Complex trait associations in rare diseases and impacts on Mendelian variant interpretation.
Nat Commun
; 15(1): 8196, 2024 Sep 18.
Article
en En
| MEDLINE
| ID: mdl-39294130
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenotipo
/
Predisposición Genética a la Enfermedad
/
Herencia Multifactorial
/
Enfermedades Raras
Límite:
Child
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido