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Human genetics

VNTRs and disease risk

Nature Genetics volume 55, page 1421 (2023)Cite this article

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Variable numbers of tandem repeats (VNTRs) are a category of genomic variants whose contribution to disease risk remains underexplored, owing to challenges in genotyping VNTRs accurately in large population samples. To overcome these challenges, Mukamel et al. applied a statistical imputation approach to estimate haplotype-resolved repeat lengths at 9,561 multiallelic VNTR loci in 418,136 participants in the UK Biobank, using a reference panel constructed from whole-genome sequencing data of 4,688 unrelated individuals from the Simons Simplex Collection. They then tested these VNTR length estimates for association with a broad range of common diseases and quantitative traits, and identified 58 VNTRs for which fine-mapping analyses showed a high probability of causality. Notable examples include an expanded 28-bp repeat sequence in an intron of TMCO1 that was associated with increased intraocular pressure and glaucoma risk, and an expanded 27-bp repeat sequence downstream of EIF3H that was associated with colon polyps and colorectal cancer risk. Detailed follow-up analyses at these two loci uncovered evidence of allelic dosage effects. Intriguingly, neither of these VNTRs appears to mediate their effects on disease risk by altering TMCO1 or EIF3H expression, so further work is needed to elucidate the mechanisms by which these expanded VNTRs influence disease susceptibility.

Original references: Cell 186, 3659–3673.e23 (2023)

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    Kyle Vogan

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  1. Kyle Vogan
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Vogan, K. VNTRs and disease risk. Nat Genet 55, 1421 (2023). https://doi.org/10.1038/s41588-023-01513-9

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