Genetic Susceptibility to Infectious Diseases in the Qatari Population

Background: Infectious diseases (IDs) account for 8% of deaths annually in Qatar, and therefore, represent a significant challenge for public health. Interestingly, the spread and severity of viral infections vary considerably between individuals and populations. The most recent example is SARS-CoV-2, which ranges from mild/asymptomatic to a severe respiratory syndrome. It has been previously reported that polymorphisms in genes linked to immunity can influence individuals' responses to infections as observed in tuberculosis, influenza, and HIV; however, studies exploring causal host genetic variants in IDs are still limited and dramatically skewed with regard to population inclusion. In fact, the genetic susceptibility to IDs in the Qatari population is largely unknown. Aim: To perform a comprehensive genetic screening to investigate the presence and frequency of variants previously associated with various infections in the Qatari population. Methods: Whole-genome sequencing was previously performed for 18,000 QBB participants using Illumina HiSeq X Ten1 sequencers. The initial data processing and quality assessment of the raw data has also been performed and variant calling files (VCF) were created. We were granted the access to the VCF files of 6,218 sequenced samples. The genetic variant data was then converted to PLINK file format using PLINK-1.9. Standardized quality-assurance and quality control (QA/QC) methods were followed to generate high quality and confidence on both SNPs and sample levels. The final file used for calculating allele frequency contained 6,047 subjects. Additionally, list of infections-related SNPs that were previously reported in the literature and deposited in GWAS catalog was extracted and used to calculate and compare the allelic frequency in the Qatari genomes compared to other populations. Results: The frequency of infections-related SNPs in the Qatari population was significantly lower for most infections. Most variants (78%) showed negative fold change in the Qatari genomes. Only 22% of all variants were more prevalent in Qatari population compared to others. The most significant differences were observed in genes related to TB and HIV (200-940 and 160-710 fold change, respectively). Conclusion: This study reports a lower susceptibility of the Qatari population to IDs in general. Nonetheless, this might also indicate the presence of unknown Qatari-unique variants and hence, highlights the need for further investigation in future GWAS

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

Genome-wide association study identifies several loci for HEV seropositivity

Hepatitis E viral (HEV) infection imposes a heavy global health burden. The variability in the prevalence of serological markers of HEV infection between different ethnic groups proposes a host genetic influence. Here, we report genetic polymorphisms associated with anti-HEV antibody positivity and level using binary- and quantitative-trait genome-wide association studies (GWAS) on a population from Qatar (n = 5829). We identified a region in 12p11.1 (lead SNP: rs559856097, allele: A, p = 2.3 × 10−10) significantly associated with anti-HEV antibodies level. This intergenic variant is located near SNORD112, a small nucleolar RNA (snoRNA). Additional gene-set and pathway enrichment analyses highlighted a strong correlation with anti-viral response-related pathways, including IFNs (alpha/beta) and interleukin-21 (IL-21) signaling. This is the first GWAS on the response to HEV infection. Further replication and functional experimentation are warranted to validate these findings.This study was funded by Qatar University High Impact Grant (Grant number: QUHI-BRC-20_21-1). The work makes use of data generated by the Qatar Genome Program (QGP) and Qatar Biobank (QBB), which are funded by Qatar foundation for Education, Science and Community

Reduced expression of PML predisposes to Paget's disease of bone by increasing osteoclast differentiation and bone resorption

Paget's disease of bone (PDB) is characterized by focal increases in bone remodelling. Genome-wide association studies identified a susceptibility locus for PDB tagged by rs5742915, which is located within the PML gene. Here, we have assessed the candidacy of PML as the predisposing gene for PDB at this locus. We found that the PDB-risk allele of rs5742915 was associated with lower PML expression and that PML expression in blood cells from individuals with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml-/- mice was increased compared with wild type. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml-/- was significantly blunted compared with wild type. Bone nodule formation was also increased in osteoblasts from Pml-/- mice when compared with wild type. Although microCT analysis of trabecular bone showed no differences between Pml-/- mice and wild type, bone histomorphometry showed that Pml-/- mice had high bone turnover with increased indices of bone resorption and increased mineral apposition rate. These data indicate that reduced expression of PML predisposes an individual to PDB and identify PML as a novel regulator of bone metabolism. This article has an associated First Person interview with the first author of the paper

Metabolic GWAS of elite athletes reveals novel genetically-influenced metabolites associated with athletic performance

Genetic research of elite athletic performance has been hindered by the complex phenotype and the relatively small effect size of the identified genetic variants. The aims of this study were to identify genetic predisposition to elite athletic performance by investigating genetically-influenced metabolites that discriminate elite athletes from non-elite athletes and to identify those associated with endurance sports. By conducting a genome wide association study with high-resolution metabolomics profiling in 490 elite athletes, common variant metabolic quantitative trait loci (mQTLs) were identified and compared with previously identified mQTLs in non-elite athletes. Among the identified mQTLs, those associated with endurance metabolites were determined. Two novel genetic loci in FOLH1 and VNN1 are reported in association with N-acetyl-aspartyl-glutamate and Linoleoyl ethanolamide, respectively. When focusing on endurance metabolites, one novel mQTL linking androstenediol (3alpha, 17alpha) monosulfate and SULT2A1 was identified. Potential interactions between the novel identified mQTLs and exercise are highlighted. This is the first report of common variant mQTLs linked to elite athletic performance and endurance sports with potential applications in biomarker discovery in elite athletic candidates, non-conventional anti-doping analytical approaches and therapeutic strategies

Targeted sequencing of the Paget's disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget's disease of bone

Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by increased but disorganized bone remodelling. Previous genome-wide association studies identified a locus on chromosome 14q32 tagged by rs10498635 which was significantly associated with susceptibility to PDB in several European populations. Here we conducted fine-mapping and targeted sequencing of the candidate locus to identify possible functional variants. Imputation in 741 PDB patients and 2699 controls confirmed that the association was confined to a 60 kb region in the RIN3 gene and conditional analysis adjusting for rs10498635 identified no new independent signals. Sequencing of the RIN3 gene identified a common missense variant (p.R279C) that was strongly associated with the disease (OR = 0.64; P = 1.4 × 10(−9)), and was in strong linkage disequilibrium with rs10498635. A further 13 rare missense variants were identified, seven of which were novel and detected only in PDB cases. When combined, these rare variants were over-represented in cases compared with controls (OR = 3.72; P = 8.9 × 10(−10)). Most rare variants were located in a region that encodes a proline-rich, intrinsically disordered domain of the protein and many were predicted to be pathogenic. RIN3 was expressed in bone tissue and its expression level was ∼10-fold higher in osteoclasts compared with osteoblasts. We conclude that susceptibility to PDB at the 14q32 locus is mediated by a combination of common and rare coding variants in RIN3 and suggest that RIN3 may contribute to PDB susceptibility by affecting osteoclast function

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.Funding: ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework programme 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. CABRIO was supported by the Instituto de Salud Carlos III and Fondos FEDER from the EU (PI 11/1092 and PI12/615). The AOGC study was funded by the Australian National Health and Medical Research Council (Project grant 511132). Lothian Birth Cohort 1921 phenotype collection was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping of the cohorts was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Research work on Slovenian case and control samples was funded by Slovenian Research Agency (project no. P3-0298 and J3-2330). The Danish National Birth Cohort (DNBC) is a result of major grants from the Danish National Research Foundation, the Danish Pharmacists’Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. The DNBC biobank is a part of the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. Dr Bjarke Feenstra is supported by an Oak Foundation Fellowship. The Framingham Study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and R01 AR061162; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was performed within the Genetic Factors for Osteoporosis (GEFOS) consortium, funded by the European Commission (HEALTH-F2-2008-201865-GEFOS).Acknowledgments: The authors are grateful to the patients and controls from the different centres who agreed to participate in this study. We would like to thank Ms Dilruba Kabir at the Rheumatology and Bone Disease Unit, CGEM-IGMM, Edinburgh, UK; Mr Matt Sims at the MRC Epidemiology Unit, University of Cambridge, UK; Ms Mila Jhamai and Ms Sarah Higgins at the Genetics Laboratory of Erasmus MC, Rotterdam, The Netherlands; Ms Johanna Hadler, Ms Kathryn A Addison and Ms Karena Pryce of the University of Queensland Centre for Clinical Genomics, Brisbane, Australia, for technical support on the genotyping stage; and Mr Marijn Verkerk and Dr Anis Abuseiris at the Genetics Laboratory of Erasmus MC, Rotterdam, for assistance on the data analysis. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. We would also like to thank Professor Nick Gilbert and Dr Giovanny Rodriguez-Blanco for their comments and advice on the manuscript preparation. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk