The UAE Genome Program: Unique Genetic Insights from 43,608 Individuals

Abstract

Here, we present a comprehensive genomic characterization of a cohort of 43,608 Emirati genomes sequenced as part of the Emirati Genome Program (EGP). This study identified more than 421 million single-nucleotide variants and indels and more than 600 million copy-number and structural variants. Small variants had 756 million molecular effects annotated. Of 7.7 million polymorphic variants having an allele frequency (AF) of more than 5% in EGP, 1,348 have a predicted deleterious effect on a protein. Characterization with respect to global variation shows that EGP represents a genetic continuum encompassing the range of African, Asian, and European populations. It is best described by two Arabian, an Eurasian, and an African component, with the predominant Arabian component linked to mitochondrial haplogroups J and T that are commonly attributed to the Middle East. Various aneuploidies of sex chromosomes were detected in 93 individuals overall, and aneuploidy of chromosome 21 was identified in 41 individuals. Median inbreeding coefficient and cumulative runs of homozygosity (ROHs) lengths were increased due to extensive consanguinity, were largest in the groups with Arabian main ancestry components, and were higher than reported for Qatar. Families were identified based on genetic relatedness and classified into 264 families with unrelated parents and 247 families with third- and fourth-degree consanguineous parents. Representative consanguineous pedigrees of families in EGP were outlined. Cumulative ROHs were affected by the main ancestry component and significantly increased in offspring of consanguineous parents, with a pronounced difference between 3rd and 4th-degree relatedness. Investigation of cumulative AFs of variants causing Mendelian diseases highlighted genes related to alpha- and beta-thalassemia (HBB, HBA2) and showed a high burden of variants causing severe recessive diseases, metabolic and retinal disorders, and hearing loss. In summary, EGP represents a landmark effort in characterizing the genetic diversity of the Emirati population, leveraging the largest Middle Eastern cohort reported to date.