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

Creator(s)

Craig Smail, Children's Mercy Kansas CityFollow
Bing Ge
Marissa R. Keever-Keigher, Children's Mercy Kansas CityFollow
Carl F. Schreck, Children's Mercy Kansas CityFollow
Warren A. Cheung, Children's Mercy HospitalFollow
Jeffrey J. Johnston, Children's Mercy HospitalFollow
Cassandra Barrett, Children's Mercy Kansas CityFollow
Genomic Answers for Kids Consortium
Keith Feldman, Children's Mercy HospitalFollow
Ana S A Cohen, Children's Mercy HospitalFollow
Emily G. Farrow, Children's Mercy HospitalFollow
Isabelle Thiffault, Children's Mercy HospitalFollow
Elin Grundberg, Children's Mercy HospitalFollow
Tomi Pastinen, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

9-18-2024

Identifier

DOI: 10.1038/s41467-024-52407-1; PMCID: PMC11411080

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.

Journal Title

Nat Commun

Volume

15

Issue

1

First Page

8196

Last Page

8196

MeSH Keywords

Humans; Multifactorial Inheritance; Rare Diseases; Genetic Predisposition to Disease; Phenotype; Genetic Variation; Male; Female; Genome-Wide Association Study; Penetrance; Child; Cohort Studies

Keywords

Multifactorial Inheritance; Rare Diseases; Genetic Predisposition to Disease; Phenotype; Genetic Variation; Genome-Wide Association Study; Penetrance; Cohort Studies

Comments

Grants and funding

• R35GM146966/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
• R21HG012422/U.S. Department of Health & Human Services | National Institutes of Health (NIH)

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Publisher's Link: https://www.nature.com/articles/s41467-024-52407-1

Recommended Citation

Smail C, Ge B, Keever-Keigher MR, et al. Complex trait associations in rare diseases and impacts on Mendelian variant interpretation. Nat Commun. 2024;15(1):8196. Published 2024 Sep 18. doi:10.1038/s41467-024-52407-1