Larger datasets uncover multiple regulatory switches for gene expression
A University of Michigan-led study reports that expanding expression and splicing quantitative trait locus data can reveal additional regulatory regions that control a gene. Earlier work using GTEx data often hit a ceiling in the number of such loci detected per gene. The findings may help connect GWAS signals to specific genes and potential drug targets.
TOPMed, an NHLBI program, supplied 14,324 RNA sequencing samples, including 6,454 whole blood and 1,291 lung samples. Mapping expression and splicing quantitative trait loci yielded tens of thousands of high-resolution signals. TOPMed's diversity mattered: roughly one in six whole blood signals involved variants rare or absent in European-ancestry groups, while just 1.3% appeared in four large mostly European eQTL resources.
Earlier GTEx-based studies often appeared to reach a ceiling in regulatory loci per gene. The new results suggest that limit depended on sample size. Linking GWAS variants to expression and splicing may sharpen drug-target identification, because genetic support for a target is associated with greater clinical success.
This work may affect people with complex diseases by helping researchers connect disease-associated variants to specific genes, potentially improving target selection for medicines. Drug developers could use broader, more diverse datasets to prioritize candidates, while participants from underrepresented ancestries may benefit if findings become more generalizable. However, translation to treatments could take years, and larger datasets alone may not resolve every regulatory mechanism.