Host Genetic Variants Potentially Associated With SARS-CoV-2: A Multi-Population Analysis.

Clinical outcomes of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showed enormous inter-individual and inter-population differences, possibly due to host genetics differences. Earlier studies identified single nucleotide polymorphisms (SNPs) associated with SARS-CoV-1 in Eastern Asian (EAS) populations. In this report, we aimed at exploring the frequency of a set of genetic polymorphisms that could affect SARS-CoV-2 susceptibility or severity, including those that were previously associated with SARS-CoV-1. We extracted the list of SNPs that could potentially modulate SARS-CoV-2 from the genome wide association studies (GWAS) on SARS-CoV-1 and other viruses. We also collected the expression data of these SNPs from the expression quantitative trait loci (eQTLs) databases. Sequences from Qatar Genome Programme (QGP, = 6,054) and 1000Genome project were used to calculate and compare allelic frequencies (AF). A total of 74 SNPs, located in 10 genes: , -γ, , , , , , , and promoter, were identified. Analysis of Qatari genomes revealed significantly lower AF of risk variants linked to SARS-CoV-1 severity (, , , , and ) compared to that of 1000Genome and/or the EAS population (up to 25-fold change). Conversely, SNPs in , -γ, , and were more common among Qataris (average 2-fold change). Inter-population analysis showed that the distribution of risk alleles among Europeans differs substantially from Africans and EASs. Remarkably, Africans seem to carry extremely lower frequencies of SARS-CoV-1 susceptibility alleles, reaching to 32-fold decrease compared to other populations. Multiple genetic variants, which could potentially modulate SARS-CoV-2 infection, are significantly variable between populations, with the lowest frequency observed among Africans. Our results highlight the importance of exploring population genetics to understand and predict COVID-19 outcomes. Indeed, further studies are needed to validate these findings as well as to identify new genetic determinants linked to SARS-CoV-2.This work was supported by the Qatar University High Impact Grant (Grant Number: QUHI-BRC-20_21-1). OA was supported by a startup grant from the College of Health and Life Sciences, Hamad Bin Khalifa University. This work makes use of data generated by the Qatar Genome Programme (QGP) and Qatar Biobank (QBB), which are funded by Qatar Foundation for Education, Science and Community

T2DM GWAS in the Lebanese population confirms the role of TCF7L2 and CDKAL1 in disease susceptibility

Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are crucial to the understanding of Type 2 Diabetes Mellitus (T2DM) pathophysiology. We report a GWAS on the genetic basis of T2DM in a 3,286 Lebanese participants. More than 5,000,000 SNPs were directly genotyped or imputed using the 1000 Genomes Project reference panels. We identify genome-wide significant variants in two loci CDKAL1 and TCF7L2, independent of sex, age and BMI, with leading variants rs7766070 (OR = 1.39, P = 4.77 × 10(−9)) and rs34872471 (OR = 1.35, P = 1.01 × 10(−8)) respectively. The current study is the first GWAS to find genomic regions implicated in T2DM in the Lebanese population. The results support a central role of CDKAL1 and TCF7L2 in T2DM susceptibility in Southwest Asian populations and provide a plausible component for understanding molecular mechanisms involved in the disease

Multivariate epidemiologic analysis of type 2 diabetes mellitus risks in the Lebanese population

Background: The burden of diabetes in Lebanon requires well-targeted interventions for screening type 2 diabetes mellitus (T2DM) and prediabetes and prevention of risk factors. Newly recruited 998 Lebanese individuals, in addition to 7,292 already available, were studied to investigate the prevalence of diabetes, prediabetes and their associated risk factors. Methods: Participants had fasting blood sugar and glycohemoglobin tests in addition to a lipid profile. Clinical and demographic information were obtained from a detailed questionnaire. The relationship between T2DM, its risk factors, and its complications were tested. Comparisons of these risk factors among diabetics, healthy, and coronary artery disease (CAD) patients were performed. Results: The prevalence of T2DM significantly increased with increasing BMI (p < 0.0001). Exercise activity level negatively correlated with the disease (p = 0.002), whereas the prevalence of T2DM (p < 0.0001) and CAD family history (p = 0.006) positively correlated with the affection status. The mean levels of triglycerides and LDL-C were significantly higher in diabetics (1.87; 1.35) compared to individuals with prediabetes (1.63; 1.26) and unaffected controls (1.49; 1.19). People with T2DM showed a significant decrease in HDL-C levels. A strong correlation of overall hyperlipidemia with the diabetes affection status was shown (p < 0.0001). Other comorbid factors such as hypertension (p < 0.0001) and self-reported obesity (p < 0.0001) were highly associated with T2DM and prediabetes. Reproductive health of women showed a strong correlation between giving birth to a baby with a high weight and the occurrence of T2DM and prediabetes later in life (p < 0.0001). Retinopathy and peripheral neuropathy were significantly correlated with diabetes and prediabetes (p < 0.0001). Conclusions: The present study shows an alarming prevalence of diabetes and prediabetes in the studied subgroups representative of the Lebanese population. Electronic supplementary material The online version of this article (doi:10.1186/1758-5996-6-89) contains supplementary material, which is available to authorized users

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

The Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in Qatar, a Population-Based Study

Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes mellitus. In this study, we estimated the prevalence and genetic spectrum of MODY in the Middle Eastern population of Qatar using whole-genome sequencing (WGS) of 14,364 subjects from the population-based Qatar biobank (QBB) cohort. We focused our investigations on 14 previously identified genes ascribed to the cause of MODY and two potentially novel MODY-causing genes, RFX6 and NKX6-1. Genetic variations within the 16 MODY-related genes were assessed for their pathogenicity to identify disease-causing mutations. Analysis of QBB phenotype data revealed 72 subjects (0.5%) with type 1 diabetes, 2915 subjects (20.3%) with type 2 diabetes and 11,377 (79.2%) without diabetes. We identified 22 mutations in 67 subjects that were previously reported in the Human Genetic Mutation Database (HGMD) as disease-causing (DM) or likely disease causing (DM?) for MODY. We also identified 28 potentially novel MODY-causing mutations, predicted to be among the top 1% most deleterious mutations in the human genome, which showed complete (100%) disease penetrance in 34 subjects. Overall, we estimated that MODY accounts for around 2.2–3.4% of diabetes patients in Qatar. This is the first population-based study to determine the genetic spectrum and estimate the prevalence of MODY in the Middle East. Further research to characterize the newly identified mutations is warranted

Type II diabetes mellitus and hyperhomocysteinemia: a complex interaction

Background: Elevated homocysteine (Hc) levels have a well-established and clear causal relationship to epithelial damage leading to coronary artery disease. Furthermore, it is strongly associated with other metabolic syndrome variables, such as hypertension, which is correlated with type II diabetes mellitus (T2DM). Studies on T2DM in relation to Hc levels have shown both positive and negative associations. The aim of the present study is to examine the relationship between Hc levels and risk of T2DM in the Lebanese population. Methods: We sought to identify whether Hc associates positively or negatively with diabetes in a case–control study, where 2755 subjects enrolled from patients who had been catheterized for coronary artery diagnosis and treatment. We further sought to identify whether the gene variant MTHFR 667C>T is associated with T2DM, and how Hc and MTHFR 667C>T also impact other correlates of T2DM, including the widely used diuretics in this study population. Results: We found that Hc levels were significantly reduced among subjects with diabetes compared to those without diabetes when adjusted for all potential confounders (OR 0.640; 95% CI [0.44–0.92]; p = 0.0200). The associations between Hc levels and other variates contradicted the result: hypertension associates positively with high Hc levels, and with T2DM. The MTHFR 667C>T only associated significantly with high Hc levels. Conclusion: These results suggest population-specific variations among a range of mechanisms that modulate the association of Hc and T2DM, providing a probe for future studies

T2DM GWAS in the Lebanese population confirms the role of TCF7L2 and CDKAL1 in disease susceptibility

Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are crucial to the understanding of Type 2 Diabetes Mellitus (T2DM) pathophysiology. We report a GWAS on the genetic basis of T2DM in a 3,286 Lebanese participants. More than 5,000,000 SNPs were directly genotyped or imputed using the 1000 Genomes Project reference panels. We identify genome-wide significant variants in two loci CDKAL1 and TCF7L2, independent of sex, age and BMI, with leading variants rs7766070 (OR = 1.39, P = 4.77 × 10−9) and rs34872471 (OR = 1.35, P = 1.01 × 10−8) respectively. The current study is the first GWAS to find genomic regions implicated in T2DM in the Lebanese population. The results support a central role of CDKAL1 and TCF7L2 in T2DM susceptibility in Southwest Asian populations and provide a plausible component for understanding molecular mechanisms involved in the disease

One Year of SARS-CoV-2: Genomic Characterization of COVID-19 Outbreak in Qatar

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

The QChip1 knowledgebase and microarray for precision medicine in Qatar

Risk genes for Mendelian (single-gene) disorders (SGDs) are consistent across populations, but pathogenic risk variants that cause SGDs are typically population-private. The goal was to develop "QChip1," an inexpensive genotyping microarray to comprehensively screen newborns, couples, and patients for SGD risk variants in Qatar, a small nation on the Arabian Peninsula with a high degree of consanguinity. Over 108 variants in 8445 Qatari were identified for inclusion in a genotyping array containing 165,695 probes for 83,542 known and potentially pathogenic variants in 3438 SGDs. QChip1 had a concordance with whole-genome sequencing of 99.1%. Testing of QChip1 with 2707 Qatari genomes identified 32,674 risk variants, an average of 134 pathogenic alleles per Qatari genome. The most common pathogenic variants were those causing homocystinuria (1.12% risk allele frequency), and Stargardt disease (2.07%). The majority (85%) of Qatari SGD pathogenic variants were not present in Western populations such as European American, South Asian American, and African American in New York City and European and Afro-Caribbean in Puerto Rico; and only 50% were observed in a broad collection of data across the Greater Middle East including Kuwait, Iran, and United Arab Emirates. This study demonstrates the feasibility of developing accurate screening tools to identify SGD risk variants in understudied populations, and the need for ancestry-specific SGD screening tools. 2022, The Author(s).This is a collaborative work between Qatar Genome, Qatar Biobank, Weill Cornell (New York and Qatar), Hamad Medical Corporation and Sidra Medicine. We are thankful for everyone who contributed to this endeavor from all participating institutes. We would like to especially thank all participants in this study for their continuous support. We thank Dr. Fatemeh Abbaszadeh, for quality control and implementing QChip in the diagnostic services; N. Mohamed for editorial support, E. Betancourt for administrative support, E. Guzman for IT support, and J. Pillardy for high-performance computing support. J.R.F. also thanks Alan R. Shuldiner and Regeneron Genetics Center for supporting, J.R.F. to help complete this project. Special thanks to Alphonse Tharangeval at the Dasman Diabetes Institute in Kuwait for providing allele frequency lookups, and to the Center for Arab Genetic Studies in UAE, the GME Variome at University of California at San Diego and the Iranomefor providing public access to their databases. The authors are saddened by the passing of Andrew Brooks after the manuscript was submitted to the journal for review. This publication was made possible by The Qatar Foundation, the Weill Cornell Medical College in Qatar; NPRP 09-741-3 193, NPRP 5-436-3-116, NPRP 7-1425-3-370, NPRP 7-1301-3-336, and NPRP P8-1913-3-396 from the Qatar National Research Fund (a member of the Qatar Foundation). The findings achieved herein are solely the responsibility of the authors.Scopu