Allergy is a major world health challenge affecting 25% of people with a rising incidence. Peanut allergy
alone affects 2.2% of school children in the US and can be life-threatening. Allergy is a complex disease, with
both genetic and environmental factors contributing to risk. In order to pinpoint the underlying genetic risk
variants, genome-wide association studies (GWAS) have been performed on hundreds of thousands of
patients and controls, identifying >100 associated loci. The vast majority of hits are in poorly annotated
noncoding regions of the genome and are thought to influence gene regulation. A major challenge for
understanding allergy (and all complex diseases) is pinpointing the causal variant(s) and defining molecular
mechanisms. The extensive follow up work required is often not undertaken and thus allergy GWAS rarely
contribute to our understanding of disease etiology. In order to mine the rich resource of human disease
associations, new methods are needed to systematically annotate regulatory effects. Existing catalogs are
sparse and biased toward specific cell types (blood), contexts (steady state conditions), molecular
mechanisms (perturbation of gene expression), and populations (Caucasians). Given the highly cell type and
context specific nature of gene regulation, this limited window is unlikely to be sufficient for identifying
most human risk variants. The most comprehensive effort to date to map regulatory effects is the Genotype-
Tissue Expression Project (GTEx), which mapped loci that influence gene expression (eQTLs) in 54 tissues
using autopsy specimens from hundreds of healthy individuals. Despite its scope, the GTEx catalog thus far
explains only 11% of the genetic risk of complex disease, suggesting additional assays and specimens are
needed to unearth the majority of regulatory effects contributing to disease. In this application I propose an
innovative approach to systematically catalog the gene regulatory effects of genetic variants on a massive
scale across diverse allergy-relevant cell types and patient specimens. Crucially, this scalable approach can
accommodate cell stimulation conditions (e.g., allergen challenge), inclusion of diverse human ancestry
groups, and is deployable on scant human tissue and blood specimens. By leveraging a single cell
framework, we are able to probe rare cell populations that play essential roles as mediators of disease. I will
apply this method to allergy relevant GTEx tissues as well as a large-scale allergy biobank representing
heterogenous cases. This study is expected to provide a greatly expanded window into the biology of genetic
loci linked to allergy and elucidate the potential of multi-omic single cell approaches, pathophysiological
stimuli, and patient biospecimens to unearth missing complex disease heritability.
