOva 9.7501e-09 0.000785852 False
T.4SP69+.Th 1.01601e-08 0.000789917 False
Tgd.vg2+24alo.Th 1.27289e-08 0.000825648 False
Tgd.vg2-.Sp.TCRbko 8.78036e-09 0.000952023 False
Tgd.vg2+24ahi.Th 1.09829e-08 0.00101376 False
T.8Mem.Sp.OT1.d45.LisOva 1.01302e-08 0.00112147 False

Here, all significant cell types are either T cell or natural killer cells. The significance of natural killer cells may reflect their real role in asthma, or their strong transcriptomic overlap with T cells3, or both.

Corces et al. ATAC-seq data

Next, I applied S-LDSC using the Corces blood-cell ATAC-seq data as a reference.

Name Coefficient Coefficient_P_value Reject Null
CD4 2.0966e-07 3.20707e-05 True
CD8 1.78171e-07 8.74402e-05 True
NK 1.52311e-07 0.0025469 False
Bcell 4.71654e-08 0.0924839 False
HSC 2.82408e-08 0.137143 False
MPP 2.86087e-08 0.137208 False
LMPP 1.76042e-08 0.314867 False
Mono 2.26418e-08 0.334303 False
CLP 1.45358e-08 0.345982 False
MEP 7.94853e-09 0.350748 False
GMP 8.7878e-09 0.373874 False
CMP 2.81872e-09 0.455809 False
Erythro -8.14228e-08 0.931757 False

Yet again, we see strong significance of T-cell types.

Cahoy and GTEx-Brain data

Consistent with a disease that is not primarily neurological, there were not significant cell types in the Cahoy or GTEx-brain datasets.

Name Coefficient Coefficient_P_value Reject Null
Astrocyte 2.68341e-09 0.134337 False
Neuron -7.26051e-11 0.51659 False
Oligodendrocyte -3.19043e-09 0.905963 False
Name Coefficient Coefficient_P_value Reject Null
Brain_Cerebellum 7.49537e-09 0.00285985 False
Brain_Cerebellar_Hemisphere 2.88573e-09 0.0952969 False
Brain_Spinal_cord_(cervical_c-1) 7.39534e-10 0.336336 False
Brain_Cortex 5.27257e-10 0.373407 False
Brain_Amygdala 1.55599e-10 0.469241 False
Brain_Frontal_Cortex_(BA9) -4.11044e-10 0.622353 False
Brain_Nucleus_accumbens_(basal_ganglia) -8.97294e-10 0.716098 False
Brain_Anterior_cingulate_cortex_(BA24) -1.45618e-09 0.853186 False
Brain_Putamen_(basal_ganglia) -2.16576e-09 0.885143 False
Brain_Caudate_(basal_ganglia) -1.98446e-09 0.910509 False
Brain_Hippocampus -2.43085e-09 0.921089 False
Brain_Hypothalamus -2.56127e-09 0.928584 False
Brain_Substantia_nigra -3.06368e-09 0.974794 False

  1. Yi Han, Qiong Jia, Pedram Shafiei Jahani, Benjamin P Hurrell, Calvin Pan, Pin Huang, Janet Gukasyan, Nicholas C Woodward, Eleazar Eskin, Frank D Gilliland, and others. Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma. Nature Communications, 11(1):1776, 2020. URL: https://www.nature.com/articles/s41467-020-15649-3. ↩

  2. 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/. ↩

  3. Stephanie Vargas Aguilar, Oscar Aguilar, Rhys Allan, El Ad David Amir, Veronique Angeli, Maxim N Artyomov, Natasha Asinovski, Jilian Astarita, K Frank Austen, Geetika Bajpai, and others. ImmGen at 15. Nature Immunology, 21(7):700–703, 2020. URL: https://escholarship.org/content/qt75r8v4bt/qt75r8v4bt.pdf. ↩