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

Ronen E Mukamel; Robert E Handsaker; Maxwell A Sherman; Alison R Barton; Margaux L A Hujoel; Steven A McCarroll; Po-Ru Loh

doi:10.1016/j.cell.2023.07.002

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

Cell. 2023 Aug 17;186(17):3659-3673.e23. doi: 10.1016/j.cell.2023.07.002. Epub 2023 Jul 31.

Authors

Ronen E Mukamel¹, Robert E Handsaker², Maxwell A Sherman³, Alison R Barton⁴, Margaux L A Hujoel⁵, Steven A McCarroll⁶, Po-Ru Loh⁷

Affiliations

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.

PMID: 37527660
PMCID: PMC10528368 (available on 2024-08-17)
DOI: 10.1016/j.cell.2023.07.002

Abstract

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Calcium Channels* / genetics
Colorectal Neoplasms* / genetics
Eukaryotic Initiation Factor-3* / genetics
Genome, Human
Glaucoma* / genetics
Humans
Minisatellite Repeats*
Polymorphism, Genetic

Substances

Calcium Channels
TMCO1 protein, human
Eukaryotic Initiation Factor-3

Abstract

Publication types

MeSH terms

Substances

Grants and funding