A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank
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.
Authors
- Bharati Jadhav
- Mariya Shadrina (ORCID: https://orcid.org/0000-0001-5962-0771)
- Paras Garg (ORCID: https://orcid.org/0000-0002-7128-1124)
- Alejandro Martin-Trujillo (ORCID: https://orcid.org/0000-0003-1089-3941)
- Andrew J. Sharp (ORCID: https://orcid.org/0000-0003-1415-5129)
- Celine A. Manigbas (ORCID: https://orcid.org/0009-0001-5624-6355)
- William Lee (ORCID: https://orcid.org/0000-0002-0650-1442)
- Gabrielle Altman (ORCID: https://orcid.org/0000-0003-3556-1492)
Institutions
- Child Health and Development Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1038/s41467-024-54678-0
- Citations
- 9
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.41
Funders
- U.S. Department of Health and Human Services
- Andrea and Charles Bronfman Philanthropies
- Women's Health Initiative
- Van Andel Research Institute
- University of Pennsylvania
- Harvard University
- University of Chicago
- North Carolina State University
- Broad Institute
- Leidos
- Georgia Clinical and Translational Science Alliance
- Université de Genève
- National Institutes of Health
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Common Fund