A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank
Abstract Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54678-0 |
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| author | Celine A. Manigbas Bharati Jadhav Paras Garg Mariya Shadrina William Lee Gabrielle Altman Alejandro Martin-Trujillo Andrew J. Sharp |
| author_facet | Celine A. Manigbas Bharati Jadhav Paras Garg Mariya Shadrina William Lee Gabrielle Altman Alejandro Martin-Trujillo Andrew J. Sharp |
| author_sort | Celine A. Manigbas |
| collection | DOAJ |
| description | Abstract Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing fine-mapped associations with 73 traits. We replicate 23 of 31 (74%) of these associations in the All of Us cohort. While this set includes several known repeat expansion disorders, novel associations we found are attributable to common polymorphic variation in TR length rather than rare expansions and include e.g. a coding polyhistidine motif in HRCT1 influencing risk of hypertension and a poly(CGC) in the 5’UTR of GNB2 influencing heart rate. Fine-mapped TRs are strongly enriched for associations with local gene expression and DNA methylation. Our study highlights the contribution of multi-allelic TRs to the “missing heritability” of the human genome. |
| format | Article |
| id | doaj-art-dd07da69aaaa4e69bd9ae62b1c6a5b53 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dd07da69aaaa4e69bd9ae62b1c6a5b532024-12-08T12:36:32ZengNature PortfolioNature Communications2041-17232024-12-0115111210.1038/s41467-024-54678-0A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK BiobankCeline A. Manigbas0Bharati Jadhav1Paras Garg2Mariya Shadrina3William Lee4Gabrielle Altman5Alejandro Martin-Trujillo6Andrew J. Sharp7Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at MountAbstract Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing fine-mapped associations with 73 traits. We replicate 23 of 31 (74%) of these associations in the All of Us cohort. While this set includes several known repeat expansion disorders, novel associations we found are attributable to common polymorphic variation in TR length rather than rare expansions and include e.g. a coding polyhistidine motif in HRCT1 influencing risk of hypertension and a poly(CGC) in the 5’UTR of GNB2 influencing heart rate. Fine-mapped TRs are strongly enriched for associations with local gene expression and DNA methylation. Our study highlights the contribution of multi-allelic TRs to the “missing heritability” of the human genome.https://doi.org/10.1038/s41467-024-54678-0 |
| spellingShingle | Celine A. Manigbas Bharati Jadhav Paras Garg Mariya Shadrina William Lee Gabrielle Altman Alejandro Martin-Trujillo Andrew J. Sharp A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank Nature Communications |
| title | A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank |
| title_full | A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank |
| title_fullStr | A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank |
| title_full_unstemmed | A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank |
| title_short | A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank |
| title_sort | phenome wide association study of tandem repeat variation in 168 554 individuals from the uk biobank |
| url | https://doi.org/10.1038/s41467-024-54678-0 |
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