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S-LDSC Analysis

I applied Stratified Linkage Disequilibrium Score Regression (S-LDSC)1 to summary statistics from Xue et al.'s GWAS of whole brainstem volume2

Reference Data Sources

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

GTEx and Franke lab tissue expression data

Surprisingly, no cell types were significant using this reference dataset under a false discovery rate of 0.01.

Roadmap Chromatin data

I next applied S-LDSC to the brainstem volume GWAS using reference data generated by Finucane et al.1 from the Roadmap Epigenetics Project.

The following graph and table show the results:

Results of application of S-LDSC to Xue et al.'s Brainstem volume GWAS using the epigenetics reference 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.

Name Coefficient Coefficient_P_value Reject Null
Ganglion_Eminence_derived_primary_cultured_neurospheres__H3K4me3 8.93377e-07 1.38452e-06 True
Ganglion_Eminence_derived_primary_cultured_neurospheres__H3K4me1 3.59493e-07 3.12384e-06 True
Brain_Germinal_Matrix__H3K4me3 9.57527e-07 3.17663e-06 True
Cortex_derived_primary_cultured_neurospheres__H3K4me1 2.45846e-07 4.809e-06 True
Brain_Cingulate_Gyrus__H3K4me3 7.91621e-07 2.80948e-05 True
Cortex_derived_primary_cultured_neurospheres__H3K4me3 9.87131e-07 4.46674e-05 True
Brain_Hippocampus_Middle__H3K4me3 5.56671e-07 4.60966e-05 True
Fetal_Brain_Female__H3K4me3 6.22638e-07 6.9113e-05 True
Brain_Inferior_Temporal_Lobe__H3K4me3 6.32571e-07 0.00013192 True
Brain_Hippocampus_Middle__H3K36me3 2.62924e-07 0.000298371 False
NHDF-Ad_Adult_Dermal_Fibroblast_Primary_Cells__H3K36me3 5.47195e-07 0.000606413 False
Brain_Anterior_Caudate__H3K9ac 4.13716e-07 0.000631442 False
Brain_Inferior_Temporal_Lobe__H3K36me3 2.41796e-07 0.00118244 False
Brain_Substantia_Nigra__H3K4me3 5.54222e-07 0.00141824 False
Psoas_Muscle__H3K36me3 3.70217e-07 0.00168427 False
Brain_Anterior_Caudate__H3K36me3 2.37851e-07 0.00181957 False
Brain_Dorsolateral_Prefrontal_Cortex__H3K4me3 4.77128e-07 0.00213604 False
Brain_Cingulate_Gyrus__H3K27ac 1.61001e-07 0.00248331 False

As might be expected, the significant cell/tissue types are all central nervous system related. Interestingly, a number of these significant cell/tissue types are related to brain development. Examples include Fetal_Brain_Female__H3K4me3, Brain_Germinal_Matrix__H3K4me3, and primary_cultured_neurospheres. This may suggest that the key transcriptional programs affecting absolute brainstem volume are active early in development.

ImmGen data

Next, I applied S-LDSC using reference data from the ImmGen project.

There were no significant cell types.

Corces et al. ATAC-seq data

I next applied S-LDSC using the Corces ATAC-seq reference dataset. There were no significant cell types.

Cahoy and GTEx-Brain data

There were no significant cell types when the Cahoy and GTEx-Brain datasets were used as a reference. This is surprising, but also consistent with the null result when using the GTEx/Franke lab datasets. The contrast between these results and those generated when the roadmap chromatin dataset is used as a reference is striking. It may simply indicate that the genetic mechanisms that control brainstem volume are better understood through epigenetics than through RNA expression.

  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. Hui Xue, Jilian Fu, Zuojun Geng, Jingliang Cheng, Meiyun Wang, Longjiang Zhang, Guangbin Cui, Yongqiang Yu, Weihua Liao, Hui Zhang, and others. The genetic architecture of brainstem structures. Nature Communications, 2025. URL: https://www.nature.com/articles/s41467-025-67221-6_reference.pdf. ↩