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A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability

Nature Genetics volume 56, pages 2322–2332 (2024) Cite this article

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Abstract

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE–trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay.

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Fig. 1: Confirmation of expanded GC-rich TRs as the underlying cause of rare gains of methylation at 24 loci in the human genome.
The alternative text for this image may have been generated using AI.
Fig. 2: Validation of GC-rich repeat expansions using long-read sequencing.
The alternative text for this image may have been generated using AI.
Fig. 3: Results of phenome-wide association analysis for expansions of six GC-rich tandem repeats.
The alternative text for this image may have been generated using AI.
Fig. 4: AFF3 expansions are enriched specifically in unsolved probands with ID in the 100kGP.
The alternative text for this image may have been generated using AI.
Fig. 5: PacBio HiFi GS data of two trios carrying AFF3 expansions.
The alternative text for this image may have been generated using AI.
Fig. 6: Relative effects of the AFF3 expansion on educational attainment compared with recurrent microdeletions/duplications.
The alternative text for this image may have been generated using AI.
Fig. 7: SNVs that associate with presence of the AFF3 repeat expansion are the same as those identified in previous GWASs of intelligence, cognitive ability and educational attainment.
The alternative text for this image may have been generated using AI.

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Data availability

Project MinE DNA methylation data are available from the European Genome–phenome Archive via accession no. EGAS00001004587. Project MinE sequencing data are accessible to approved researchers via an online data request: https://www.projectmine.com/research/data-sharing. The GTEx DNA methylation data are available from https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE213478, the GTEx normalized expression level data from https://storage.googleapis.com/adult-gtex/bulk-gex/v8/rna-seq/GTEx_Analysis_2017-06-05_v8_RNASeQCv1.1.9_gene_tpm.gct.gz and the GTEx allele-specific expression data from https://www.google.com/url?q=https://console.cloud.google.com/storage/browser/fc-secure-ff8156a3-ddf3-42e4-9211-0fd89da62108/GTEx_Analysis_2017-06-05_v8_ASE_WASP_counts_by_subject/&sa=D&source=docs&ust=1678389406863768&usg=AOvVaw1McwIkcmsHEds7G5NSMcf6. The UKB Data Showcase is available from https://biobank.ctsu.ox.ac.uk/crystal/search.cgi. Access to the tandem repeat genotypes generated here will be provided by the UKB (https://www.ukbiobank.ac.uk). PacBio genome sequences will be available to approved researchers via the Genomics England research environment. Information on how to access the 100 kGP data by joining a Genomics England Clinical Interpretation Partnership is available online: https://www.genomicsengland.co.uk/join-a-gecip-domain. AoU Researcher Workbench is available from https://www.researchallofus.org/data-tools/workbench. Genotypes generated from AoU participants cannot be shared owing to the terms of the Data Access Agreement under which we accessed AoU GS data.

Code availability

Code utilized for the present study is available as follows: ExpansionHunter classifier, https://zenodo.org/doi/10.5281/zenodo.10821643 (ref. 76); Global ancestry assignment, https://zenodo.org/doi/10.5281/zenodo.10820994 (ref. 73); pbmm2, https://github.com/PacificBiosciences/pbmm2; TRGT and TRGT-denovo, https://zenodo.org/doi/10.5281/zenodo.10839644 (ref. 81); Repeat catalogs for TRGT, https://doi.org/10.5281/zenodo.7987365 (ref. 86).

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Acknowledgements

We thank K. Temple, University of Southampton, UK, for her support. This work was supported by the National Institutes of Health (NIH) grants (nos. AG075051, NS105781, HD103782 and NS120241 to A.J.S.), National Heart, Lung, and Blood Institute Biodata Catalyst fellowship (no. 5120339 to A.M.T.), funding from the Prinses Beatrix Spierfonds (grant no. W.OR20-08 to J.J.F.A.V.), funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant no. 772376—EScORIAL to J.V.) and funding from UK Research and Innovation (grant no. MR/S006753/1), Barts charity (grant no. MGU0569) and a Medical Research Council (MRC) Clinician Scientist award (no. MR/S006753/1; all to A.T.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (grant no. UL1TR004419) from the National Center for Advancing Translational Sciences. Research reported in this paper was supported by the Office of Research Infrastructure of the NIH under award no. S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research was made possible through access to the data and findings generated by the 100kGP. The 100kGP is managed by Genomics England Limited (a company wholly owned by the Department of Health and Social Care). The 100kGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the MRC have also funded research infrastructure. The 100kGP uses data provided by patients and collected by the NHS as part of their care and support. The AoU Research Program is supported by the NIH, office of the director: regional medical centers: 1 OT2 OD026549, 1 OT2 OD026554, 1 OT2 OD026557, 1 OT2 OD026556, 1 OT2 OD026550, 1 OT2 OD 026552, 1 OT2 OD026553, 1 OT2 OD026548, 1 OT2 OD026551, 1 OT2 OD026555 and IAA no. AOD 16037; federally qualified health centers: HHSN 263201600085U; data and research center: 5 U2C OD023196; biobank: 1 U24 OD023121; the participant center: U24 OD023176; participant technology systems center: 1 U24 OD023163; communications and engagement: 3 OT2 OD023205 and 3 OT2 OD023206; and community partners: 1 OT2 OD025277, 3 OT2 OD025315, 1 OT2 OD025337 and 1 OT2 OD025276. In addition, the AoU Research Program would not be possible without the partnership of its participants.

Author information

Author notes

  1. Miten Jain

    Present address: Northeastern University, Boston, MA, USA

  2. These authors contributed equally: Bharati Jadhav, Paras Garg.

  3. Full lists of members and their affiliations appear in the Supplementary Information.

Authors and Affiliations

  1. Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bharati Jadhav, Paras Garg, William Lee, Mariya Shadrina, Alejandro Martin-Trujillo, Scott J. Gies, Gabrielle Altman, Mafalda Barbosa & Andrew J. Sharp

  2. Department of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands

    Joke J. F. A. van Vugt, J. H. Veldink & Jan Veldink

  3. William Harvey Research Institute, Queen Mary University of London, London, UK

    Kristina Ibanez, Delia Gagliardi, A. Tucci & Arianna Tucci

  4. Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK

    Delia Gagliardi, Clarissa Rocca & Henry Houlden

  5. Pacific Biosciences, Menlo Park, CA, USA

    Tom Mokveld & Egor Dolzhenko

  6. UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA

    Miten Jain & Benedict Paten

  7. SW Thames Centre for Genomics, St George’s University of London & St George’s University Hospitals NHS, London, UK

    Nayana Lahiri

  8. Wessex Clinical Genetics Service, University Hospital Southampton NHS Trust and Department of Human Genetics and Genomic Medicine, Southampton University, Southampton, UK

    Katherine Lachlan

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  1. Bharati Jadhav
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Consortia

Genomics England Research Consortium

  • A. Tucci

Project MinE ALS Sequencing Consortium

  • J. H. Veldink

Contributions

B.J., P.G., J.J.F.A.V., K.I., W.L., M.S., T.M. and E.D. designed bioinformatics pipelines and performed data analyses. D.G., M.J., A.M.T., S.L.G., G.A., C.R. and M.B. performed data analyses. N.L. and K.L. contributed clinical information. H.H., B.P., J.V. and A.T. supervised and advised on the project. A.J.S. conceived the study, performed data analyses, supervised the project and drafted the manuscript. All authors reviewed and approved the final draft.

Corresponding author

Correspondence to Andrew J. Sharp.

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Competing interests

PacBio provided research support for the HiFi sequencing performed in the present study. E.D. and T.M. are employees and shareholders of PacBio. The remaining authors declare no competing interests.

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Nature Genetics thanks David Nelson, Christel Depienne and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Jadhav, B., Garg, P., van Vugt, J.J.F.A. et al. A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability. Nat Genet 56, 2322–2332 (2024). https://doi.org/10.1038/s41588-024-01917-1

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