| Title: | A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability |
| Journal: | Nature Genetics |
| Published: | 23 Sep 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39313615/ |
| DOI: | https://doi.org/10.1038/s41588-024-01917-1 |
Publication 13559
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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.</p>
22 Authors
- Bharati Jadhav
- Paras Garg
- Joke J. F. A. van Vugt
- Kristina Ibanez
- Delia Gagliardi
- William Lee
- Mariya Shadrina
- Tom Mokveld
- Egor Dolzhenko
- Alejandro Martin-Trujillo
- Scott J. Gies
- Gabrielle Altman
- Clarissa Rocca
- Mafalda Barbosa
- Miten Jain
- Nayana Lahiri
- Katherine Lachlan
- Henry Houlden
- Benedict Paten
- Jan Veldink
- Arianna Tucci
- Andrew J. Sharp
1 Application
| Application ID | Title |
|---|---|
| 32568 | Phenomewide Heritability Analysis |
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