Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease.

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease

dhimmel/lincs v2.0: Refined consensus signatures from LINCS L1000

This repository creates user-friendly datasets for LINCS L1000. We extend the L1000 data offerings with consensus signatures, compound mappings, and chemical similarities. Read about this release on Thinklab

Consensus signatures for LINCS L1000 perturbations

<div>LINCS L1000 measures the transcriptional response to perturbations. However, a single perturbagen is often assessed at several conditions, such as dosages, timepoints, or cell lines. A consensus signature meta-analyzes several input signatures and condenses them into a single output signature.</div><div><br></div>We've computed consensus signatures for:<div><br></div><div>+ 1,170 DrugBank compounds</div><div>+ 4,326 gene knockdowns</div><div>+ 2,413 gene overexpressions</div><div>+ 38,327 L1000 perturbations</div><div><br></div><div>Each signature contains dysregulation z-scores for 7,467 genes (978 measured and 6,489 inferred, see `genes.tsv`). The `consensi-{type}.tsv.bz2` files contain the perturbagen × gene matrix of z-scores. The `dysreg-{type}.tsv` files contain significantly dysregulated genes. The `dysreg-{type}-summary.tsv` files provide the counts of significantly up/down-regulated genes per perturbagen.</div><div><br></div><div>Our methods are available [on Thinklab](https://doi.org/10.15363/thinklab.d43#7). The [project GitHub repository](https://github.com/dhimmel/lincs) contains all of the datasets here besides `consensi-pert_id.tsv.bz2` due to its large file size.</div><div><br></div><div><div>If using these datasets, please attribute this figshare deposition and the LINCS L1000 project. Also please abide by the data release policy for the [NIH LINCS Program](http://www.lincsproject.org/data/data-release-policy/).</div><div><br></div><div>This is not an official LINCS L1000 repository. Users are warned that our modifications may have introduced errors or removed signal that was present the original data. We thank the L1000 team for posting their data and providing support including online office hours.</div><div><div></div></div></div

Pairwise molecular similarities between DrugBank compounds

<p>Molecular similarities were calculated between pairs of DrugBank compounds using structures from the DrugBank SDF download. First, a Morgan (circular) fingerprint with radius 2 was calculated for each compound. Dice coefficients were used to quantify fingerprint similarity.</p

Heterochromatin formation via recruitment of DNA repair proteins.

Heterochromatin formation and nuclear organization are important in gene regulation and genome fidelity. Proteins involved in gene silencing localize to sites of damage and some DNA repair proteins localize to heterochromatin, but the biological importance of these correlations remains unclear. In this study, we examined the role of double-strand-break repair proteins in gene silencing and nuclear organization. We find that the ATM kinase Tel1 and the proteins Mre11 and Esc2 can silence a reporter gene dependent on the Sir, as well as on other repair proteins. Furthermore, these proteins aid in the localization of silenced domains to specific compartments in the nucleus. We identify two distinct mechanisms for repair protein-mediated silencing-via direct and indirect interactions with Sir proteins, as well as by tethering loci to the nuclear periphery. This study reveals previously unknown interactions between repair proteins and silencing proteins and suggests insights into the mechanism underlying genome integrity

Heterochromatin formation via recruitment of DNA repair proteins.

Heterochromatin formation and nuclear organization are important in gene regulation and genome fidelity. Proteins involved in gene silencing localize to sites of damage and some DNA repair proteins localize to heterochromatin, but the biological importance of these correlations remains unclear. In this study, we examined the role of double-strand-break repair proteins in gene silencing and nuclear organization. We find that the ATM kinase Tel1 and the proteins Mre11 and Esc2 can silence a reporter gene dependent on the Sir, as well as on other repair proteins. Furthermore, these proteins aid in the localization of silenced domains to specific compartments in the nucleus. We identify two distinct mechanisms for repair protein-mediated silencing-via direct and indirect interactions with Sir proteins, as well as by tethering loci to the nuclear periphery. This study reveals previously unknown interactions between repair proteins and silencing proteins and suggests insights into the mechanism underlying genome integrity