Abstract Short tandem repeats (STRs), genomic regions each consisting of a sequence of 1-6 base pairs repeated in succession, represent one of the largest sources of human genetic variation. However, many STR effects are not captured well by standard genome-wide association studies (GWAS) or downstream analyses that are mostly based on single nucleotide polymorphisms (SNPs). To study the involvement of STRs in complex traits, we imputed genotypes for 445,720 autosomal STRs into genotype array data from 408,153 White British UK Biobank participants and tested for association with 44 blood and serum biomarker phenotypes. We used two fine-mapping methods, SuSiE and FINEMAP, to identify 119 high-confidence STR-trait associations across 93 unique STRs predicted as causal variants under all fine-mapping settings tested. Using these results, we estimate that STRs account for 5.2-7.6% of causal variants identifiable from GWAS signals for these traits. Our high confidence STR-trait associations implicate STRs in some of the strongest hits for multiple phenotypes, including a CTG repeat in APOB associated with circulating apolipoprotein B levels, a CGG repeat in the promoter of CBL associated with multiple platelet traits and a poly-A repeat in TAOK1 associated with mean platelet volume. Replication analyses in additional population groups and orthogonal expression data further support the role of a subset of the candidate STRs we identify. Together, our study suggests that polymorphic tandem repeats make widespread contributions to complex traits, provides a set of stringently selected candidate causal STRs, and demonstrates the need to routinely consider a more complete view of human genetic variation in GWAS.

Polymorphic short tandem repeats make widespread contributions to blood and serum traits