Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes
Open accessPublished version of a preprint
Abstract
When present in coding regions, tandem repeats (TRs) may have large effects on protein structure and function contributing to health and disease. We use a family-based design to identify de novo TRs and assess their impact at the population level in 148,607 European ancestry participants from the UK Biobank. The 427 loci with de novo TR mutations are enriched for targets of microRNA-184 (21.1-fold, P = 4.30 × 10 −5 , FDR = 9.50 × 10 −3 ). There are 123 TR-phenotype associations with posterior probabilities > 0.95. These relate to body structure, cognition, and cardiovascular, metabolic, psychiatric, and respiratory outcomes. We report several loci with large likely causal effects on tissue microstructure, including the FAN1 -[TG] N and carotid intima-media thickness (mean thickness: beta = 5.22, P = 1.22 × 10 −6 , FDR = 0.004; maximum thickness: beta = 6.44, P = 1.12 × 10 −6 , FDR = 0.004). Two exonic repeats FNBP4 -[GGT] N and BTN2A1 -[CCT] N alter protein structure. In this work, we contribute clear and testable hypotheses of dose-dependent TR implications linking genetic variation and protein structure with health and disease outcomes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., Landray, M., et al. (2015) · PLOS Medicine · doi:10.1371/journal.pmed.1001779 · Cited by 12,728 · see citing works
Second-generation PLINK: rising to the challenge of larger and richer datasets
Chang, C. C., Chow, C. C., Tellier, L. C., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015) · Gigascience · doi:10.1186/s13742-015-0047-8 · Cited by 12,709 · see citing works
UniProt: the Universal Protein knowledgebase
Apweiler, R., Bairoch, A., Wu, C. H., Barker, W. C., Boeckmann, B., Ferro, S., Gasteiger, E., Huang, H.-Z., Lopez, R., Magrane, M., et al. (2004) · Nucleic Acids Res. · doi:10.1093/nar/gkh131 · Cited by 8,795 · see citing works
ShinyGO: a graphical gene-set enrichment tool for animals and plants
Ge, S. X., Jung, D., & Yao, R. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btz931 · Cited by 5,270 · see citing works
Functional mapping and annotation of genetic associations with FUMA
Watanabe, K., Taskesen, E., van Bochoven, A., & Posthuma, D. (2017) · Nature Communications · doi:10.1038/s41467-017-01261-5 · Cited by 4,083 · see citing works
The InterPro protein families and domains database: 20 years on
Blum, M., Chang, H.-Y., Chuguransky, S., Grego, T., Kandasaamy, S., Mitchell, A., Nuka, G., Paysan-Lafosse, T., Qureshi, M., Raj, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa977 · Cited by 2,231 · see citing works
A framework for the interpretation of de novo mutation in human disease
Samocha, K. E., Robinson, E. B., Sanders, S. J., Stevens, C., Sabo, A., McGrath, L. M., Kosmicki, J. A., Rehnström, K., Mallick, S., Kirby, A., et al. (2014) · Nature Genetics · doi:10.1038/ng.3050 · Cited by 979 · see citing works
Notch Signaling in Development, Tissue Homeostasis, and Disease
Siebel, C., & Lendahl, U. (2017) · Physiological Reviews · doi:10.1152/physrev.00005.2017 · Cited by 968 · see citing works
FINEMAP: efficient variable selection using summary data from genome-wide association studies
Benner, C., Spencer, C. C. A., Havulinna, A. S., Salomaa, V., Ripatti, S., & Pirinen, M. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw018 · Cited by 815 · see citing works
New insights into the generation and role of de novo mutations in health and disease
Acuña‐Hidalgo, R., Veltman, J. A., & Hoischen, A. (2016) · Genome biology · doi:10.1186/s13059-016-1110-1 · Cited by 451 · see citing works
Tandem repeats mediating genetic plasticity in health and disease
Hannan, A. J. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2017.115 · Cited by 446 · see citing works
30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?
Depienne, C., & Mandel, J.-L. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.03.011 · Cited by 429 · see citing works
Abundant contribution of short tandem repeats to gene expression variation in humans
Gymrek, M., Willems, T., Guilmatre, A., Zeng, H., Markus, B., Georgiev, S., Daly, M. J., Price, A. L., Pritchard, J. K., Sharp, A. J., et al. (2016) · Nature Genetics · doi:10.1038/ng.3461 · Cited by 410 · see citing works
Efficient storage of high throughput DNA sequencing data using reference-based compressionPreprint
Fritz, M. H.-Y., Leinonen, R., Cochrane, G., & Birney, E. (2011) · Genome Research · doi:10.1101/gr.114819.110 · Cited by 388 · see citing works
Chaitanya, L., Breslin, K., Zuñiga, S., Wirken, L., Pośpiech, E., Kukla-Bartoszek, M., Sijen, T., Knijff, P. D., Liu, F., Branicki, W., et al. (2018) · Forensic Science International: Genetics · doi:10.1016/j.fsigen.2018.04.004 · Cited by 335 · see citing works
Genome-wide profiling of heritable and de novo STR variations
Willems, T., Zielinski, D., Yuan, J., Gordon, A., Gymrek, M., & Erlich, Y. (2017) · Nature Methods · doi:10.1038/nmeth.4267 · Cited by 329 · see citing works
The impact of short tandem repeat variation on gene expression
Feupe, S. F., Margoliash, J., Wang, C., Saini, S., Yanicky, R., Shleizer-Burko, S., Goren, A., & Gymrek, M. (2019) · Nature Genetics · doi:10.1038/s41588-019-0521-9 · Cited by 271 · see citing works
Profiling the genome-wide landscape of tandem repeat expansions
(2019) · doi:10.1093/nar/gkz501 · Cited by 270 · see citing works
Rüb, U., Seidel, K., Heinsen, H., Vonsattel, J. P., den Dunnen, W. F., & Korf, H. W. (2016) · Brain Pathology · doi:10.1111/bpa.12426 · Cited by 206 · see citing works
Patterns of de novo tandem repeat mutations and their role in autism
Mitra, I., Huang, B., Mousavi, N., Ma, N., Lamkin, M., Yanicky, R., Shleizer-Burko, S., Lohmueller, K. E., & Gymrek, M. (2021) · Nature · doi:10.1038/s41586-020-03078-7 · Cited by 194 · see citing works
Protein-coding repeat polymorphisms strongly shape diverse human phenotypes
Mukamel, R. E., Handsaker, R. E., Sherman, M. A., Barton, A. R., Zheng, Y., McCarroll, S. A., & Loh, P.-R. (2021) · Science · doi:10.1126/science.abg8289 · Cited by 178 · see citing works
Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios
Besenbacher, S., Liu, S. M., Izarzugaza, J. M. G., Grove, J., Belling, K., Bork‐Jensen, J., Huang, S., Als, T. D., Li, S., Yadav, R., et al. (2015) · Nature Communications · doi:10.1038/ncomms6969 · Cited by 173 · see citing works
Liu, F., Visser, M., Duffy, D. L., Hysi, P. G., Jacobs, L. C., Lao, O., Zhong, K., Walsh, S., Chaitanya, L., Wollstein, A., et al. (2015) · Human Genetics · doi:10.1007/s00439-015-1559-0 · Cited by 172 · see citing works
Hannan, A. J. (2010) · Trends in Genetics · doi:10.1016/j.tig.2009.11.008 · Cited by 156 · see citing works
Reduced thalamic volumes in major depressive disorder
Nugent, A. C., Davis, R., Zarate, C. A., & Drevets, W. C. (2013) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2013.05.004 · Cited by 105 · see citing works
Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells
Lü, S., & Archer, M. C. (2009) · International Journal of Cancer · doi:10.1002/ijc.24761 · Cited by 91 · see citing works
FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders
Deshmukh, A. L., Porro, A., Mohiuddin, M., Lanni, S., Panigrahi, G. B., Caron, M., Masson, J., Sartori, A. A., & Pearson, C. E. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200448 · Cited by 67 · see citing works
TRTools: a toolkit for genome-wide analysis of tandem repeats
Mousavi, N., Margoliash, J., Pusarla, N., Saini, S., Yanicky, R., & Gymrek, M. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa736 · Cited by 65 · see citing works
Diagnostic Role of Carotid Intima‐Media Thickness for Coronary Artery Disease: A Meta‐Analysis
Liu, D., Du, C.-J., Shao, W., & Ma, G. (2020) · BioMed Research International · doi:10.1155/2020/9879463 · Cited by 60 · see citing works
microRNA-184 Induces a Commitment Switch to Epidermal Differentiation
Nagosa, S., Leesch, F., Putin, D., Bhattacharya, S., Altshuler, A., Serror, L., Amitai-Lange, A., Nasser, W., Aberdam, É., Rouleau, M., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.030 · Cited by 55 · see citing works
Regional Cerebral Blood Flow in Children and Young Adults with Chronic Kidney Disease
Liu, H.-S., Hartung, E. A., Jawad, A. F., Ware, J. B., Laney, N. C., Port, A. M., Gur, R. C., Hooper, S. R., Radcliffe, J., Furth, S. L., et al. (2018) · Radiology · doi:10.1148/radiol.2018171339 · Cited by 54 · see citing works
McGinnis, R. E., Fox, H. C., Yates, P., Cameron, L.-A., Barnes, M. R., Gray, I. C., Spurr, N. K., Hurko, O., & Clair, D. S. (2001) · Nature Genetics · doi:10.1038/88839 · Cited by 53 · see citing works
DNA-based predictive models for the presence of freckles
Kukla‐Bartoszek, M., Pośpiech, E., Woźniak, A., Boroń, M., Karłowska-Pik, J., Teisseyre, P., Zubańska, M., Bronikowska, A., Grzybowski, T., Płoski, R., et al. (2019) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2019.07.012 · Cited by 46 · see citing works
Matsushima, Y., Kawano, H., Koide, Y., Baba, T., Toda, G., Seto, S., & Yano, K. (2004) · Clinical Cardiology · doi:10.1002/clc.4960271110 · Cited by 45 · see citing works
Polyglutamine (polyQ) disorders
Cohen-Carmon, D., & Meshorer, E. (2012) · Nucleus · doi:10.4161/nucl.21481 · Cited by 41 · see citing works
Butyrophilins: an important new element of resistance
Malinowska, M., Tokarz–Deptuła, B., & Deptuła, W. (2017) · Central European Journal of Immunology · doi:10.5114/ceji.2017.72806 · Cited by 39 · see citing works
Accuracy of short tandem repeats genotyping tools in whole exome sequencing data
Halman, A., & Oshlack, A. (2020) · F1000Research · doi:10.12688/f1000research.22639.1 · Cited by 35 · see citing works
Quickly identifying identical and closely related subjects in large databases using genotype data
Jin, Y., Schäffer, A. A., Sherry, S. T., & Feolo, M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179106 · Cited by 35 · see citing works
Deshmukh, A. L., Caron, M., Mohiuddin, M., Lanni, S., Panigrahi, G. B., Khan, M., Engchuan, W., Shum, N., Faruqui, A., Wang, P., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110078 · Cited by 30 · see citing works
Tumor Suppressor miR-184 Enhances Chemosensitivity by Directly Inhibiting SLC7A5 in Retinoblastoma
He, T., Xiao, Z., Xing, Y., Yang, H.-J., Qiu, H., & Chen, J. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01163 · Cited by 30 · see citing works
A critical role for miR-184 in the fate determination of oligodendrocytes
Afrang, N., Tavakoli, R., Tasharrofi, N., Alian, A., Sohi, A. N., Kabiri, M., Fathi‐Roudsari, M., Zomorrod, M. S., Rajaei, F., Soleimani, M., et al. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1208-y · Cited by 27 · see citing works
Population-based structural variation discovery with Hydra-Multi
Lindberg, M. R., Hall, I. M., & Quinlan, A. R. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu771 · Cited by 24 · see citing works
STR-realigner: a realignment method for short tandem repeat regions
Kojima, K., Kawai, Y., Misawa, K., Mimori, T., & Nagasaki, M. (2016) · BMC Genomics · doi:10.1186/s12864-016-3294-x · Cited by 24 · see citing works
Statistical Approaches to Detecting and Analyzing Tandem Repeats in Genomic Sequences
Anisimova, M. O., Pečerska, J., & Schaper, E. (2015) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2015.00031 · Cited by 22 · see citing works
Kondo, Y., Koshimizu, E., Mégarbané, A., Hamanoue, H., Okada, I., Nishiyama, K., Kodera, H., Miyatake, S., Tsurusaki, Y., Nakashima, M., et al. (2013) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.35983 · Cited by 20 · see citing works
Missing heritability may be hiding in repeats
Gymrek, M., & Goren, A. (2021) · Science · doi:10.1126/science.abl7794 · Cited by 19 · see citing works
The SOX9-MMS22L Axis Promotes Oxaliplatin Resistance in Colorectal Cancer
Liu, Y., Wu, H., Luo, T., Luo, Q., Meng, Z., Shi, Y. K., Li, F., Liu, M., Peng, X., Liu, J., et al. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.646542 · Cited by 17 · see citing works
Brain structure and function changes in ulcerative colitis
Kornelsen, J., Witges, K., Labus, J. S., Mayer, E. A., & Bernstein, C. N. (2021) · Neuroimage Reports · doi:10.1016/j.ynirp.2021.100064 · Cited by 17 · see citing works
Multiparametric characterization of white matter alterations in early stage Huntington disease
Adanyeguh, I., Branzoli, F., Delorme, C., Méneret, A., Monin, M., Luton, M.-P., Durr, A., Sabidussi, E., & Mochel, F. (2021) · Scientific Reports · doi:10.1038/s41598-021-92532-1 · Cited by 13 · see citing works
In-silico characterization of Formin Binding Protein 4 Family of proteins
Das, A., Bhattacharya, S., Bagchi, A., & Dasgupta, R. (2014) · Interdisciplinary Sciences Computational Life Sciences · doi:10.1007/s12539-013-0040-9 · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A deep population reference panel of tandem repeat variation
Jam, H. Z., Li, Y., DeVito, R., Mousavi, N., Ma, N., Lujumba, I., Adam, Y., Maksimov, M., Huang, B. B., Dolzhenko, E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42278-3 · Cited by 77 · see citing works
Characterization of genome-wide STR variation in 6487 human genomes
Shi, Y., Niu, Y., Zhang, P., Luo, H., Liu, S., Zhang, S., Wang, J., Li, Y., Liu, X., Song, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37690-8 · Cited by 67 · see citing works
Huang, Y., Wang, M., Wang, Z., Liu, X., Feng, Y., Zhong, J., Huang, H., Geng, J., Tang, T., Liu, C., et al. (2025) · Science Advances · doi:10.1126/sciadv.adx1590 · Cited by 7 · see citing works
Expanding horizons of tandem repeats in biology and medicine: Why ‘genomic dark matter’ matters
Hannan, A. J. (2023) · Emerging Topics in Life Sciences · doi:10.1042/etls20230075 · Cited by 7 · see citing works
The role of tandem repeat expansions in brain disorders
Panoyan, M. A., & Wendt, F. R. (2023) · Emerging Topics in Life Sciences · doi:10.1042/etls20230022 · Cited by 6 · see citing works
Self-citationPopulation-scale repeat expansions elucidate disease risk and brain atrophy
Pounraja, V. K., Sul, J. H., Herman, J. L., O’Keeffe, S., Rajagopal, V. M., Bai, X., Kessler, M. D., Parikshak, N., Landheer, K., Zhang, X., et al. (2026) · Nature · doi:10.1038/s41586-026-10345-6 · Cited by 4 · see citing works
The impact of Short Tandem Repeats on grey matter brain imaging derived phenotypes in UK BiobankPreprint
Sproviero, W., Ghose, U., Winchester, L. M., Fernandes, M., Newby, D., Sproviero, D., Amin, N., Smets, B., He, K., Khramtsova, E. A., et al. (2023) · medRxiv · doi:10.1101/2023.02.27.23286496 · Cited by 3 · see citing works
Fitness landscapes of human microsatellites
Haasl, R. J., & Payseur, B. A. (2024) · PLoS Genetics · doi:10.1371/journal.pgen.1011524 · Cited by 2 · see citing works
Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participantsPreprint
Panoyan, M. A., Shi, Y., Abbatangelo, C. L., Adler, N., Moo-Choy, A., Parra, E. J., Polimanti, R. A., Hu, P., & Wendt, F. R. (2023) · medRxiv · doi:10.1101/2023.12.11.23299818 · Cited by 2 · see citing works
Self-citationLiao, X., Zhou, J., Zhang, B., Xu, X., Li, H., & Gao, X. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.17.553659 · Cited by 1 · see citing works
Multi-ancestry tandem repeat association study of hair colour using exome-wide sequencingPreprint
Fazzari, V., Moo-Choy, A., Panoyan, M. A., Abbatangelo, C. L., Polimanti, R. A., Novroski, N. M. M., & Wendt, F. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.24.581865 · Cited by 1 · see citing works
Self-citationAssociation between suicidal ideation and tandem repeats in contactins
Parikh, K., Reis, A. Q., & Wendt, F. R. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1236540
Self-citation
- Authors
- Wendt, F. R., Pathak, G. A., & Polimanti, R.
- Affiliations
- University of Toronto (CA)
- Yale University (US)
- Corresponding author
- Wendt, Frank R.
- Venue
- Nature Communications
- Published
- 2022-12-12
- Volume
- 13
- Issue
- 1
- Pages
- 7682-7682
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9744822
- OpenAlex
- W4311219478
- Cited by
- 12
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 7
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- medRxiv (acceptedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH122058)
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (DA047527)
- U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (DC018098)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- de novo mutations, phenome-wide association study, FAN1, carotid intima-media thickness, BTN2A1, protein structure, cardiovascular outcomes, body structure, cognitive outcomes, mental health outcomes, respiratory outcomes, metabolic outcomes
- MeSH terms
- United Kingdom, Phenotype, Proteins, Biological Specimen Banks, Tandem Repeat Sequences, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Carotid Intima-Media Thickness
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
