An integrated cell atlas of the human lung in health and disease

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas. ### Competing Interest Statement PRT serves as a consultant for Surrozen Inc., Cellarity Inc., and Celldom Inc. and currently acting CEO of Iolux Inc. FJT consults for Immunai Inc., Singularity Bio B.V., CytoReason Ltd, and Omniscope Ltd, and has ownership interest in Dermagnostix GmbH and Cellarity. JAK reports grants/contracts from Boehringer Ingleheim, Bristol-Myers-Squibb, consulting fees from Janssen and Boehringer Ingelheim, study support from Genentech, and is a member of the scientific advisory board of APIE Therapeutics. SAT, in the past three years, has received remuneration for consulting and Scientific Advisory Board Membership from Genentech, Roche, Biogen, GlaxoSmithKline, Foresite Labs and Qiagen. SAT is a co-founder, board member and holds equity in Transition Bio. DS is a founder of Pliant Therapeutics, a member of the Genentech Scientific Advisory Board and has a sponsored research agreement with Abbvie. OE serves in advisory capacity to Pieris Pharmaceuticals, Blade Therapeutics, Delta 4 and YAP Therapeutics. NK served as a consultant to Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos, and Thyron over the last 3 years, reports Equity in Pliant and Thyron, and a grant from Veracyte, Boehringer Ingelheim, BMS and non-financial support from MiRagen and Astra Zeneca. NK has IP on novel biomarkers and therapeutics in IPF licensed to Biotech. OR is a co-inventor on patent applications filed by the Broad Institute for inventions related to single cell genomics. ORR is an employee of Genentech since October 19, 2020.