Contribution of rare coding variants to complex trait heritability-Reference-Cited by-同舟云学术

Contribution of rare coding variants to complex trait heritability

Published:2022-11-22 Issue: Volume: Page:
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Author:

Pathan Nazia¹^ORCID,Deng Wei Q.²^ORCID,Khan Mohammad¹^ORCID,Scipio Matteo Di¹,Mao Shihong¹,Morton Robert W.³^ORCID,Lali Ricky¹,Pigeyre Marie¹,Chong Michael R.⁴,Paré Guillaume⁵^ORCID

Affiliation:

1. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada; Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada

2. Peter Boris Centre for Addictions Research, St. Joseph’s Healthcare Hamilton, Hamilton, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada

3. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada

4. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada

5. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada; Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Can

Abstract

Abstract It has been postulated that rare coding variants (RVs; MAF<0.01) contribute to the “missing” heritability of complex traits. We developed a novel framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h2RV) 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 h2RV. Using unaggregated variants, 27 traits had h2RV>5%, with height having the highest h2RV 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 h2RV, enabling the assessment of gene-level characteristics and revealing 12 novel 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, novel methods are needed to predict RV functionality.

Publisher

Research Square Platform LLC

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