A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank

Celine A. Manigbas, Bharati Jadhav, Paras Garg, Mariya Shadrina, William Lee, Gabrielle Altman, Alejandro Martin-Trujillo and Andrew J. Sharp ()
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Celine A. Manigbas: Icahn School of Medicine at Mount
Bharati Jadhav: Icahn School of Medicine at Mount
Paras Garg: Icahn School of Medicine at Mount
Mariya Shadrina: Icahn School of Medicine at Mount
William Lee: Icahn School of Medicine at Mount
Gabrielle Altman: Icahn School of Medicine at Mount
Alejandro Martin-Trujillo: Icahn School of Medicine at Mount
Andrew J. Sharp: Icahn School of Medicine at Mount

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54678-0

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