Abstract Ancestry-specific genetic mapping of transcriptome regulation is pivotal for understanding genome function, especially in underrepresented consanguineous populations. Here we characterized 1,882 Qatar Biobank participants, integrating blood RNA sequencing, whole-genome sequencing and phenotypic data across 45 clinically relevant traits. We cataloged ~7 million significant quantitative trait loci (QTLs), both short and structural variants, impacting gene expression, isoform usage, splicing and allele-specific expression, uncovering 1,379 novel eGenes. Fine-mapping resolved 29,953 high-confidence, independent causal loci including 24% previously unreported as well as those with effect alleles showing significant divergence across global populations, while 1,371 were absent from public databases. Leveraging elevated autozygosity, we found that causal variants are depleted from runs of homozygosity, consistent with purifying selection, while recent autozygosity increased the burden of homozygous regulatory variants. We identified QTLs with recessive deleterious effects on 10 Mendelian disease genes and homozygous QTLs causing extreme outlier expression in 66 genes including dosage-sensitive ones. Colocalization analysis revealed 58 causal variants acting on 20 clinically relevant phenotypes, implicating novel genes including ATP6V0B and RQCD1 in metabolic and blood disorders. These findings establish this QTL catalog as a valuable Middle Eastern resource for genome interpretation and genomic medicine.