Background

Modern genomics is severely biased toward Western population data. This is due to the fact that the majority of Genome-Wide Association Studies (GWAS) and expression Quantitative Trait Loci (eQTL) studies have been accumulated based on European ancestry. This population imbalance has been identified as a reason why the benefits of genomic medicine do not reach non-European patients evenly.

The Middle Eastern population is located at a crucial geographical junction in the history of human migration and settlement, having experienced unique genetic drift, admixture, and high rates of consanguinity over long periods. This is the background for why their genomic structure and linkage disequilibrium (LD) patterns are distinctly different from those of Europeans. Nevertheless, resources for the large-scale elucidation of their organ-specific transcriptomic regulatory mechanisms were virtually non-existent. This was the reason why prediction accuracy inevitably dropped significantly when estimating disease risk for Middle Eastern patients or interpreting the functions of non-coding variants using European-centric data. There was an urgent need for a high-resolution regulatory map integrating the unique genomic and transcriptomic profiles of the Middle East.

Key Findings

The researchers performed a linked analysis of Whole Genome Sequencing (WGS) and whole blood RNA sequencing data from thousands of participants in a large-scale Middle Eastern biobank. Based on this, they completed a transcriptome map that aggregates genetic regulatory effects at the transcriptomic level.

As a result of the analysis, the researchers precisely identified millions of cis-eQTLs located near target genes and tens of thousands of trans-eQTLs acting on distant chromosomal regions. Among these, approximately 20% of the regulatory variants were confirmed to be Middle East-specific variants that were either undetected or had extremely low allele frequencies in existing large-scale cohorts centered on Europeans. In addition to differences in allele frequency, distinct population differences were observed in the regulatory direction and binding affinity that control gene expression.

The research team then performed colocalization analysis between GWAS data for type 2 diabetes, cardiovascular disease, and specific autoimmune diseases—which have high prevalence in the Middle Eastern population—and expression association signals. As a result, it was clearly revealed which specific immune and metabolic genes are upregulated or downregulated by dozens of non-coding risk variants that had been classified as having unknown functions in previous studies. In particular, it was proven through specific expression value comparisons that mutations in certain transcription factor binding sites involved in insulin signaling and lipid metabolism act as key switches regulating disease susceptibility in the Middle Eastern population.

Significance and Outlook

This study is significant in that it establishes a functional genomics reference standard encompassing Middle Eastern populations, which have long been overlooked in precision medicine. A decisive resource has been secured to address the technical barrier where polygenic risk score (PRS) models, which encompass multiple ethnicities, have shown significantly lower predictive power in non-European populations. Furthermore, it is regarded as a turning point that will broaden the scope of drug target discovery pipelines biased toward specific populations.

However, the fact that the transcriptomic analysis was conducted primarily focusing on whole blood as a single tissue is a clear limitation. It is difficult to represent all tissue-specific eQTL signals from key metabolic organs such as pancreatic beta cells, liver, or adipose tissue, where disease pathophysiology occurs. In follow-up studies, it will be necessary to perform single-cell RNA sequencing (scRNA-seq) in parallel to reveal detailed mechanisms by cell fraction and expand the cohort scale to include minority ethnic groups.