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

2025-12-31 genetic and genomic medicine Title + abstract only

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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...

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

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