Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes

ABSTRACT Background Tandem repeats (TRs) are a major source of variation in the human genome under-investigated by large-scale genetic studies. When present in coding regions, TRs may have large effects on protein structure and function contributing to health and disease. Methods In a family-based design of 39 European ancestry trios from the UK Biobank (UKB), the GangSTR and MonSTR methods were used to identify de novo TRs in whole-exome sequences. TRs were annotated for association with gene expression and gene set enrichment. The loci harboring de novo TRs were investigated in a phenome-wide association study in up to 148,607 unrelated UKB participants of European descent. Linear and logistic regression included age, sex, sex×age, age 2 , sex×age 2 , and ten within-ancestry principal components as covariates. TR loci were fine-mapped to identify likely causal associations. Results There were 427 mutated TRs with a trend towards expansions versus contractions ( χ 2 =5.46, df=1, P =0.019). These TRs were enriched for targets of the tumor suppressor microRNA-184 (21.1-fold, P =4.30×10 −5 ). There were 123 TR-phenotype associations with posterior probabilities>0.95. These were related to body structure, cognition, and cardiovascular, metabolic, psychiatric, and respiratory outcomes. The most significant was between NCOA6 -[GT] N and “ ease of skin tanning ” (beta=0.069, se=0.003, P =1.51×10 −155 ). There were several loci with large likely causal effects on tissue microstructure, including the association of FAN1 -[TG] N with carotid intima-media thickness (mean thickness: beta=5.22, se=1.08, P =1.22×10 −6 ; maximum thickness: beta=6.44, se=1.32, P =1.12×10 −6 . Conclusions Combined with the TR de novo mutational background characterized herein, TR-phenotype associations contribute clear and testable hypotheses of dose-dependent TR implications linking genetic variation and protein structure with health and disease outcomes.