Hypothesis
Most complex-trait GWAS variants act by changing the baseline expression of nearby genes, so eQTL colocalization and related methods should recover the known causal genes.
What failed
Across 220 gene-trait pairs where the causal gene is known from protein-coding variants, baseline-expression methods implicated few of those genes: colocalization 8%, transcriptome-wide association 2%, and regulatory annotations plus distance 4%, despite eQTLs lying near most GWAS hits.
Broken assumption
Trait-associated non-coding variants mostly coincide with homeostatic expression QTLs measured in standard datasets.
Why
The authors argue the results point to a deficit in the assumed model itself rather than just limited data, and call the gap 'missing regulation'.
From the published paper: Connally et al. eLife, 2022. ↗CC BY