32 results on '"Albagha OME"'
Search Results
2. LOCI FOR REGULATION OF BMD IN MEN AND WOMEN THE FAMOS STUDY
- Author
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Ralston, SH, Galwey, N, MacKay, I, Albagha, OME, Cardon, L, Compston, JE, Cooper, C, Duncan, E, Keen, R, Langdahl, B, McLellan, A, O'Riordan, J, Pols, HA, Reid, DM, Uitterlinden, AG, Wass, JA, and Bennett, ST
- Published
- 2016
3. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci
- Author
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Reppe, S, Wang, Y, Thompson, WK, McEvoy, LK, Schork, AJ, Zuber, V, LeBlanc, M, Bettella, F, Mills, IG, Desikan, RS, Djurovic, S, Gautvik, KM, Dale, AM, Andreassen, OA, Estrada, K, Styrkarsdottir, U, Evangelou, E, Hsu, YH, Duncan, EL, Ntzani, EE, Oei, L, Albagha, OME, Amin, N, Kemp, JP, Koller, DL, Li, G, Liu, CT, Minster, RL, Moayyeri, A, Vandenput, L, Willner, D, Xiao, SM, Yerges-Armstrong, LM, Zheng, HF, Alonso, N, Eriksson, J, Kammerer, CM, Kaptoge, SK, Leo, PJ, Thorleifsson, G, Wilson, SG, Wilson, JF, Aalto, V, Alen, M, Aragaki, AK, Aspelund, T, Center, JR, Dailiana, Z, Duggan, DJ, Garcia, M, Garcia-Giralt, N, Giroux, S, Hallmans, G, Hocking, LJ, Husted, LB, Jameson, KA, Khusainova, R, Kim, GS, Kooperberg, C, Koromila, T, Kruk, M, Laaksonen, M, and Lacroix, AZ
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musculoskeletal diseases ,General Science & Technology ,MD Multidisciplinary - Abstract
© 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.
- Published
- 2015
4. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture
- Author
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Estrada, K, Styrkarsdottir, U, Evangelou, E, Hsu, YH, Duncan, EL, Ntzani, EE, Oei, L, Albagha, OME, Amin, N, Kemp, JP, Koller, DL, Li, G, Liu, CT, Minster, RL, Moayyeri, A, Vandenput, L, Willner, D, Xiao, SM, Yerges-Armstrong, LM, Zheng, HF, Alonso, N, Eriksson, J, Kammerer, CM, Kaptoge, SK, Leo, PJ, Thorleifsson, G, Wilson, SG, Wilson, JF, Aalto, V, Alen, M, Aragaki, AK, Aspelund, T, Center, JR, Dailiana, Z, Duggan, DJ, Garcia, M, Garcia-Giralt, N, Giroux, S, Hallmans, G, Hocking, LJ, Husted, LB, Jameson, KA, Khusainova, R, Kim, GS, Kooperberg, C, Koromila, T, Kruk, M, Laaksonen, M, Lacroix, AZ, Lee, SH, Leung, PC, Lewis, JR, Masi, L, Mencej-Bedrac, S, Nguyen, TV, Nogues, X, Patel, MS, Prezelj, J, Rose, LM, Scollen, S, Siggeirsdottir, K, Smith, AV, Svensson, O, Trompet, S, Trummer, O, Van Schoor, NM, Woo, J, Zhu, K, Balcells, S, Brandi, ML, Buckley, BM, Cheng, S, Christiansen, C, Cooper, C, Dedoussis, G, Ford, I, Frost, M, Goltzman, D, González-Macías, J, Kähönen, M, Karlsson, M, Khusnutdinova, E, Koh, JM, Kollia, P, Langdahl, BL, Leslie, WD, Lips, P, Ljunggren, Ø, Lorenc, RS, Marc, J, Mellström, D, Obermayer-Pietsch, B, Olmos, JM, Pettersson-Kymmer, U, Reid, DM, Riancho, JA, Ridker, PM, Rousseau, F, Lagboom, PES, and Tang, NLS
- Subjects
musculoskeletal diseases ,Male ,Genotype ,Quantitative Trait Loci ,European Continental Ancestry Group ,Mitochondrial Membrane Transport Proteins ,Polymorphism, Single Nucleotide ,Fractures, Bone ,Risk Factors ,Bone Density ,Humans ,Genetic Predisposition to Disease ,Glycoproteins ,Extracellular Matrix Proteins ,Lumbar Vertebrae ,Femur Neck ,Gene Expression Profiling ,Spectrin ,Computational Biology ,Phosphoproteins ,Low Density Lipoprotein Receptor-Related Protein-5 ,Osteoporosis ,Intercellular Signaling Peptides and Proteins ,Female ,Developmental Biology ,Genome-Wide Association Study - Abstract
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10 -8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10 -4, Bonferroni corrected), of which six reached P < 5 × 10 -8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. © 2012 Nature America, Inc. All rights reserved.
- Published
- 2012
5. Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol.
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Alenbawi J, Al-Sarraj YA, Umlai UI, Kadhi A, Hendi NN, Nemer G, and Albagha OME
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- Humans, Male, Female, Intestinal Diseases genetics, Intestinal Diseases blood, Adult, Cholesterol blood, Cholesterol analogs & derivatives, Hypercholesterolemia genetics, Hypercholesterolemia blood, Middle Aged, Lipoproteins blood, Lipoproteins genetics, ATP-Binding Cassette Transporters genetics, Genome-Wide Association Study, Phytosterols blood, Phytosterols genetics, Phytosterols adverse effects, Polymorphism, Single Nucleotide genetics, Sitosterols blood, Lipid Metabolism, Inborn Errors genetics, Lipid Metabolism, Inborn Errors blood, ATP Binding Cassette Transporter, Subfamily G, Member 5 genetics, ATP Binding Cassette Transporter, Subfamily G, Member 8 genetics
- Abstract
Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R
2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies., (© 2024. The Author(s).)- Published
- 2024
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6. Genome-wide association study and polygenic score assessment of insulin resistance.
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Aliyu U, Umlai UI, Toor SM, Elashi AA, Al-Sarraj YA, Abou Samra AB, Suhre K, and Albagha OME
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- Humans, Female, Male, Middle Aged, Adult, Qatar epidemiology, Polymorphism, Single Nucleotide, Insulin-Secreting Cells metabolism, Aged, Body Mass Index, Cohort Studies, Genetic Predisposition to Disease, Insulin Resistance genetics, Genome-Wide Association Study, Multifactorial Inheritance, Diabetes Mellitus, Type 2 genetics
- Abstract
Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly conducted in European populations, while Middle Eastern populations remain largely underrepresented. We conducted a GWAS on the indices of IR (HOMA2-IR) and beta cell function (HOMA2-%B) in 6,217 non-diabetic individuals from the Qatar Biobank (QBB; Discovery cohort; n = 2170, Replication cohort; n = 4047) with and without body mass index (BMI) adjustment. We also developed polygenic scores (PGS) for HOMA2-IR and compared their performance with a previously derived PGS for HOMA-IR (PGS003470). We replicated 11 loci that have been previously associated with HOMA-IR and 24 loci that have been associated with HOMA-%B, at nominal statistical significance. We also identified a novel locus associated with beta cell function near VEGFC gene, tagged by rs61552983 ( P = 4.38 × 10
-8 ). Moreover, our best performing PGS (Q-PGS4; Adj R2 = 0.233 ± 0.014; P = 1.55 x 10-3 ) performed better than PGS003470 (Adj R2 = 0.194 ± 0.014; P = 5.45 x 10-2 ) in predicting HOMA2-IR in our dataset. This is the first GWAS on HOMA2 and the first GWAS conducted in the Middle East focusing on IR and beta cell function. Herein, we report a novel locus in VEGFC that is implicated in beta cell dysfunction. Inclusion of under-represented populations in GWAS has potentials to provide important insights into the genetic architecture of IR and beta cell function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Aliyu, Umlai, Toor, Elashi, Al-Sarraj, Abou−Samra, Suhre and Albagha.)- Published
- 2024
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7. Correction: Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus.
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Elashi AA, Toor SM, Umlai UI, Al-Sarraj YA, Taheri S, Suhre K, Abou-Samra AB, and Albagha OME
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- 2024
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8. Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus.
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Elashi AA, Toor SM, Umlai UI, Al-Sarraj YA, Taheri S, Suhre K, Abou-Samra AB, and Albagha OME
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- Humans, Qatar epidemiology, Male, Female, Middle Aged, Genetic Loci, Case-Control Studies, Body Mass Index, Ethnicity genetics, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
- Abstract
Background: The genetic basis of type 2 diabetes (T2D) is under-investigated in the Middle East, despite the rapidly growing disease prevalence. We aimed to define the genetic determinants of T2D in Qatar., Methods: Using whole genome sequencing of 11,436 participants (2765 T2D cases and 8671 controls) from the population-based Qatar Biobank (QBB), we conducted a genome-wide association study (GWAS) of T2D with and without body mass index (BMI) adjustment., Results: We replicated 93 known T2D-associated loci in a BMI-unadjusted model, while 96 known loci were replicated in a BMI-adjusted model. The effect sizes and allele frequencies of replicated SNPs in the Qatari population generally concurred with those from European populations. We identified a locus specific to our cohort located between the APOBEC3H and CBX7 genes in the BMI-unadjusted model. Also, we performed a transethnic meta-analysis of our cohort with a previous GWAS on T2D in multi-ancestry individuals (180,834 T2D cases and 1,159,055 controls). One locus in DYNC2H1 gene reached genome-wide significance in the meta-analysis. Assessing polygenic risk scores derived from European- and multi-ancestries in the Qatari population showed higher predictive performance of the multi-ancestry panel compared to the European panel., Conclusion: Our study provides new insights into the genetic architecture of T2D in a Middle Eastern population and identifies genes that may be explored further for their involvement in T2D pathogenesis., (© 2024. The Author(s).)
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- 2024
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9. The genetic landscape of autism spectrum disorder in the Middle Eastern population.
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Al-Sarraj Y, Taha RZ, Al-Dous E, Ahram D, Abbasi S, Abuazab E, Shaath H, Habbab W, Errafii K, Bejaoui Y, AlMotawa M, Khattab N, Aqel YA, Shalaby KE, Al-Ansari A, Kambouris M, Abouzohri A, Ghazal I, Tolfat M, Alshaban F, El-Shanti H, and Albagha OME
- Abstract
Introduction: Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong clinical heterogeneity. Genetic factors play an important role in ASD, but about 75% of ASD cases have an undetermined genetic risk. Methods: We extensively investigated an ASD cohort made of 102 families from the Middle Eastern population of Qatar. First, we investigated the copy number variations (CNV) contribution using genome-wide SNP arrays. Next, we employed Next Generation Sequencing (NGS) to identify de novo or inherited variants contributing to the ASD etiology and its associated comorbid conditions in families with complete trios (affected child and the parents). Results: Our analysis revealed 16 CNV regions located in genomic regions implicated in ASD. The analysis of the 88 ASD cases identified 41 genes in 39 ASD subjects with de novo (n = 24) or inherited variants (n = 22). We identified three novel de novo variants in new candidate genes for ASD ( DTX4 , ARMC6 , and B3GNT3 ). Also, we have identified 15 de novo variants in genes that were previously implicated in ASD or related neurodevelopmental disorders ( PHF21A , WASF1 , TCF20 , DEAF1 , MED13 , CREBBP , KDM6B, SMURF1 , ADNP , CACNA1G , MYT1L , KIF13B , GRIA2 , CHM , and KCNK9 ). Additionally, we defined eight novel recessive variants ( RYR2 , DNAH3 , TSPYL2 , UPF3B KDM5C , LYST , and WNK3 ), four of which were X-linked. Conclusion: Despite the ASD multifactorial etiology that hinders ASD genetic risk discovery, the number of identified novel or known putative ASD genetic variants was appreciable. Nevertheless, this study represents the first comprehensive characterization of ASD genetic risk in Qatar's Middle Eastern population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Al-Sarraj, Taha, Al-Dous, Ahram, Abbasi, Abuazab, Shaath, Habbab, Errafii, Bejaoui, AlMotawa, Khattab, Aqel, Shalaby, Al-Ansari, Kambouris, Abouzohri, Ghazal, Tolfat, Alshaban, El-Shanti and Albagha.)
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- 2024
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10. Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.
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Shrine N, Izquierdo AG, Chen J, Packer R, Hall RJ, Guyatt AL, Batini C, Thompson RJ, Pavuluri C, Malik V, Hobbs BD, Moll M, Kim W, Tal-Singer R, Bakke P, Fawcett KA, John C, Coley K, Piga NN, Pozarickij A, Lin K, Millwood IY, Chen Z, Li L, Wijnant SRA, Lahousse L, Brusselle G, Uitterlinden AG, Manichaikul A, Oelsner EC, Rich SS, Barr RG, Kerr SM, Vitart V, Brown MR, Wielscher M, Imboden M, Jeong A, Bartz TM, Gharib SA, Flexeder C, Karrasch S, Gieger C, Peters A, Stubbe B, Hu X, Ortega VE, Meyers DA, Bleecker ER, Gabriel SB, Gupta N, Smith AV, Luan J, Zhao JH, Hansen AF, Langhammer A, Willer C, Bhatta L, Porteous D, Smith BH, Campbell A, Sofer T, Lee J, Daviglus ML, Yu B, Lim E, Xu H, O'Connor GT, Thareja G, Albagha OME, Suhre K, Granell R, Faquih TO, Hiemstra PS, Slats AM, Mullin BH, Hui J, James A, Beilby J, Patasova K, Hysi P, Koskela JT, Wyss AB, Jin J, Sikdar S, Lee M, May-Wilson S, Pirastu N, Kentistou KA, Joshi PK, Timmers PRHJ, Williams AT, Free RC, Wang X, Morrison JL, Gilliland FD, Chen Z, Wang CA, Foong RE, Harris SE, Taylor A, Redmond P, Cook JP, Mahajan A, Lind L, Palviainen T, Lehtimäki T, Raitakari OT, Kaprio J, Rantanen T, Pietiläinen KH, Cox SR, Pennell CE, Hall GL, Gauderman WJ, Brightling C, Wilson JF, Vasankari T, Laitinen T, Salomaa V, Mook-Kanamori DO, Timpson NJ, Zeggini E, Dupuis J, Hayward C, Brumpton B, Langenberg C, Weiss S, Homuth G, Schmidt CO, Probst-Hensch N, Jarvelin MR, Morrison AC, Polasek O, Rudan I, Lee JH, Sayers I, Rawlins EL, Dudbridge F, Silverman EK, Strachan DP, Walters RG, Morris AP, London SJ, Cho MH, Wain LV, Hall IP, and Tobin MD
- Published
- 2023
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11. Integrated epigenome, whole genome sequence and metabolome analyses identify novel multi-omics pathways in type 2 diabetes: a Middle Eastern study.
- Author
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Yousri NA, Albagha OME, and Hunt SC
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- Humans, Phosphofructokinase-2, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Epigenome, Metabolome, Multiomics, Middle Eastern People genetics
- Abstract
Background: T2D is of high prevalence in the middle east and thus studying its mechanisms is of a significant importance. Using 1026 Qatar BioBank samples, epigenetics, whole genome sequencing and metabolomics were combined to further elucidate the biological mechanisms of T2D in a population with a high prevalence of T2D., Methods: An epigenome-wide association study (EWAS) with T2D was performed using the Infinium 850K EPIC array, followed by whole genome-wide sequencing SNP-CpG association analysis (> 5.5 million SNPs) and a methylome-metabolome (CpG-metabolite) analysis of the identified T2D sites., Results: A total of 66 T2D-CpG associations were identified, including 63 novel sites in pathways of fructose and mannose metabolism, insulin signaling, galactose, starch and sucrose metabolism, and carbohydrate absorption and digestion. Whole genome SNP associations with the 66 CpGs resulted in 688 significant CpG-SNP associations comprising 22 unique CpGs (33% of the 66 CPGs) and included 181 novel pairs or pairs in novel loci. Fourteen of the loci overlapped published GWAS loci for diabetes related traits and were used to identify causal associations of HK1 and PFKFB2 with HbA1c. Methylome-metabolome analysis identified 66 significant CpG-metabolite pairs among which 61 pairs were novel. Using the identified methylome-metabolome associations, methylation QTLs, and metabolic networks, a multi-omics network was constructed which suggested a number of metabolic mechanisms underlying T2D methylated genes. 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) - a triglyceride-associated metabolite, shared a common network with 13 methylated CpGs, including TXNIP, PFKFB2, OCIAD1, and BLCAP. Mannonate - a food component/plant shared a common network with 6 methylated genes, including TXNIP, BLCAP, THBS4 and PEF1, pointing to a common possible cause of methylation in those genes. A subnetwork with alanine, glutamine, urea cycle (citrulline, arginine), and 1-carboxyethylvaline linked to PFKFB2 and TXNIP revealed associations with kidney function, hypertension and triglyceride metabolism. The pathway containing STYXL1-POR was associated with a sphingosine-ceramides subnetwork associated with HDL-C and LDL-C and point to steroid perturbations in T2D., Conclusions: This study revealed several novel methylated genes in T2D, with their genomic variants and associated metabolic pathways with several implications for future clinical use of multi-omics associations in disease and for studying therapeutic targets., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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12. Transcriptome profiling and network enrichment analyses identify subtype-specific therapeutic gene targets for breast cancer and their microRNA regulatory networks.
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Elango R, Rashid S, Vishnubalaji R, Al-Sarraf R, Akhtar M, Ouararhni K, Decock J, Albagha OME, and Alajez NM
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- Humans, Gene Expression Profiling, Transcriptome genetics, RNA, Messenger genetics, MicroRNAs genetics, Triple Negative Breast Neoplasms
- Abstract
Previous studies have suggested that breast cancer (BC) from the Middle East and North Africa (MENA) is presented at younger age with advanced tumor stage, indicating underlying biological differences. Given the scant transcriptomic data on BC from the MENA region and to better understand the biology of this disease, we performed mRNA and microRNA (miRNA) transcriptomic profiling on a local cohort of BC (n = 96) from Qatar. Our data revealed the differentially expressed genes and miRNAs as function of BC molecular subtypes (HR
+ , HER2+ , HER2+ HR+ , and TNBC), tumor grade (GIII vs GI-II), patients' age (young (≤40) vs old (>40)), and ethnicity (MENA vs non-MENA). Our profiling data revealed close similarity between TNBC and HER2+ , while the transcriptome of HER2+ HR+ tumor was resemblant of that from HR+ tumors. Network analysis identified complex miRNA-mRNA regulatory networks in each BC molecular subtype, in high vs low grade tumors, in tumors from young vs old patients, and in tumors from MENA vs non-MENA, thus implicating miRNA-mediated gene regulation as an essential mechanism in shaping the transcriptome of BC. Integration of our transcriptomic data with CRISPR-Cas9 functional screen data and the OncoKB database identified numerous dependencies and therapeutic vulnerabilities in each BC molecular subtype, while CDC123 was functionally validated as potential therapeutic target for TNBC. Cox regression survival analyses identified mRNA and miRNA-based signatures predicative of worse and better relapse free survival (RFS), which were validated in larger BC cohorts. Our data provides comprehensive transcriptomic profiling and unraveled the miRNA-mRNA regulatory networks in BC patients from the region and identified novel actionable gene targets, employing integrated approach. Findings from the current study have potential implications to improve the current standard-of-care for BC from the MENA as well as patients from other ethnicities., (© 2023. The Author(s).)- Published
- 2023
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13. Genome-wide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.
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Alonso N, Albagha OME, Azfer A, Larraz-Prieto B, Berg K, Riches PL, Ostanek B, Kocjan T, Marc J, Langdahl BL, and Ralston SH
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- Humans, Female, Bone Density, Teriparatide therapeutic use, Genome-Wide Association Study, Bone Density Conservation Agents therapeutic use, Osteoporosis, Osteoporosis, Postmenopausal drug therapy
- Abstract
Objectives: Teriparatide (TPTD) is an effective treatment for osteoporosis but the individual response to therapy is variable for reasons that are unclear. This study aimed to determine whether the response to TPTD might be influenced by genetic factors., Methods: We searched for predictors of the response of bone mineral density (BMD) to TPTD using a two-stage genome-wide association study in 437 patients with osteoporosis from three referral centres. Demographic and clinical data including the response of BMD to treatment at the lumbar spine and hip were extracted from the medical records of each participant., Results: Allelic variation at rs6430612 on chromosome 2, close to the CXCR4 gene was associated with the response of spine BMD to TPTD at a genome wide significant level (p=9.2×10
-9 beta=-0.35 (-0.47 to -0.23)). The increase in BMD was almost twice as great in AA homozygotes at rs6430612 as compared with GG homozygotes with intermediate values in heterozygotes. The same variant was also associated with response of femoral neck and total hip BMD (p=0.007). An additional locus on chromosome 19 tagged by rs73056959 was associated with the response of femoral neck BMD to TPTD (p=3.5×10-9 , beta=-1.61 (-2.14 to -1.07))., Conclusions: Genetic factors influence the response to TPTD at the lumbar spine and hip with a magnitude of effect that is clinically relevant. Further studies are required to identify the causal genetic variants and underlying mechanisms as well as to explore how genetic testing for these variants might be implemented in clinical practice., Competing Interests: Competing interests: BLL has served on advisory boards and received lecture honoraria from Amgen, UCB, Gideon-Richter, Astellas and Astra-Zeneca. She holds research grants from Novo Nordisk and Amgen. SHR holds research grants from Amgen, Eli Lilly and UCB., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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14. Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations.
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Thareja G, Belkadi A, Arnold M, Albagha OME, Graumann J, Schmidt F, Grallert H, Peters A, Gieger C, Consortium TQGPR, and Suhre K
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- Humans, Genome-Wide Association Study, Genetics, Population, Arabs genetics, Quantitative Trait Loci, White People genetics
- Abstract
Polygenic scores (PGS) can identify individuals at risk of adverse health events and guide genetics-based personalized medicine. However, it is not clear how well PGS translate between different populations, limiting their application to well-studied ethnicities. Proteins are intermediate traits linking genetic predisposition and environmental factors to disease, with numerous blood circulating protein levels representing functional readouts of disease-related processes. We hypothesized that studying the genetic architecture of a comprehensive set of blood-circulating proteins between a European and an Arab population could shed fresh light on the translatability of PGS to understudied populations. We therefore conducted a genome-wide association study with whole-genome sequencing data using 1301 proteins measured on the SOMAscan aptamer-based affinity proteomics platform in 2935 samples of Qatar Biobank and evaluated the replication of protein quantitative traits (pQTLs) from European studies in an Arab population. Then, we investigated the colocalization of shared pQTL signals between the two populations. Finally, we compared the performance of protein PGS derived from a Caucasian population in a European and an Arab cohort. We found that the majority of shared pQTL signals (81.8%) colocalized between both populations. About one-third of the genetic protein heritability was explained by protein PGS derived from a European cohort, with protein PGS performing ~20% better in Europeans when compared to Arabs. Our results are relevant for the translation of PGS to non-Caucasian populations, as well as for future efforts to extend genetic research to understudied populations., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2023
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15. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.
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Shrine N, Izquierdo AG, Chen J, Packer R, Hall RJ, Guyatt AL, Batini C, Thompson RJ, Pavuluri C, Malik V, Hobbs BD, Moll M, Kim W, Tal-Singer R, Bakke P, Fawcett KA, John C, Coley K, Piga NN, Pozarickij A, Lin K, Millwood IY, Chen Z, Li L, Wijnant SRA, Lahousse L, Brusselle G, Uitterlinden AG, Manichaikul A, Oelsner EC, Rich SS, Barr RG, Kerr SM, Vitart V, Brown MR, Wielscher M, Imboden M, Jeong A, Bartz TM, Gharib SA, Flexeder C, Karrasch S, Gieger C, Peters A, Stubbe B, Hu X, Ortega VE, Meyers DA, Bleecker ER, Gabriel SB, Gupta N, Smith AV, Luan J, Zhao JH, Hansen AF, Langhammer A, Willer C, Bhatta L, Porteous D, Smith BH, Campbell A, Sofer T, Lee J, Daviglus ML, Yu B, Lim E, Xu H, O'Connor GT, Thareja G, Albagha OME, Suhre K, Granell R, Faquih TO, Hiemstra PS, Slats AM, Mullin BH, Hui J, James A, Beilby J, Patasova K, Hysi P, Koskela JT, Wyss AB, Jin J, Sikdar S, Lee M, May-Wilson S, Pirastu N, Kentistou KA, Joshi PK, Timmers PRHJ, Williams AT, Free RC, Wang X, Morrison JL, Gilliland FD, Chen Z, Wang CA, Foong RE, Harris SE, Taylor A, Redmond P, Cook JP, Mahajan A, Lind L, Palviainen T, Lehtimäki T, Raitakari OT, Kaprio J, Rantanen T, Pietiläinen KH, Cox SR, Pennell CE, Hall GL, Gauderman WJ, Brightling C, Wilson JF, Vasankari T, Laitinen T, Salomaa V, Mook-Kanamori DO, Timpson NJ, Zeggini E, Dupuis J, Hayward C, Brumpton B, Langenberg C, Weiss S, Homuth G, Schmidt CO, Probst-Hensch N, Jarvelin MR, Morrison AC, Polasek O, Rudan I, Lee JH, Sayers I, Rawlins EL, Dudbridge F, Silverman EK, Strachan DP, Walters RG, Morris AP, London SJ, Cho MH, Wain LV, Hall IP, and Tobin MD
- Subjects
- Humans, Genome-Wide Association Study, Genetic Predisposition to Disease genetics, Smoking adverse effects, Smoking genetics, Polymorphism, Single Nucleotide genetics, Lung, Pulmonary Disease, Chronic Obstructive genetics
- Abstract
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., (© 2023. The Author(s).)
- Published
- 2023
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16. Circulating MicroRNA Profiling Identifies Distinct MicroRNA Signatures in Acute Ischemic Stroke and Transient Ischemic Attack Patients.
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Toor SM, Aldous EK, Parray A, Akhtar N, Al-Sarraj Y, Abdelalim EM, Arredouani A, El-Agnaf O, Thornalley PJ, Pananchikkal SV, Pir GJ, Ayadathil R, Shuaib A, Alajez NM, and Albagha OME
- Subjects
- Humans, Biomarkers, Circulating MicroRNA genetics, Ischemic Attack, Transient genetics, Ischemic Stroke genetics, MicroRNAs metabolism, Stroke therapy
- Abstract
Transient ischemic attack (TIA) refers to a momentary neurologic deficit caused by focal cerebral, spinal or retinal ischemic insult. TIA is associated with a high risk of impending acute ischemic stroke (AIS), a neurologic dysfunction characterized by focal cerebral, spinal or retinal infarction. Understanding the differences in molecular pathways in AIS and TIA has merit for deciphering the underlying cause for neuronal deficits with long-term effects and high risks of morbidity and mortality. In this study, we performed comprehensive investigations into the circulating microRNA (miRNA) profiles of AIS (n = 191) and TIA (n = 61) patients. We performed RNA-Seq on serum samples collected within 24 hrs of clinical diagnosis and randomly divided the study populations into discovery and validation cohorts. We identified a panel of 11 differentially regulated miRNAs at FDR < 0.05. Hsa-miR-548c-5p, -20a-5p, -18a-5p, -484, -652-3p, -486-3p, -24-3p, -181a-5p and -222-3p were upregulated, while hsa-miR-500a-3p and -206 were downregulated in AIS patients compared to TIA patients. We also probed the previously validated gene targets of our identified miRNA panel to highlight the molecular pathways affected in AIS. Moreover, we developed a multivariate classifier with potential utilization as a discriminative biomarker for AIS and TIA patients. The underlying molecular pathways in AIS compared to TIA may be explored further in functional studies for therapeutic targeting in clinical translation.
- Published
- 2022
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17. The Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in Qatar, a Population-Based Study.
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Elashi AA, Toor SM, Diboun I, Al-Sarraj Y, Taheri S, Suhre K, Abou-Samra AB, and Albagha OME
- Subjects
- Humans, Qatar epidemiology, Hepatocyte Nuclear Factor 1-alpha genetics, Mutation, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics
- Abstract
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.
- Published
- 2022
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18. Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population.
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Zaghlool SB, Halama A, Stephan N, Gudmundsdottir V, Gudnason V, Jennings LL, Thangam M, Ahlqvist E, Malik RA, Albagha OME, Abou-Samra AB, and Suhre K
- Subjects
- Humans, Proteomics, Arabs, Insulin, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 1
- Abstract
Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes., (© 2022. The Author(s).)
- Published
- 2022
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19. Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population.
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Belkadi A, Thareja G, Abbaszadeh F, Badii R, Fauman E, Albagha OME, and Suhre K
- Abstract
Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery., Competing Interests: E.B.F. is an employee of Pfizer., (© 2022 The Author(s).)
- Published
- 2022
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20. Identification of distinct circulating microRNAs in acute ischemic stroke patients with type 2 diabetes mellitus.
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Toor SM, Aldous EK, Parray A, Akhtar N, Al-Sarraj Y, Abdelalim EM, Arredouani A, El-Agnaf O, Thornalley PJ, Pananchikkal SV, Pir GJ, Kuni RAT, Shuaib A, Alajez NM, and Albagha OME
- Abstract
Stroke is the second leading cause of global mortality and continued efforts aim to identify predictive, diagnostic, or prognostic biomarkers to reduce the disease burden. Circulating microRNAs (miRNAs) have emerged as potential biomarkers in stroke. We performed comprehensive circulating miRNA profiling of ischemic stroke patients with or without type 2 diabetes mellitus (T2DM), an important risk factor associated with worse clinical outcomes in stroke. Serum samples were collected within 24 h of acute stroke diagnosis and circulating miRNAs profiled using RNA-Seq were compared between stroke patients with T2DM (SWDM; n = 92) and those without T2DM (SWoDM; n = 98). Our analysis workflow involved random allocation of study cohorts into discovery ( n = 96) and validation ( n = 94) datasets. Five miRNAs were found to be differentially regulated in SWDM compared to SWoDM patients. Hsa-miR-361-3p and -664a-5p were downregulated, whereas miR-423-3p, -140-5p, and -17-3p were upregulated. We also explored the gene targets of these miRNAs and investigated the downstream pathways associated with them to decipher the potential pathways impacted in stroke with diabetes as comorbidity. Overall, our novel findings provide important insights into the differentially regulated miRNAs, their associated pathways and potential utilization for clinical benefits in ischemic stroke patients with diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Toor, Aldous, Parray, Akhtar, Al-Sarraj, Abdelalim, Arredouani, El-Agnaf, Thornalley, Pananchikkal, Pir, Kuni, Shuaib, Alajez and Albagha.)
- Published
- 2022
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21. Identification of a Gene Panel Predictive of Triple-Negative Breast Cancer Response to Neoadjuvant Chemotherapy Employing Transcriptomic and Functional Validation.
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Vishnubalaji R, Abdel-Razeq H, Gehani S, Albagha OME, and Alajez NM
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Doxorubicin therapeutic use, Female, Humans, Neoadjuvant Therapy, Neoplasm Recurrence, Local drug therapy, Neoplasm, Residual drug therapy, Transcriptome, Breast Neoplasms pathology, Cation Transport Proteins genetics, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
Triple-negative breast cancer (TNBC) patients exhibiting pathological complete response (pCR) have better clinical outcomes compared to those with residual disease (RD). Therefore, robust biomarkers that can predict pCR may help with triage and resource prioritization in patients with TNBC. Herein, we identified a gene panel predictive of RD and pCR in TNBC from the discovery ( n = 90) treatment-naive tumor transcriptomic data. Eight RD-derived genes were identified as TNBC-essential genes, which were highly predicative of overall survival (OS) and relapse-free survival (RFS) in an additional cohort of basal breast cancer ( n = 442). Mechanistically, targeted depletion of the eight genes reduced the proliferation potential of TNBC cell models, while most remarkable effects were for combined SLC39A7, TIMM13, BANF1, and MVD knockdown in conjunction with doxorubicin. Orthogonal partial least squares-discriminant analysis (OPLS-DA) and receiver operating characteristic curve (ROC) analyses revealed significant predictive power for the identified gene panels with an area under the curve (AUC) of 0.75 for the validation cohort ( n = 50) to discriminate RD from pCR. Protein-Protein Interaction (PPI) network analysis of the pCR-derived gene signature identified an 87-immune gene signature highly predictive of pCR, which correlated with better OS, RFS, and distant-metastasis-free survival (DMFS) in an independent cohort of basal and, to a lesser extent, HER2+ breast cancer. Our data have identified gene signatures predicative of RD and pCR in TNBC with potential clinical implications.
- Published
- 2022
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22. The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects.
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Diboun I, Al-Sarraj Y, Toor SM, Mohammed S, Qureshi N, Al Hail MSH, Jayyousi A, Al Suwaidi J, and Albagha OME
- Abstract
Familial hypercholesterolemia (FH) is an inherited disease characterized by reduced efficiency of low-density lipoprotein-cholesterol (LDL-C) removal from the blood and, consequently, an increased risk of life-threatening early cardiovascular complications. In Qatar, the prevalence of FH has not been determined and the disease, as in many countries, is largely underdiagnosed. In this study, we combined whole-genome sequencing data from the Qatar Genome Program with deep phenotype data from Qatar Biobank for 14,056 subjects to determine the genetic spectrum and estimate the prevalence of FH in Qatar. We used the Dutch Lipid Clinic Network (DLCN) as a diagnostic tool and scrutinized 11 FH-related genes for known pathogenic and possibly pathogenic mutations. Results revealed an estimated prevalence of 0.8% (1:125) for definite/probable cases of FH in the Qatari population. We detected 16 known pathogenic/likely pathogenic mutations in LDLR and one in PCSK9; all in a heterozygous state with high penetrance. The most common mutation was rs1064793799 (c.313+3A >C) followed by rs771019366 (p.Asp90Gly); both in LDLR . In addition, we identified 18 highly penetrant possibly pathogenic variants, of which 5 were Qatari-specific, in LDLR , APOB , PCSK9 and APOE , which are predicted to be among the top 1% most deleterious mutations in the human genome but further validations are required to confirm their pathogenicity. We did not detect any homozygous FH or autosomal recessive mutations in our study cohort. This pioneering study provides a reliable estimate of FH prevalence in Qatar based on a significantly large population-based cohort, whilst uncovering the spectrum of genetic variants associated with FH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Diboun, Al-Sarraj, Toor, Mohammed, Qureshi, Al Hail, Jayyousi, Al Suwaidi and Albagha.)
- Published
- 2022
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23. Epigenetic DNA Methylation Signatures Associated With the Severity of Paget's Disease of Bone.
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Diboun I, Wani S, Ralston SH, and Albagha OME
- Abstract
Background: Paget's disease of bone (PDB) is characterized by focal areas of dysregulated bone turnover resulting in increased bone loss and abnormal bone formation with variable severity. PDB has a complex etiology and both genetics and environmental factors have been implicated. A recent study has identified many differentially methylated loci in PDB compared to healthy subjects. However, associations between DNA methylation profiles and disease severity of PDB have not been investigated. Objectives: To investigate the association between DNA methylation signals and PDB severity. Methods: Using 232 well-characterized PDB subjects from the PRISM trial, a disease severity score was devised based on the clinical features of PDB. DNA methylation profiling was performed using Illumina Infinium HumanMethylation 450K array. Results: We identified 100 CpG methylation sites significantly associated with PDB severity at FDR <0.05. Additionally, methylation profiles in 11 regions showed Bonferroni-significant association with disease severity including six islands (located in VCL , TBX5 , CASZ1 , ULBP2 , NUDT15 and SQSTM1 ), two gene bodies ( CXCR6 and DENND1A ), and 3 promoter regions ( RPL27 , LINC00301 and VPS29 ). Moreover, FDR-significant effects from region analysis implicated genes with genetic variants previously associated with PDB severity, including RIN3 and CSF1 . A multivariate predictor model featuring the top severity-associated CpG sites revealed a significant correlation (R = 0.71, p = 6.9 × 10
-16 ) between observed and predicted PDB severity scores. On dichotomizing the severity scores into low and high severity, the model featured an area under curve (AUC) of 0.80, a sensitivity of 0.74 and a specificity of 0.68. Conclusion: We identified several CpG methylation markers that are associated with PDB severity in this pioneering study while also highlighting the novel molecular pathways associated with disease progression. Further work is warranted to affirm the suitability of our model to predict the severity of PDB in newly diagnosed patients or patients with family history of PDB., Competing Interests: SR has recieved research funding from Amgen, Eli Lilly, Novartis and Pfizer, unrelated to the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Diboun, Wani, Ralston and Albagha.)- Published
- 2022
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24. Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study.
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Thareja G, Evans AM, Wood SD, Stephan N, Zaghlool S, Halama A, Kastenmüller G, Belkadi A, Albagha OME, The Qatar Genome Program Research Consortium, and Suhre K
- Abstract
Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here we propose ratios between related drug metabolites as GWAS phenotypes that can drastically increase power to detect genetic associations between pairs of biochemically related molecules. As a proof-of-concept we conducted a GWAS with 520 individuals from the Qatar Biobank for who at least five of the nine available acetaminophen metabolites have been detected. We identified compelling evidence for genetic variance in acetaminophen glucuronidation and methylation by UGT2A15 and COMT, respectively. Based on the metabolite ratio association profiles of these two loci we hypothesized the chemical structure of one of their products or substrates as being 3-methoxyacetaminophen, which we then confirmed experimentally. Taken together, our study suggests a novel approach to analyze metabolites with a high degree of missingness in a GWAS setting with ratios, and it also demonstrates how pharmacological pathways can be mapped out using non-targeted metabolomics measurements in large population-based studies.
- Published
- 2022
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25. The Paget's disease of bone risk gene PML is a negative regulator of osteoclast differentiation and bone resorption.
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Wani S, Daroszewska A, Salter DM, van 't Hof RJ, Ralston SH, and Albagha OME
- Subjects
- Animals, Genome-Wide Association Study, Humans, Mice, Osteoclasts metabolism, Osteogenesis, Promyelocytic Leukemia Protein, Bone Resorption, Osteitis Deformans genetics
- Abstract
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., Competing Interests: Competing interests S.H.R. has received research funding from Amgen, Eli Lilly, Novartis and Pfizer unrelated to the submitted work. The other authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2022
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26. Identification of Novel Circulating miRNAs in Patients with Acute Ischemic Stroke.
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Aldous EK, Toor SM, Parray A, Al-Sarraj Y, Diboun I, Abdelalim EM, Arredouani A, El-Agnaf O, Thornalley PJ, Akhtar N, Pananchikkal SV, Shuaib A, Alajez NM, and Albagha OME
- Subjects
- Biomarkers, Gene Expression Profiling, Humans, ROC Curve, Circulating MicroRNA genetics, Ischemic Stroke diagnosis, Ischemic Stroke genetics, MicroRNAs genetics, Stroke genetics
- Abstract
Ischemic strokes are associated with significant morbidity and mortality, but currently there are no reliable prognostic or diagnostic blood biomarkers. MicroRNAs (miRNAs) regulate various molecular pathways and may be used as biomarkers. Using RNA-Seq, we conducted comprehensive circulating miRNA profiling in patients with ischemic stroke compared with healthy controls. Samples were collected within 24 h of clinical diagnosis. Stringent analysis criteria of discovery (46 cases and 95 controls) and validation (47 cases and 96 controls) cohorts led to the identification of 10 differentially regulated miRNAs, including 5 novel miRNAs, with potential diagnostic significance. Hsa-miR-451a was the most significantly upregulated miRNA (FC; 4.8, FDR; 3.78 × 10
-85 ), while downregulated miRNAs included hsa-miR-574-5p and hsa-miR-142-3p, among others. Importantly, we computed a multivariate classifier based on the identified miRNA panel to differentiate between ischemic stroke patients and healthy controls, which showed remarkably high sensitivity (0.94) and specificity (0.99). The area under the ROC curve was 0.97 and it is superior to other current available biomarkers. Moreover, in samples collected one month following stroke, we found sustained upregulation of hsa-miR-451a and downregulation of another 5 miRNAs. Lastly, we report 3 miRNAs that were significantly associated with poor clinical outcomes of stroke, as defined by the modified Rankin scores. The clinical translation of the identified miRNA panel may be explored further.- Published
- 2022
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27. Comprehensive Transcriptomic Profiling of Murine Osteoclast Differentiation Reveals Novel Differentially Expressed Genes and LncRNAs.
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Toor SM, Wani S, and Albagha OME
- Abstract
Osteoclasts are the sole bone resorbing cells, which undertake opposing roles to osteoblasts to affect skeletal mass and structure. However, unraveling the comprehensive molecular mechanisms behind osteoclast differentiation is necessitated to overcome limitations and scarcity of available data, particularly in relation with the emerging roles of long non-coding RNAs (LncRNAs) in gene expression. In this study, we performed comprehensive and progressive analyses of the dynamic transcriptomes of murine osteoclasts, generated in vitro . We compared the total RNA-based transcriptomes of murine bone marrow derived cells with differentiated osteoclasts, while focusing on potentially novel genes and LncRNAs, to uncover critical genes and their associated pathways, which are differentially regulated during osteoclast differentiation. We found 4,214 differentially regulated genes during osteoclast differentiation, which included various types of LncRNAs. Among the upregulated protein coding genes not previously associated with osteoclast are Pheta1 , Hagh , Gfpt1 and Nol4 , while downregulated genes included Plau , Ltf , Sell and Zfp831 . Notably, we report Nol4 as a novel gene related to osteoclast activity since Nol4 knockout mice Nol4
em1(International Mouse Phenotyping Consortium)J exhibit increased bone mineral density. Moreover, the differentially expressed LncRNAs included antisense and long intergenic non-coding RNAs, among others. Overall, immune-related and metabolism-related genes were downregulated, while anatomical morphogenesis and remodeling-related genes were upregulated in early-differentiated osteoclasts with sustained downregulation of immune-related genes in mature osteoclasts. The gene signatures and the comprehensive transcriptome of osteoclast differentiation provided herein can serve as an invaluable resource for deciphering gene dysregulation in osteoclast-related pathologic conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Toor, Wani and Albagha.)- Published
- 2021
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28. Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice.
- Author
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Alonso N, Wani S, Rose L, Van't Hof RJ, Ralston SH, and Albagha OME
- Subjects
- Animals, Homozygote, Humans, Mice, Mutagenesis, Insertional, Mutation, Osteoclasts, Phenotype, RANK Ligand genetics, Receptor Activator of Nuclear Factor-kappa B genetics, Osteitis Deformans genetics, Osteopetrosis genetics
- Abstract
Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a
75dup27/- ) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27/- animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a75dup27/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)- Published
- 2021
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29. Family-Based Genome-Wide Association Study of Autism Spectrum Disorder in Middle Eastern Families.
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Al-Sarraj Y, Al-Dous E, Taha RZ, Ahram D, Alshaban F, Tolfat M, El-Shanti H, and Albagha OME
- Subjects
- Adult, Case-Control Studies, Child, Female, Gene Expression genetics, Genome-Wide Association Study methods, Humans, Male, Middle East, Polymorphism, Single Nucleotide genetics, Autism Spectrum Disorder genetics, Genetic Predisposition to Disease genetics, White People genetics
- Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by abnormalities in language and social communication with substantial clinical heterogeneity. Genetic factors play an important role in ASD with heritability estimated between 70% to 80%. Genome-wide association studies (GWAS) have identified multiple loci associated with ASD. However, most studies were performed on European populations and little is known about the genetic architecture of ASD in Middle Eastern populations. Here, we report the first GWAS of ASD in the Middle eastern population of Qatar. We analyzed 171 families with ASD, using linear mixed models adjusting for relatedness and other confounders. Results showed that common single nucleotide polymorphisms (SNP) in seven loci are associated with ASD ( p < 1 × 10
-5 ). Although the identified loci did not reach genome-wide significance, many of the top associated SNPs are located within or near genes that have been implicated in ASD or related neurodevelopmental disorders. These include GORASP2, GABBR2, ANKS6, THSD4, ERCC6L , ARHGEF6 , and HDAC8 . Additionally, three of the top associated SNPs were significantly associated with gene expression. We also found evidence of association signals in two previously reported ASD-susceptibility loci (rs10099100 and rs4299400). Our results warrant further functional studies and replication to provide further insights into the genetic architecture of ASD.- Published
- 2021
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30. Whole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits.
- Author
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Thareja G, Al-Sarraj Y, Belkadi A, Almotawa M, Suhre K, and Albagha OME
- Subjects
- Biological Specimen Banks, Gene Frequency genetics, Genetic Loci, Humans, Japan, Linkage Disequilibrium genetics, Multifactorial Inheritance genetics, Principal Component Analysis, Qatar, Genetics, Population, Genome, Human, Genome-Wide Association Study, Quantitative Trait, Heritable, Sequence Analysis, DNA
- Abstract
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.
- Published
- 2021
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31. Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.
- Author
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Alonso N, Estrada K, Albagha OME, Herrera L, Reppe S, Olstad OK, Gautvik KM, Ryan NM, Evans KL, Nielson CM, Hsu YH, Kiel DP, Markozannes G, Ntzani EE, Evangelou E, Feenstra B, Liu X, Melbye M, Masi L, Brandi ML, Riches P, Daroszewska A, Olmos JM, Valero C, Castillo J, Riancho JA, Husted LB, Langdahl BL, Brown MA, Duncan EL, Kaptoge S, Khaw KT, Usategui-Martín R, Del Pino-Montes J, González-Sarmiento R, Lewis JR, Prince RL, D'Amelio P, García-Giralt N, Nogués X, Mencej-Bedrac S, Marc J, Wolstein O, Eisman JA, Oei L, Medina-Gómez C, Schraut KE, Navarro P, Wilson JF, Davies G, Starr J, Deary I, Tanaka T, Ferrucci L, Gianfrancesco F, Gennari L, Lucas G, Elosua R, Uitterlinden AG, Rivadeneira F, and Ralston SH
- Subjects
- Aged, Aged, 80 and over, Bone Density genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide, Postmenopause, Quantitative Trait Loci, Chromosomes, Human, Pair 2 genetics, Osteoporotic Fractures genetics, Spinal Fractures genetics
- Abstract
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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)- Published
- 2018
- Full Text
- View/download PDF
32. Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget's Disease.
- Author
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Obaid R, Wani SE, Azfer A, Hurd T, Jones R, Cohen P, Ralston SH, and Albagha OME
- Subjects
- Animals, Cell Cycle Proteins, Cells, Cultured, Eye Proteins genetics, Membrane Transport Proteins, Mice, Osteoclasts metabolism, Osteogenesis, RANK Ligand metabolism, Signal Transduction, Cell Differentiation, Eye Proteins metabolism, Interferon-beta metabolism, NF-kappa B metabolism, Osteitis Deformans metabolism, Osteoclasts cytology
- Abstract
Paget's disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how this leads to the development of PDB. Here, we show that OPTN acts as a negative regulator of osteoclast differentiation in vitro and that mice with a loss-of-function mutation in Optn have increased osteoclast activity and bone turnover. Osteoclasts derived from Optn mutant mice have an increase in NF-κB activation and a reduction in interferon beta expression in response to RANKL when compared to wild-type mice. These studies identify OPTN as a regulator of bone resorption and are consistent with a model whereby genetically determined reductions in OPTN expression predispose to PDB by enhancing osteoclast differentiation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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