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S-LDSC

Stratified Linkage Disequilibrium Score Regression (S-LDSC)1 was applied to summary statistics from Bellenguez et al.'s 2019 Meta-GWAS of Multisite Chronic Pain (MCP)2.

Reference Data Sources

This analysis used standard reference datasets recommended and preprocessed by the authors of the S-LDSC method:

Results

GTEx and Franke lab tissue expression data

Similarly to the GTEx MAGMA results, all of the significant tissues in the S-LDSC analysis were related to the brain. Here are the cell/tissue types which were significant after correction using FDR < 0.01:

s-ldsc_gene-expression

Name Coefficient Coefficient_P_value Reject Null
Brain_Putamen_(basal_ganglia) 4.34441e-09 3.82164e-06 True
Brain_Hippocampus 3.82353e-09 1.05092e-05 True
Brain_Anterior_cingulate_cortex_(BA24) 4.01219e-09 1.20613e-05 True
A08.186.211.464.Limbic.System 4.46162e-09 1.69685e-05 True
A08.186.211.Brain 4.63755e-09 2.05309e-05 True
A08.186.211.730.885.287.500.Cerebral.Cortex 4.40563e-09 2.35024e-05 True
Brain_Caudate_(basal_ganglia) 3.86268e-09 2.77883e-05 True
A08.186.211.464.710.225.Entorhinal.Cortex 4.31141e-09 3.79579e-05 True
Brain_Nucleus_accumbens_(basal_ganglia) 3.90441e-09 3.98038e-05 True
Brain_Substantia_nigra 3.64814e-09 7.10008e-05 True
A08.186.211.464.405.Hippocampus 4.02239e-09 9.10287e-05 True
A08.186.211.132.Brain.Stem 3.93812e-09 9.55746e-05 True
Brain_Cortex 3.33234e-09 0.000107207 True
Brain_Frontal_Cortex_(BA9) 3.37624e-09 0.000121439 True
Brain_Hypothalamus 3.49643e-09 0.000125905 True
A08.186.211.730.885.287.500.670.Parietal.Lobe 3.92277e-09 0.000169976 True
A08.186.211.730.885.287.500.571.735.Visual.Cortex 3.86084e-09 0.000205957 True
A09.371.729.Retina 3.80165e-09 0.000437482 True
Brain_Cerebellar_Hemisphere 3.2938e-09 0.000438075 True
Brain_Cerebellum 3.3889e-09 0.000656342 True

Roadmap chromatin data

Next, reference data generated by Finucane et al.1 from the Roadmap Epigenetics Project was used in S-LDSC.

In this analysis, almost all significant cell types were again related to the brain, though there were also significant cell types related to the thymus and pancreas. The results can be seen in the plot and table below.

s-ldsc_chromatin

Name Coefficient Coefficient_P_value Reject Null
Fetal_Brain_Male__DNase 1.43001e-07 2.73722e-14 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K27ac 6.61265e-08 2.54719e-12 True
Fetal_Brain_Female__DNase 1.47145e-07 2.80074e-12 True
Fetal_Brain_Male__H3K4me1 5.76271e-08 4.75756e-11 True
Fetal_Brain_Female__H3K4me3 2.05782e-07 8.23918e-11 True
Brain_Germinal_Matrix__H3K4me3 2.18197e-07 3.26595e-10 True
Fetal_Brain_Female__H3K4me1 8.26879e-08 1.78154e-09 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K9ac 1.36486e-07 3.0457e-09 True
Brain_Angular_Gyrus__H3K27ac 5.53797e-08 6.53728e-09 True
Brain_Inferior_Temporal_Lobe__H3K27ac 4.16002e-08 9.83202e-09 True
Brain_Cingulate_Gyrus__H3K9ac 1.05355e-07 1.33459e-08 True
Brain_Anterior_Caudate__H3K27ac 4.3185e-08 3.52913e-08 True
Brain_Germinal_Matrix__H3K4me1 9.23593e-08 4.07106e-08 True
Brain_Inferior_Temporal_Lobe__H3K4me3 1.45077e-07 4.87189e-08 True
Ganglion_Eminence_derived_primary_cultured_neurospheres__H3K4me3 1.55603e-07 5.02739e-08 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K4me1 6.95193e-08 5.60795e-08 True
Cortex_derived_primary_cultured_neurospheres__H3K4me3 1.8869e-07 3.12638e-07 True
Brain_Hippocampus_Middle__H3K4me3 1.02857e-07 3.66736e-07 True
Brain_Angular_Gyrus__H3K9ac 9.12812e-08 9.82823e-07 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K4me3 1.3679e-07 1.31053e-06 True
Brain_Cingulate_Gyrus__H3K4me3 1.35205e-07 1.49391e-06 True
Brain_Cingulate_Gyrus__H3K27ac 3.84211e-08 2.11232e-06 True
Brain_Anterior_Caudate__H3K4me1 4.59498e-08 2.50698e-06 True
Thymus__H3K36me3 6.10717e-08 4.4298e-06 True
Brain_Angular_Gyrus__H3K4me1 4.81968e-08 7.71062e-06 True
Brain_Angular_Gyrus__H3K4me3 1.30377e-07 1.11768e-05 True
Brain_Inferior_Temporal_Lobe__H3K9ac 6.47697e-08 1.46867e-05 True
Brain_Anterior_Caudate__H3K9ac 7.81552e-08 2.02698e-05 True
Brain_Anterior_Caudate__H3K4me3 1.0891e-07 3.78601e-05 True
Brain_Hippocampus_Middle__H3K27ac 2.76599e-08 4.79293e-05 True
Brain_Cingulate_Gyrus__H3K4me1 3.80237e-08 5.54432e-05 True
Brain_Hippocampus_Middle__H3K4me1 2.86062e-08 7.46838e-05 True
Brain_Inferior_Temporal_Lobe__H3K4me1 4.24281e-08 0.00014697 True
Brain_Substantia_Nigra__H3K4me3 9.29301e-08 0.000196596 True
Brain_Germinal_Matrix__H3K36me3 4.96089e-08 0.000445616 True
Ganglion_Eminence_derived_primary_cultured_neurospheres__H3K4me1 3.96413e-08 0.000473806 True
Pancreatic_Islets__H3K27ac 1.04942e-07 0.00051186 True
Fetal_Thymus__H3K36me3 1.97113e-08 0.000667859 True

ImmGen data

In the ImmGen dataset, there were no significant cell types. The following graph and table show the cell types with the lowest p values.

s-ldsc_immgen

Name Coefficient Coefficient_P_value Reject Null
T.DPsm.Th 2.63206e-09 0.0065909 False
T.8Eff.Sp.OT1.d15.LisOva 2.24374e-09 0.0173596 False
Tgd.vg2+24ahi.Th 2.24909e-09 0.0210461 False
T.8Eff.Sp.OT1.d8.VSVOva 1.94559e-09 0.0306731 False
T.DP69+.Th.v2 2.07881e-09 0.0313165 False

Corces et al. ATAC-seq data

There were no significant hematopoietic-related cell types in the Corces ATAC-seq dataset.

Name Coefficient Coefficient_P_value Reject Null
HSC 9.54732e-09 0.237687 False
GMP 7.81531e-09 0.273387 False
LMPP 7.72366e-09 0.306756 False
CMP 5.13328e-09 0.335868 False
Erythro 7.49673e-09 0.355135 False
MEP 3.51756e-09 0.394091 False
MPP 2.5947e-09 0.416588 False
Bcell -7.28211e-09 0.717223 False
Mono -1.5232e-08 0.775996 False
NK -1.02646e-08 0.791595 False
CLP -1.81887e-08 0.872501 False
CD4 -2.39266e-08 0.968438 False
CD8 -2.37645e-08 0.971765 False

Cahoy and GTEx-Brain data

There were no significant cell types when analyzing the neurological cell types in the Cahoy dataset using S-LDSC:

Name Coefficient Coefficient_P_value Reject Null
Neuron 2.57912e-09 0.0117611 False
Oligodendrocyte 8.92979e-10 0.217456 False
Astrocyte -8.78228e-10 0.816394 False

Similarly, there were no significant tissues when testing the GTEx brain tissues using S-LDSC:

Name Coefficient Coefficient_P_value Reject Null
Brain_Cortex 2.57871e-09 0.00388189 False
Brain_Anterior_cingulate_cortex_(BA24) 2.07682e-09 0.0103041 False
Brain_Cerebellum 2.05731e-09 0.0341111 False
Brain_Cerebellar_Hemisphere 1.69167e-09 0.0639314 False
Brain_Frontal_Cortex_(BA9) 1.15989e-09 0.0914603 False
Brain_Nucleus_accumbens_(basal_ganglia) 1.05259e-09 0.125348 False
Brain_Caudate_(basal_ganglia) 6.12944e-10 0.263903 False
Brain_Putamen_(basal_ganglia) 1.48494e-10 0.440862 False
Brain_Amygdala -5.54761e-10 0.722775 False
Brain_Hippocampus -1.10526e-09 0.887114 False
Brain_Hypothalamus -1.22832e-09 0.904589 False
Brain_Spinal_cord_(cervical_c-1) -1.70661e-09 0.97087 False
Brain_Substantia_nigra -2.03971e-09 0.986552 False

In this S-LDSC analysis, tissue gene sets were defined as those genes specifically expressed in a tissue relative to other tissues. Thus, a dataset restricted to only brain tissues will exclude general brain genes which are highly expressed in multiple brain tissues. If these general genes are truly causal, excluding them can reduce the ability for S-LDSC to detect true effects. This likely explains why there were no brain tissues significant in this analysis, while several brain tissues were significant in the GTEx MAGMA analysis which instead controlled for average expression across all GTEx body tissues.

  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. Keira JA Johnston, Mark J Adams, Barbara I Nicholl, Joey Ward, Rona J Strawbridge, Amy Ferguson, Andrew M McIntosh, Mark ES Bailey, and Daniel J Smith. Genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genetics, 15(6):e1008164, 2019. URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008164. ↩