Effect heterogeneity reveals complex pleiotropic effects of rare coding variants.

ALLSPICE reveals that rare coding variants in genes show significant heterogeneity across 124 of 11,810 gene-trait pairs in the UK Biobank, highlighting complex pleiotropic effects.

• Why it matters: Understanding how rare variants influence multiple traits is crucial for interpreting genetic architecture and disease mechanisms, but existing methods are limited to common variants and cannot distinguish proportional from heterogeneous effects.
• What they did: Researchers developed ALLSPICE, a likelihood-based R package that tests whether rare-variant effects are proportional or heterogeneous across traits, accounting for phenotypic correlations using summary statistics, and applied it to 359 traits.
• The result: The method identified numerous heterogeneous gene-trait associations, advancing the analysis of allelic heterogeneity at biobank scale and providing new insights into the complex pleiotropic roles of rare variants.