부산대학교 도서관

Background Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. Methods Here, we interrogate 6045 whole genomes from Qatar--a Middle Eastern population with high consanguinity and understudied mutational burden--enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. Results We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. Conclusions This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings. Keywords: Mendelian disorders, Rare genetic disease, Genome sequencing, Consanguinity, Qatar, Middle East, Biobank, Arab population, Pathogenic variants
Author(s): Waleed Aamer[sup.1], Aljazi Al-Maraghi[sup.1], Najeeb Syed[sup.2], Geethanjali Devadoss Gandhi[sup.1], Elbay Aliyev[sup.1], Alya A. Al-Kurbi[sup.1], Omayma Al-Saei[sup.1], Muhammad Kohailan[sup.1], Navaneethakrishnan Krishnamoorthy[sup.1], Sasirekha Palaniswamy[sup.1], Khulod Al-Malki[sup.1], Saleha Abbasi[sup.1], Nourhen Agrebi[sup.1], Fatemeh [...]