Abstract
AbstractWhen present in coding regions, tandem repeats (TRs) may have large effects on protein structure and function contributing to health and disease. We use a family-based design to identify de novo TRs and assess their impact at the population level in 148,607 European ancestry participants from the UK Biobank. The 427 loci with de novo TR mutations are enriched for targets of microRNA-184 (21.1-fold, P = 4.30 × 10−5, FDR = 9.50 × 10−3). There are 123 TR-phenotype associations with posterior probabilities > 0.95. These relate to body structure, cognition, and cardiovascular, metabolic, psychiatric, and respiratory outcomes. We report several loci with large likely causal effects on tissue microstructure, including the FAN1-[TG]N and carotid intima-media thickness (mean thickness: beta = 5.22, P = 1.22 × 10−6, FDR = 0.004; maximum thickness: beta = 6.44, P = 1.12 × 10−6, FDR = 0.004). Two exonic repeats FNBP4-[GGT]N and BTN2A1-[CCT]N alter protein structure. In this work, we contribute clear and testable hypotheses of dose-dependent TR implications linking genetic variation and protein structure with health and disease outcomes.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health
U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse
U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Cited by
9 articles.
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