Loh Lab

New preprint on repeat polymorphisms influencing glaucoma and colorectal cancer risk

We are excited to share a new preprint, “Repeat polymorphisms in non-coding DNA underlie top genetic risk loci for glaucoma and colorectal cancer” (Mukamel*, Handsaker* et al.), which identifies variable-number-of-tandem-repeat (VNTR) polymorphisms that appear to generate the strongest known contributions of any common variants to two common diseases. This collaboration with Bob Handsaker and Steve McCarroll leveraged whole-genome sequencing data in large cohorts together with long-read assemblies from HGSVC2 to analyze 9,561 VNTRs genome-wide for effects on 786 phenotypes in UK Biobank. Highlights of association and fine-mapping results include a common intronic repeat polymorphism in TMCO1 for which the longest alleles (top 3%) confer higher glaucoma risk (OR=1.51 [1.42–1.60]) than any other common variant genome-wide, and a VNTR polymorphism downstream of EIF3H at which common repeat length variation generates a >2-fold range of colorectal cancer risk across individuals. Several other associations between VNTRs and complex traits appeared to reflect regulation of gene expression or splicing mediated by non-coding VNTRs.