Complex trait associations in rare diseases and impacts on Mendelian variant interpretation

• DOI: 10.1038/s41467-024-52407-1
• Publication Date: 2024-09-19T22:55:51Z
• Authors: Craig Smail; Bing Ge; Marissa R. Keever...; Carl Schwendinger...; Warren A. Cheung; Jeffrey J. Johnston; Cassandra Barrett; ; Keith Feldman; Ana S. A. Cohen; Emily G. Farrow; Isabelle Thiffault; Elin Grundberg; Tomi Pastinen
• Keywords: Male; Multifactorial Inheritance; Science; Q; Genetic Variation; Penetrance; Article; Cohort Studies; Rare Diseases; Phenotype; Humans; Genetic Predisposition to Disease; Female; Child; Genome-Wide Association Study

AbstractEmerging evidence implicates common genetic variation – aggregated into polygenic scores (PGS) – impacting the onset and phenotypic presentation of rare diseases. In this study, we quantified individual polygenic liability for 1,151 previously published PGS in a cohort of 2,374 probands enrolled in the Genomic Answers for Kids (GA4K) rare disease study, revealing widespread associations between rare disease phenotypes and PGSs for common complex diseases and traits, blood protein levels, and brain and other organ morphological measurements. We observed increased polygenic burden in probands with variants of unknown significance (VUS) compared to unaffected carrier parents. We further observed an enrichment in overlap between diagnostic and candidate rare disease genes and large-effect PGS genes. Overall, our study supports and expands on previous findings of complex trait associations in rare disease phenotypes and provides a framework for identifying novel candidate rare disease genes and in understanding variable penetrance of candidate Mendelian disease variants.