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Clinical laboratory tests play a pivotal role in medical decision making, but little is known about their genetic variability between populations. We report a genome-wide association study with 45 clinically relevant traits from the population of Qatar using a whole genome sequencing approach in a discovery set of 6218 individuals and replication in 7768 subjects. Trait heritability is more similar between Qatari and European populations ( r  = 0.81) than with Africans ( r  = 0.44). We identify 281 distinct variant-trait-associations at genome wide significance that replicate known associations. Allele frequencies for replicated loci show higher correlations with European ( r  = 0.94) than with African ( r  = 0.85) or Japanese ( r  = 0.80) populations. We find differences in linkage disequilibrium patterns and in effect sizes of the replicated loci compared to previous reports. We also report 17 novel and Qatari-predominate signals providing insights into the biological pathways regulating these traits. We observe that European-derived polygenic scores (PGS) have reduced predictive performance in the Qatari population which could have implications for the translation of PGS between populations and their future application in precision medicine. The genetic basis for traits can vary between populations. Here the authors report a genome wide association study with 45 clinically-relevant traits in individuals from Qatar, replicating many known loci and identifying new Qatari-predominant signals.

Genomics has the potential to revolutionize medical approaches to disease prevention, diagnosis, and treatment, but it does not come without challenges. The success of a national population-based genome program, like the Qatar Genome Program (QGP), depends on the willingness of citizens to donate samples and take up genomic testing services. This study explores public attitudes of the Qatari population toward genetic testing and toward participating in the QGP. A representative sample of 837 adult Qataris was surveyed in May 2016. Approximately 71% of respondents surveyed reported that they were willing to participate in the activities of the QGP. Willingness to participate was significantly associated with basic literacy in genetics, a family history of genetic diseases, and previous experience with genetic testing through premarital screening. Respondents cited the desire to know more about their health status as the principle motivation for participating, while lack of time and information were reported as the most important barriers. With QGP plans to ramp up the scale of its national operation toward more integration into clinical care settings, it is critical to understand public attitudes and their determinants. The results demonstrate public support but also identify the need for more education and individual counseling that not only provide information on the process, challenges, and benefits of genomic testing, but that also address concerns about information security.

Arab populations are largely understudied, notably their genetic structure and history. Here we present an in-depth analysis of 6,218 whole genomes from Qatar, revealing extensive diversity as well as genetic ancestries representing the main founding Arab genealogical lineages of Qahtanite (Peninsular Arabs) and Adnanite (General Arabs and West Eurasian Arabs). We find that Peninsular Arabs are the closest relatives of ancient hunter-gatherers and Neolithic farmers from the Levant, and that founder Arab populations experienced multiple splitting events 12–20 kya, consistent with the aridification of Arabia and farming in the Levant, giving rise to settler and nomadic communities. In terms of recent genetic flow, we show that these ancestries contributed significantly to European, South Asian as well as South American populations, likely as a result of Islamic expansion over the past 1400 years. Notably, we characterize a large cohort of men with the ChrY J1a2b haplogroup (n = 1,491), identifying 29 unique sub-haplogroups. Finally, we leverage genotype novelty to build a reference panel of 12,432 haplotypes, demonstrating improved genotype imputation for both rare and common alleles in Arabs and the wider Middle East. Arab populations are relatively understudied, especially their genetic architecture and historical relationship with early founders of the ancient Near East. Here, the authors examine 6,218 Qatari whole genomes, revealing insights on migration, population history and genetic structure of populations across the Middle Eastern region.

•Clinical Relevance: CYP2C19 loss-of-function (LoF) alleles were found in 22% of patients, leading to changes in antiplatelet therapy.•Implementation Feasibility: The study demonstrated successful integration of point-of-care (POC) CYP2C19 genotyping into routine cardiovascular care in Qatar.•High Adoption Rate: 80% of PGx-guided recommendations were accepted and applied by healthcare providers.•Cost Savings: Pharmacogenetic-guided therapy resulted in an estimated cost reduction of 300 Qatari Riyals (QR) per patient annually.•Personalized Medicine in Action: PGx testing influenced prescribing decisions in PCI patients, supporting its role in precision cardiovascular therapy.•Pilot Study Design: A prospective cohort study was conducted among 376 PCI patients at the largest community healthcare provider in Qatar.•System-Level Implications: Findings support wider PGx implementation strategies to optimize antiplatelet therapy and improve outcomes in ACS/PCI settings. CYP2C19 loss-of-function (LoF) alleles are associated with increased cardiovascular risk in clopidogrel-treated percutaneous coronary intervention (PCI) patients. Despite the guidelines recommendation for newer P2Y12 inhibitors, clopidogrel remains widely prescribed. The study the potential impact and feasibility of implementing pharmacogenetics (PGx) testing to guide antiplatelet therapy and develop strategies for its clinical integration to improve patient management. A pilot study following a prospective cohort design was conducted within the largest community healthcare provider in Qatar using point-of-care (POC) CYP2C19 genotyping in tailoring antiplatelet therapy for PCI patients. Eligible patients underwent CYP2C19 genotyping, and P2Y12 inhibitor prescriptions were adjusted based on genetic results. The study measured antiplatelet prescribing patterns and identified clinically significant gene-drug interactions. Out of 376 patients tested, 283 patients received PGx-guided recommendations for anti-platelet therapy. Actionable CYP2C19 alleles were detected in 22% of those patients, prompting a change in drug therapy. PGx-guided recommendations were adopted at a rate of 80%, and CYP2C19 genotyping was a significant predictor of antiplatelet therapy adjustments. A sub-analysis of the cost impact revealed an estimated reduction of 300 QR (82.41 $) per patient annually for ACS patients who underwent PCI with stent placement. This real-world study highlights the feasibility and clinical impact of CYP2C19 genotyping in guiding antiplatelet therapy for ACS and PCI patients, supporting broader PGx testing implementation in routine cardiovascular care. HMC-IRB Registration: IRB-HMC-2021-011, IRB-MoPH Assurance: IRB-A-HMC-2019-0014. ISRCTN registration: ISRCTN15110009, https://www.isrctn.com/ISRCTN15110009.

Background/Objective: Warfarin is the standard anticoagulant for patients with mechanical heart valve replacement (HVR). However, its narrow therapeutic index and interpatient variability complicate early postoperative management. Evidence on how valve position influences warfarin sensitivity is limited. This study evaluated the impact of prosthetic valve position and clinical factors on early warfarin response and developed a prediction model to guide initial warfarin dosing in HVR patients. Methods: A retrospective study was conducted on 310 adults who underwent mechanical aortic, mitral, or double valve replacement at Hamad Medical Corporation (2015–2022). Warfarin was initiated within 24 h postoperatively, and patients were monitored for three days. Outcomes included daily warfarin dose, international normalized ratio (INR) levels, attainment of therapeutic INR, INR overshoot (≥4), and the warfarin dose index on day 3 (WDI3). Predictors of WDI3 were analyzed using multivariable regression, and a LASSO model was applied to a dose prediction algorithm for the day 1 dose. Results: Mitral valve recipients required lower doses than aortic or double valve groups (p = 0.008) but had higher INR overshoot rates (18.75% vs. 16.05% and 4.55%; p = 0.033). Female sex and a higher baseline INR were associated with greater sensitivity (p < 0.01), whereas mitral/double valve position predicted reduced sensitivity (p = 0.010). Only half of the cohort reached therapeutic INR by day 3. The prediction model explained ~28% of dose variance with moderate performance. Conclusions: Valve position, sex, and baseline INR significantly influence early postoperative warfarin response. Incorporating these clinical factors into dosing algorithms may optimize initial warfarin management in HVR patients.

Hereditary breast and ovarian cancer is an inherited condition caused by pathogenic (P) or likely pathogenic (LP) variants in the and genes. Population-level sequencing allows for the identification of asymptomatic genotype-positive participants (GPPs) before disease onset. This study assessed the feasibility and impact of returning clinically relevant results to participants at the Qatar Precision Health Institute (QPHI). We established a structured framework to identify and refer asymptomatic individuals who were found to carry P/LP variants in among 6142 QPHI participants. The process integrated genomic analysis, participant recontact, counseling, referral, variants validation, and personalized risk-reducing strategies. Six variants (four , two ) were validated in ten GPPs with a median age of 48 years (IQR: 40.5-56). Eight variants were confirmed through Sanger sequencing in a CAP-accredited laboratory at Hamad Medical Corporation. All eligible participants were referred for counseling and personalized clinical management. Four men initiated breast and prostate cancer surveillance, while four women pursued breast and ovarian surveillance. One asymptomatic GPP underwent prophylactic salpingo-oophorectomy, revealing early-stage ovarian cancer. Cascade testing identified 20 additional GPPs and, in one asymptomatic relative, facilitated the detection of early-stage uterine cancer. The genetic testing acceptability rate was 0.77 (95% CI: 0.46-0.94), with a 100% adherence to surveillance at 12- and 24-month follow-ups. This pilot demonstrates the feasibility and clinical utility of returning actionable findings and represents the first initiative in an Arabic population to implement the return of medically actionable results from a population-based biobank.

Pharmacogenetic (PGx)‐informed medication prescription is a cutting‐edge genomic application in contemporary medicine, offering the potential to overcome the conventional “trial‐and‐error” approach in drug prescription. The ability to use an individual's genetic profile to predict drug responses allows for personalized drug and dosage selection, thereby enhancing the safety and efficacy of treatments. However, despite significant scientific and clinical advancements in PGx, its integration into routine healthcare practices remains limited. To address this gap, the Qatar Genome Program (QGP) has embarked on an ambitious initiative known as QPGx‐CARES (Qatar Pharmacogenetics Clinical Applications and Research Enhancement Strategies), which aims to set a roadmap for optimizing PGx research and clinical implementation on a national scale. The goal of QPGx‐CARES initiative is to integrate PGx testing into clinical settings with the aim of improving patient health outcomes. In 2022, QGP initiated several implementation projects in various clinical settings. These projects aimed to evaluate the clinical utility of PGx testing, gather valuable insights into the effective dissemination of PGx data to healthcare professionals and patients, and identify the gaps and the challenges for wider adoption. QPGx‐CARES strategy aimed to integrate evidence‐based PGx findings into clinical practice, focusing on implementing PGx testing for cardiovascular medications, supported by robust scientific evidence. The current initiative sets a precedent for the nationwide implementation of precision medicine across diverse clinical domains.

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond.

Qatar, a country with a strong health system and a diverse population consisting mainly of expatriate residents, has experienced two large waves of COVID-19 outbreak. In this study, we report on 2634 SARS-CoV-2 whole-genome sequences from infected patients in Qatar between March-2020 and March-2021, representing 1.5% of all positive cases in this period. Despite the restrictions on international travel, the viruses sampled from the populace of Qatar mirrored nearly the entire global population’s genomic diversity with nine predominant viral lineages that were sustained by local transmission chains and the emergence of mutations that are likely to have originated in Qatar. We reported an increased number of mutations and deletions in B.1.1.7 and B.1.351 lineages in a short period. These findings raise the imperative need to continue the ongoing genomic surveillance that has been an integral part of the national response to monitor the SARS-CoV-2 profile and re-emergence in Qatar.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF-7 dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry- matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.