September 15, 2023

Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer

Author(s): Ronen E Mukamel (1), Robert E Handsaker (2), Maxwell A Sherman (3), Alison R Barton (4), Margaux L A Hujoel (5), Steven A McCarroll (6), Po-Ru Loh (7)

1 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: rmukamel@broadinstitute.org. 2 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: handsake@broadinstitute.org. 3 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. 4 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Bioinformatics and Integrative Genomics Program, Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. 5 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 6 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: smccarro@broadinstitute.org. 7 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: poruloh@broadinstitute.org.

Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene.

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 range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.

PMID: 37527660 DOI: 10.1016/j.cell.2023.07.002

Keywords: GWAS; VNTR; colorectal cancer; expression and splicing quantitative trait loci; genetic associations; genomic structural variation; glaucoma; imputation; tandem repeat; variable numbers of tandem repeats

Experimental Paper of the Month manager: Anthony Khawaja

Editorial Board: Humma Shahid, Karl Mercieca, Francisco Goni

Editors in Chief: Francesco Oddone, Manuele Michelessi