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

Craig Smail (), Bing Ge, Marissa R. Keever-Keigher, Carl Schwendinger-Schreck, Warren A. Cheung, Jeffrey J. Johnston, Cassandra Barrett, Keith Feldman, Ana S. A. Cohen, Emily G. Farrow, Isabelle Thiffault, Elin Grundberg and Tomi Pastinen ()
Additional contact information
Craig Smail: Children’s Mercy Kansas City
Bing Ge: McGill University
Marissa R. Keever-Keigher: Children’s Mercy Kansas City
Carl Schwendinger-Schreck: Children’s Mercy Kansas City
Warren A. Cheung: Children’s Mercy Kansas City
Jeffrey J. Johnston: Children’s Mercy Kansas City
Cassandra Barrett: Children’s Mercy Kansas City
Keith Feldman: University of Missouri Kansas City
Ana S. A. Cohen: Children’s Mercy Kansas City
Emily G. Farrow: Children’s Mercy Kansas City
Isabelle Thiffault: Children’s Mercy Kansas City
Elin Grundberg: Children’s Mercy Kansas City
Tomi Pastinen: Children’s Mercy Kansas City

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Emerging evidence implicates common genetic variation - aggregated into polygenic scores (PGS) - in the onset and phenotypic presentation of rare diseases. Here, we comprehensively map individual polygenic liability for 1102 open-source PGS in a cohort of 3059 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. Using this resource, we demonstrate increased polygenic liability in probands with an inherited candidate disease variant (VUS) compared to unaffected carrier parents. Further, we show an enrichment for large-effect rare variants in putative core PGS genes for associated complex traits. Overall, our study supports and expands on previous findings of complex trait associations in rare diseases, implicates polygenic liability as a potential mechanism underlying variable penetrance of candidate causal variants, and provides a framework for identifying novel candidate rare disease genes.

Date: 2024
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DOI: 10.1038/s41467-024-52407-1

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