The phenomic landscape of rare gain- and loss-of-function variation

Predicted loss-of-function variants in VNN1 are linked to lower circulating vanin-1 levels and associate with body mass index and related cardiometabolic phenotypes in the Multi-Ethnic Study of Atherosclerosis.

• Why it matters: Phenome-wide association studies often pool variants without accounting for distinct functional effects, leaving GoF versus LoF phenotype consequences insufficiently mapped at scale.
• What they did: Using whole-exome sequencing and electronic health records from the Mount Sinai Million Health Discoveries Program (50,067 participants; 1,244 binary and 202 quantitative traits), the study tested rare predicted GoF and LoF variants across 18,214 genes, including ancestry-specific analyses.
• The result: Many gene- and variant-level associations were ancestry-specific or shared, and combining predicted GoF and LoF variants attenuated gene–trait signals, supporting functional stratification to improve phenome-wide discovery.

AI summary of the abstract · may contain errors · not medical advice · read the paper.