A method to estimate the contribution of rare coding variants to complex trait heritability.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38336875.
- Also identified by DOI 10.1038/s41467-024-45407-8 and PMC identifier 10858280.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the "missing" heritability of complex traits. We developed a framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h<sup>2</sup><sub>RV</sub>) without assuming a particular genetic architecture. We applied RARity to 31 complex traits in the UK Biobank (n = 167,348) and showed that gene-level RV aggregation suffers from 79% (95% CI: 68-93%) loss of h<sup>2</sup><sub>RV</sub>. Using unaggregated variants, 27 traits had h<sup>2</sup><sub>RV</sub> > 5%, with height having the highest h<sup>2</sup><sub>RV</sub> at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h<sup>2</sup><sub>RV</sub>, enabling the assessment of gene-level characteristics and revealing 11, previously unreported, gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, innovative methods are needed to predict RV functionality.
Medical subject headings
- Multifactorial Inheritance
- Polymorphism, Single Nucleotide