Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Genetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources, including the GTEx and PsychENCODE consortia, together with genome-wide association study (GWAS) summary statistics for 48 diseases and traits with an average sample size of 86,850, to identify disease-relevant tissues and cell types. We develop and apply an approach that uses stratified LD score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We detect tissue-specific enrichments at FDR < 5% for 30 diseases and traits across a broad range of tissues that recapitulate known biology. In our analysis of traits with observed central nervous system enrichment, we detect an enrichment of neurons over other brain cell types for several brain-related traits, enrichment of inhibitory neurons over excitatory neurons for bipolar disorder, and enrichments in the cortex for schizophrenia and in the striatum for migraine. In our analysis of traits with observed immunological enrichment, we identify enrichments of alpha beta T cells for asthma and eczema, B cells for primary biliary cirrhosis, and myeloid cells for lupus and Alzheimer’s disease. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signal.