Variable number tandem repeats mediate the expression of proximal genes

Mehrdad Bakhtiari, Jonghun Park, Yuan-Chun Ding, Sharona Shleizer-Burko, Susan L. Neuhausen, Bjarni V. Halldórsson, Kári Stefánsson, Melissa Gymrek and Vineet Bafna ()
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Mehrdad Bakhtiari: University of California
Jonghun Park: University of California
Yuan-Chun Ding: Beckman Research Institute of City of Hope
Sharona Shleizer-Burko: University of California
Susan L. Neuhausen: Beckman Research Institute of City of Hope
Bjarni V. Halldórsson: deCODE Genetics
Kári Stefánsson: deCODE Genetics
Melissa Gymrek: University of California
Vineet Bafna: University of California

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Variable number tandem repeats (VNTRs) account for significant genetic variation in many organisms. In humans, VNTRs have been implicated in both Mendelian and complex disorders, but are largely ignored by genomic pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks to genotype a VNTR in 18 seconds on 55X whole genome data, while maintaining high accuracy. We use adVNTR-NN to genotype 10,264 VNTRs in 652 GTEx individuals. Associating VNTR length with gene expression in 46 tissues, we identify 163 “eVNTRs”. Of the 22 eVNTRs in blood where independent data is available, 21 (95%) are replicated in terms of significance and direction of association. 49% of the eVNTR loci show a strong and likely causal impact on the expression of genes and 80% have maximum effect size at least 0.3. The impacted genes are involved in diseases including Alzheimer’s, obesity and familial cancers, highlighting the importance of VNTRs for understanding the genetic basis of complex diseases.

Date: 2021
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DOI: 10.1038/s41467-021-22206-z

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