A method to estimate the contribution of rare coding variants to complex trait heritability
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 2 RV) without assuming a particular genetic architecture...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45407-8 |
| _version_ | 1827326949595283456 |
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| author | Nazia Pathan Wei Q. Deng Matteo Di Scipio Mohammad Khan Shihong Mao Robert W. Morton Ricky Lali Marie Pigeyre Michael R. Chong Guillaume Paré |
| author_facet | Nazia Pathan Wei Q. Deng Matteo Di Scipio Mohammad Khan Shihong Mao Robert W. Morton Ricky Lali Marie Pigeyre Michael R. Chong Guillaume Paré |
| author_sort | Nazia Pathan |
| collection | DOAJ |
| description | 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 2 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 h 2 RV. Using unaggregated variants, 27 traits had h 2 RV > 5%, with height having the highest h 2 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 h 2 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. |
| first_indexed | 2024-03-07T14:52:53Z |
| format | Article |
| id | doaj.art-c178b4267dff4643bed6e59ce258ffbb |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:53Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c178b4267dff4643bed6e59ce258ffbb2024-03-05T19:37:07ZengNature PortfolioNature Communications2041-17232024-02-0115111610.1038/s41467-024-45407-8A method to estimate the contribution of rare coding variants to complex trait heritabilityNazia Pathan0Wei Q. Deng1Matteo Di Scipio2Mohammad Khan3Shihong Mao4Robert W. Morton5Ricky Lali6Marie Pigeyre7Michael R. Chong8Guillaume Paré9Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPeter Boris Centre for Addictions Research, St. Joseph’s Healthcare HamiltonPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster UniversityAbstract 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 2 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 h 2 RV. Using unaggregated variants, 27 traits had h 2 RV > 5%, with height having the highest h 2 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 h 2 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.https://doi.org/10.1038/s41467-024-45407-8 |
| spellingShingle | Nazia Pathan Wei Q. Deng Matteo Di Scipio Mohammad Khan Shihong Mao Robert W. Morton Ricky Lali Marie Pigeyre Michael R. Chong Guillaume Paré A method to estimate the contribution of rare coding variants to complex trait heritability Nature Communications |
| title | A method to estimate the contribution of rare coding variants to complex trait heritability |
| title_full | A method to estimate the contribution of rare coding variants to complex trait heritability |
| title_fullStr | A method to estimate the contribution of rare coding variants to complex trait heritability |
| title_full_unstemmed | A method to estimate the contribution of rare coding variants to complex trait heritability |
| title_short | A method to estimate the contribution of rare coding variants to complex trait heritability |
| title_sort | method to estimate the contribution of rare coding variants to complex trait heritability |
| url | https://doi.org/10.1038/s41467-024-45407-8 |
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