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S-LDSC EDU Analysis

I applied Stratified Linkage Disequilibrium Score Regression1 (S-LDSC) to summary statistics from a GWAS of educational attainment by Lee et al.2. The goal was to identify possible key tissue and cell types affecting educational attainment levels, and in so doing learn about the strengths and weaknesses of the S-LDSC method.

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 graph below shows the coefficient p values for the cell types in the GTEx/Franke Lab dataset when S-LDSC is applied to the EDU GWAS. Cell types are grouped into categories according to the same scheme used in the original S-LDSC paper1.

edu_scatter

We can see that at a false discovery rate of 0.01, the significant tissues are exclusively in the central nervous system.

Here is a more detailed look at the top cells/tissues:

Name Coefficient Coefficient_P_value Reject Null
A08.186.211.730.885.287.500.Cerebral.Cortex 1.7625e-08 1.58411e-15 True
A08.186.211.464.405.Hippocampus 1.62863e-08 4.5446e-15 True
A08.186.211.464.710.225.Entorhinal.Cortex 1.68218e-08 6.89181e-15 True
A08.186.211.464.Limbic.System 1.67997e-08 3.90973e-14 True
A08.186.211.Brain 1.5237e-08 1.38319e-11 True
Brain_Frontal_Cortex_(BA9) 1.56443e-08 1.45016e-11 True
A08.186.211.730.885.287.500.571.735.Visual.Cortex 1.42092e-08 4.7507e-11 True
A08.186.211.730.885.287.500.270.Frontal.Lobe 1.51812e-08 1.03359e-10 True
Brain_Cortex 1.5203e-08 2.22635e-10 True
Brain_Anterior_cingulate_cortex_(BA24) 1.3785e-08 4.33289e-09 True
A08.186.211.132.810.428.200.Cerebellum 1.14043e-08 1.34142e-08 True
A08.186.211.730.885.287.500.670.Parietal.Lobe 1.26008e-08 1.82969e-08 True
A08.186.211.865.428.Metencephalon 1.10862e-08 5.21843e-08 True
Brain_Nucleus_accumbens_(basal_ganglia) 1.27456e-08 5.76169e-08 True
A08.186.211.132.Brain.Stem 1.15633e-08 6.33204e-08 True
Brain_Hippocampus 1.20156e-08 2.71743e-07 True
Brain_Amygdala 1.18184e-08 5.00604e-07 True
Brain_Hypothalamus 1.12805e-08 7.01388e-07 True
A11.872.653.Neural.Stem.Cells 1.17742e-08 2.32653e-06 True
Brain_Caudate_(basal_ganglia) 1.03365e-08 4.98279e-06 True
Brain_Putamen_(basal_ganglia) 1.04866e-08 6.18148e-06 True
Brain_Substantia_nigra 1.00114e-08 1.14614e-05 True
Brain_Cerebellum 8.55503e-09 1.65288e-05 True
A08.186.211.730.317.Diencephalon 8.06071e-09 3.4515e-05 True
Brain_Cerebellar_Hemisphere 8.30636e-09 4.29508e-05 True
A09.371.729.Retina 8.27211e-09 5.85128e-05 True
A08.186.211.730.885.287.249.Basal.Ganglia 8.17562e-09 0.000179368 True
A08.186.211.653.Mesencephalon 7.99799e-09 0.000264251 True
A08.186.211.730.317.357.Hypothalamus 9.02518e-09 0.000393007 True
A08.186.211.730.317.357.352.435.Hypothalamo.Hypophyseal.System 8.70071e-09 0.000577608 True
Brain_Spinal_cord_(cervical_c-1) 6.92728e-09 0.00131103 True
A15.145.Blood 9.14095e-09 0.00198242 False
A15.145.229.637.555.567.569.200.CD4.Positive.T.Lymphocytes 6.37535e-09 0.0049859 False
A11.118.637.555.567.562.440.Precursor.Cells..B.Lymphoid 5.41722e-09 0.0309822 False
A15.145.229.637.555.Leukocytes..Mononuclear 4.94614e-09 0.0312297 False
A11.118.637.Leukocytes 4.90028e-09 0.0324434 False
A08.186.211.730.885.287.249.487.Corpus.Striatum 3.80127e-09 0.0324954 False
A15.378.316.580.Monocytes 5.15141e-09 0.035767 False

Of note is that these results are not very specific: basically all CNS regions are deemed significant. This non-specificity could be a consequence of the details of the definition of cell-type-specific genes used to create the GTEx/Franke lab datasets. In particular, when S-LDSC is applied to the standard GTEx and Franke lab data, brain regions are not used as controls for one another. For example, when the regression for the Cerebral Cortex is run, no other brain regions are used as controls. This prevents us from assessing whether one brain region is better at explaining the GWAS data than another, and promotes non-specific results.

Roadmap Chromatin data

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

The following graph and table show the results:

edu_roadmap_scatter

Name Coefficient Coefficient_P_value Reject Null
Fetal_Brain_Female__H3K4me1 3.3967e-07 1.48993e-29 True
Fetal_Brain_Male__DNase 4.52644e-07 1.46684e-25 True
Fetal_Brain_Female__DNase 4.54212e-07 8.02637e-25 True
Fetal_Brain_Male__H3K4me1 1.89696e-07 1.13027e-19 True
Fetal_Brain_Female__H3K4me3 6.47189e-07 2.23976e-15 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K27ac 1.90671e-07 8.73872e-15 True
Brain_Germinal_Matrix__H3K4me3 5.93144e-07 1.71767e-13 True
Brain_Inferior_Temporal_Lobe__H3K27ac 1.2265e-07 1.02115e-12 True
Ganglion_Eminence_derived_primary_cultured_neurospheres__H3K4me3 4.56066e-07 5.04233e-12 True
Brain_Angular_Gyrus__H3K27ac 1.41502e-07 6.34447e-11 True
Brain_Germinal_Matrix__H3K4me1 2.78071e-07 6.92384e-11 True
Brain_Anterior_Caudate__H3K27ac 1.20617e-07 4.10239e-10 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K4me3 5.32015e-07 4.71654e-10 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K9ac 4.49235e-07 1.12064e-09 True
Cortex_derived_primary_cultured_neurospheres__H3K4me3 5.92022e-07 3.65116e-09 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K4me1 1.92453e-07 6.29012e-09 True
Fetal_Brain_Female__H3K36me3 1.35901e-07 1.00633e-08 True
Brain_Angular_Gyrus__H3K4me3 4.09788e-07 1.86578e-08 True
Brain_Anterior_Caudate__H3K4me3 3.15918e-07 3.9166e-08 True
Brain_Angular_Gyrus__H3K9ac 2.47642e-07 4.53828e-08 True
Ganglion_Eminence_derived_primary_cultured_neurospheres__H3K4me1 1.55274e-07 5.48653e-08 True
Brain_Inferior_Temporal_Lobe__H3K4me3 3.60108e-07 6.96504e-08 True
Brain_Anterior_Caudate__H3K4me1 1.21433e-07 2.15232e-07 True
Cortex_derived_primary_cultured_neurospheres__H3K4me1 1.0066e-07 2.91758e-07 True
Brain_Anterior_Caudate__H3K9ac 2.20957e-07 6.50058e-07 True
Brain_Cingulate_Gyrus__H3K4me3 3.26012e-07 1.20709e-06 True
Brain_Germinal_Matrix__H3K36me3 1.46017e-07 1.23627e-06 True
Brain_Cingulate_Gyrus__H3K9ac 2.32592e-07 2.80626e-06 True
Brain_Inferior_Temporal_Lobe__H3K9ac 1.75209e-07 4.73495e-06 True
Brain_Cingulate_Gyrus__H3K27ac 8.32185e-08 6.05097e-06 True
Brain_Angular_Gyrus__H3K4me1 1.02775e-07 7.61444e-06 True
Brain_Dorsolateral_Prefrontal_Cortex__H3K36me3 1.32893e-07 3.58725e-05 True
Brain_Cingulate_Gyrus__H3K4me1 8.40684e-08 4.28436e-05 True
skeletal_muscle_ENTEX__H3K4me1 3.55999e-08 6.17961e-05 True
Brain_Hippocampus_Middle__H3K27ac 6.5831e-08 6.30559e-05 True
Brain_Hippocampus_Middle__H3K4me3 1.87842e-07 0.000196819 True
Brain_Hippocampus_Middle__H3K4me1 5.8769e-08 0.000200932 True
Brain_Inferior_Temporal_Lobe__H3K4me1 9.74402e-08 0.000227256 True
Brain_Inferior_Temporal_Lobe__H3K36me3 9.70243e-08 0.000449288 True
Pancreatic_Islets__H3K27ac 1.52361e-07 0.00230255 False
Brain_Angular_Gyrus__H3K36me3 1.0321e-07 0.00275453 False
Brain_Anterior_Caudate__H3K36me3 7.73984e-08 0.00310657 False
Esoph-GJ_ENTEX__H3K27ac 4.55769e-08 0.00313903 False
Colon-Sigm_ENTEX__H3K36me3 6.8338e-08 0.00367321 False
Esoph-Muscularis_ENTEX__H3K4me3 1.53155e-07 0.00454078 False
Foreskin_Fibroblast_Primary_Cells_skin02__H3K4me3 6.39511e-08 0.00565107 False
Esoph-Muscularis_ENTEX__H3K27ac 4.31421e-08 0.00586156 False
Spleen__H3K36me3 4.78941e-08 0.00599588 False
Esoph-GJ_ENTEX__H3K4me3 1.3337e-07 0.00875963 False
Brain_Substantia_Nigra__H3K4me1 4.42562e-08 0.0114508 False
Brain_Cingulate_Gyrus__H3K36me3 6.88419e-08 0.0126657 False
Esoph-Mucosa_ENTEX__H3K36me3 5.47652e-08 0.0216056 False
Fetal_Brain_Male__H3K4me3 4.21314e-07 0.0237894 False
Colon-Sigm_ENTEX__H3K27ac 3.46076e-08 0.0241773 False
Brain_Substantia_Nigra__H3K4me3 1.31624e-07 0.0253406 False
Heart-LV_ENTEX__H3K4me1 4.07981e-08 0.0254759 False
Nerve-Tibial_ENTEX__H3K4me3 1.51766e-07 0.026091 False
Brain_Hippocampus_Middle__H3K36me3 5.12254e-08 0.0268535 False

Consistent with the GTEX/Franke results, here many regions of the brain are deemed significant. Because the Roadmap epigenetics dataset is entirely separate from the GTEx gene expression dataset, these results can be seen as an independent piece of evidence for the significance of the brain to educational attainment.

Similarly to the GTEx/Franke case, the non-specificity of the brain results may also be a consequence of the lack of brain controls in the regressions used to define cell-type-specific regions.

The presence of a single significant skeletal muscle cell type is unexpected. It is unclear if this is a real effect or an artifact.

ImmGen data

The next step is to use the S-LDSC reference data derived from the ImmGen project. There are no significant hits. The top non-significant results are:

Name Coefficient Coefficient_P_value Reject Null
Tgd.vg2+24ahi.Th 8.06392e-09 0.00297249 False
NKT.4+.Sp 7.13596e-09 0.00592045 False
T.8Eff.Sp.OT1.d15.LisOva 5.48845e-09 0.0103446 False
T.DPsm.Th 6.48315e-09 0.0113907 False
B.FrE.BM 5.14779e-09 0.0116146 False
B.T2.Sp 5.60899e-09 0.0119636 False
CD8.1h.LN 6.08251e-09 0.0120099 False
NK.Sp 5.82532e-09 0.0122281 False

Corces et al. ATAC-seq data

The next step is to use the Corces et al. dataset from ATAC-seq applied to blood cells.

Again, there were no significant results. The top non-significant results are:

Name Coefficient Coefficient_P_value Reject Null
Erythro 4.19012e-08 0.148498 False
MEP 2.21546e-08 0.285599 False
Bcell 1.09094e-08 0.360172 False
MPP 7.66168e-09 0.402965 False
CMP 5.85289e-09 0.426029 False
CLP 6.38071e-09 0.431636 False
HSC -1.82334e-09 0.521691 False
GMP -1.83842e-08 0.735746 False

Cahoy and GTEx-Brain data

The next two reference datasets pertain to the nervous system.

The Cahoy CNS datasets points to neurons as the key site of activity driving educational attainment, as opposed to oligodendrocytes or astrocytes:

Name Coefficient Coefficient_P_value Reject Null
Neuron 1.23199e-08 4.25819e-08 True
Oligodendrocyte -2.70708e-09 0.862452 False
Astrocyte -2.84009e-09 0.902723 False

Using the GTEx-brain dataset points to the cortex as the key region of the brain for educational attainment:

Name Coefficient Coefficient_P_value Reject Null
Brain_Frontal_Cortex_(BA9) 9.64677e-09 6.32016e-07 True
Brain_Cortex 9.55629e-09 7.00572e-06 True
Brain_Anterior_cingulate_cortex_(BA24) 6.67343e-09 0.000201072 True
Brain_Cerebellar_Hemisphere 4.16361e-09 0.02365 False
Brain_Nucleus_accumbens_(basal_ganglia) 4.34605e-09 0.0319243 False
Brain_Cerebellum 2.81524e-09 0.107455 False
Brain_Putamen_(basal_ganglia) -2.16168e-10 0.535069 False
Brain_Amygdala -1.67611e-09 0.828353 False

The strong contrast between these results (which are highly specific to the cortex) and the results from the general GTEx dataset above (which mark all brain regions) is explained in the Methods section of the Finucane et al. paper1. In the GTEx brain S-LDSC reference dataset, a gene is associated with a particular brain region only if that gene is a strongly significant predictor in a regression aimed at distinguishing the given brain region from all other brain regions. Thus we should expect the GTEx brain dataset to be more informative than the general GTEx dataset when we aim to determine the specific brain region driving the educational attainment phenotype.

Reproducing Analysis

To reproduce this analysis, run the script here.

  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. James J Lee, Robbee Wedow, Aysu Okbay, Edward Kong, Omeed Maghzian, Meghan Zacher, Tuan Anh Nguyen-Viet, Peter Bowers, Julia Sidorenko, Richard Karlsson Linnér, and others. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nature Genetics, 50(8):1112–1121, 2018. URL: https://www.nature.com/articles/s41588-018-0147-3. ↩