A method to estimate the contribution of rare coding variants to complex trait heritability

Nazia Pathan; Wei Q Deng; Matteo Di Scipio; Mohammad Khan; Shihong Mao; Robert W Morton; Ricky Lali; Marie Pigeyre; Michael R Chong; Guillaume Paré

doi:10.1038/s41467-024-45407-8

A method to estimate the contribution of rare coding variants to complex trait heritability

Nat Commun. 2024 Feb 9;15(1):1245. doi: 10.1038/s41467-024-45407-8.

Authors

Nazia Pathan^{1

2}, Wei Q Deng^{3

4}, Matteo Di Scipio^{1

5}, Mohammad Khan^{1

5}, Shihong Mao¹, Robert W Morton^{1

2}, Ricky Lali^{1

6}, Marie Pigeyre^{1

5}, Michael R Chong^{1

2

7}, Guillaume Paré^{8

9

10

11}

Affiliations

¹ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada.
² Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada.
³ Peter Boris Centre for Addictions Research, St. Joseph's Healthcare Hamilton, Hamilton, Canada.
⁴ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada.
⁵ Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada.
⁶ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
⁷ Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada.
⁸ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada. pareg@mcmaster.ca.
⁹ Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada. pareg@mcmaster.ca.
¹⁰ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada. pareg@mcmaster.ca.
¹¹ Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada. pareg@mcmaster.ca.

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 (h²_RV) 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 h²_RV. Using unaggregated variants, 27 traits had h²_RV > 5%, with height having the highest h²_RV 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 h²_RV, 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.

MeSH terms

Genome-Wide Association Study
Models, Genetic
Molecular Sequence Annotation
Multifactorial Inheritance* / genetics
Phenotype
Polymorphism, Single Nucleotide*