Repeat polymorphisms in non-coding DNA underlie top genetic risk loci for glaucoma and colorectal cancer.

Abstract

Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). We recently showed that protein-coding VNTRs underlie some of the strongest known genetic associations with diverse phenotypes. Here, we assessed the phenotypic impact of VNTRs genome-wide, 99% of which lie in non-coding regions. We applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants. Association and statistical fine-mapping analyses identified 107 VNTR-phenotype associations (involving 58 VNTRs) that were assigned a high probability of VNTR causality (PIP[≥]0.5). Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2- fold risk range across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health.