Individuals whose phenotype deviates from genetic expectation defined by common variation are enriched for rare damaging variants in genes that cause rare disease.

ABSTRACT: Polygenic scores (PGS) predict complex traits and stratify disease risk but often fail to fully capture individual-level variation. "Misaligned" individuals, whose observed phenotypes deviate from their genetically expected values based on polygenic scores (PGS), provide a powerful model for identifying factors beyond common-variant effects, including additional genetic factors. Here, we apply misalignment classification and enrichment testing frameworks to seven continuous and three dichotomous traits, assessing whether misaligned individuals in the UK Biobank are enriched for rare (minor allele frequency (MAF) < 0.1%) damaging genetic variation. We identify significant enrichment (false discovery rate (FDR)-adjusted P < 0.05) of predicted loss-of-function (pLoF) variants in COP

SUBMITTER: Baya NA 

PROVIDER: S-EPMC12772651 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature