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

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 445,735 autosomal STRs into SNP 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 118 high-confidence STR-trait associations predicted as causal variants under all fine-mapping settings tested. Using these results, we estimate that STRs drive 5.2-9.7% of GWAS signals for these traits. Our high confidence STR-trait associations implicate STRs in some of the strongest hits for multiple phenotypes, including a trinucleotide STR in APOB associated with LDL cholesterol and a CGG repeat in the promoter of CBL associated with multiple platelet traits. 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.

A deep population reference panel of tandem repeat variation

“…Multiple TRs have recently been implicated as causal drivers of genotype-phenotype associations discovered using genome-wide association studies (GWAS) 10, 36 . In these cases, although the TRs are likely causal, the signals were originally identified using nearby tagging SNPs in at least moderate linkage disequilibrium (LD) with the TR.…”

“…The TR dataset presented here provides important improvements over previous population-wide TR panels and their applications. Previous TR panels were primarily based on hg19 and on a single TR genotyper 4, 15, 37 , or are under controlled access restrictions and have limited representation of diverse ancestries 16, 18, 20, 36 . In contrast, this dataset is made freely available, is based on the hg38 reference genome, and integrates TR calls from four different tools.…”

Repeat polymorphisms in non-coding DNA underlie top genetic risk loci for glaucoma and colorectal cancer

“…Our read-depth and haplotype-modeling approach accurately captured larger-scale VNTR length variation (>100bp) but produced noisier genotype estimates for less-variable VNTRs, reducing power to analyze such VNTRs. Moreover, we excluded all short tandem repeat (STR) loci from analysis, for which other methods are required (Saini et al 2018, Margoliash et al 2022). The set of VNTRs we considered was also limited by our GRCh38-based VNTR ascertainment strategy (which required multiple repeat units to be present in the human reference) and the need for mappability of short reads.…”

Short tandem repeats bind transcription factors to tune eukaryotic gene expression

“…STRs are enriched in cis-regulatory elements across eukaryotic genomes (3), including in humans [~25% of enhancers contain an STR (4, 5); fig. S5], and can activate or repress transcription in Homo sapiens (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), Mus musculus (22,23), Saccharomyces cerevisiae (3), Drosophila melanogaster (24,25), and others (26). Dinucleotide STRs are associated with broad activity of cis-regulatory elements across cell types in D. melanogaster (27), and variation in STRs has been proposed to account for "missing heritability" in genome-wide association studies (5,28).…”