Genetic variants could influence the transcription of miRNAs. Integration of genomics and miRNAs enables interrogation of the genetic architecture of miRNAs, revealing their clinical importance, and providing valuable resources for future studies of miRNAs in human disease. Here we present genome-wide association studies of >2000 plasma circulating miRNAs measured by RNA-sequencing in the Rotterdam Study to identify miRNA-expression quantitative trait loci (miRNA-eQTLs). We report both cis and trans miRNA-eQTLs at p-value <0.05 and those that have been replicated across two independent cohorts. Many of miRNA-eQTLs overlap with gene expression, protein, and metabolite-QTLs and with disease-associated variants reported in previous GWAS studies. The consequences of perturbation in miRNA transcription on a wide range of clinical conditions are systematically investigated in phenome-wide association studies, with their causality tested using Mendelian randomization in the UK Biobank.