A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io. [Display omitted] •A new gene expression profiling method, L1000, dramatically lowers cost•The Connectivity Map now includes 1.3 million publicly accessible L1000 profiles•Facilitates discovery of small-molecule mechanism and annotation of genetic variants•The work establishes feasibility and utility of a truly comprehensive Connectivity Map The next generation Connectivity Map, a large-scale compendium of functional perturbations in cultured human cells coupled to a gene-expression readout, facilitates the discovery of connections between genes, drugs, and diseases.