The contribution of short tandem repeats to splicing variation in the human prefrontal cortex

Abstract Background Splicing disruption has been implicated in a range of heritable phenotypes, including numerous psychiatric and neurological disorders. Recent studies have focused largely on single nucleotide polymorphisms or short indels. Despite growing evidence that genetic variation at short tandem repeats (STRs) influences splicing, large-scale studies of STR-mediated splicing in the brain have been limited by low sample sizes of available RNA-seq data or exclusion of certain classes of STRs. Results Here, we leverage deep RNA-seq and SNP array data from 336 human dorsolateral prefrontal cortex (DLPFC) samples collected by the Human Brain Collection Core. We identify 51,343 unique STRs for which copy number is significantly associated with one or multiple alternative splicing events of nearby genes (spliceSTRs). We prioritize and characterize candidate causal spliceSTRs using three orthogonal fine-mapping strategies, identifying 1,313 high-confidence fine-mapped spliceSTRs, and further find strong associations between copy number of certain repeat units and binding of specific RNA-binding proteins (RBPs). Co-localization analyses using summary statistics from genome-wide association studies for 6 brain-related disorders identified multiple signals that may be driven by fine-mapped spliceSTRs, including a previously identified ( GT ) n repeat that is a spliceSTR for PLEKHA1 associated with Alzheimer’s disease as well as a newly identified ( AGG ) n spliceSTR in SEPTIN3 co-localized with schizophrenia. Conclusions Our findings highlight the role of STRs in regulating alternative splicing in the human brain, suggesting a general relationship between STR polymorphism and RBP-mediated splicing events, and identify specific spliceSTRs detected by co-localization analysis as candidate causal variants for brain-related disorders.