Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease

Individuals whose observed phenotype deviates from polygenic score enriched for rare damaging variants in Mendelian genes

An original approach identifies UK Biobank individuals 'misaligned' from polygenic score predictions, showing they are enriched for rare damaging variants in Mendelian disease genes. For bone mineral density, enrichment for pLoF variants in COPB2 and GORAB was identified. For stature, shorter-than-expected individuals were enriched for ACAN and IGF1 variants, taller-than-expected for FBN1. For type 2 diabetes, patients with HNF1A/HNF4A pathogenic variants had lower polygenic risk, consistent with a liability threshold model.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 'misalignment' approach is elegant for detecting rare large-effect variants in complex diseases. Implications for understanding variable penetrance of Mendelian variants in the polygenic background are important. A promising avenue for genetic counseling of carriers with variable penetrance variants.