{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:45:18Z","timestamp":1785761118001,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The Middle East region experiences a high prevalence of vitamin D deficiency, yet most genetic studies on vitamin D have focused on European populations. Furthermore, there is a lack of research on the genomic risk factors affecting elderly people, who are more susceptible to health burdens. We investigated the genetic determinants of 25-hydroxyvitamin D concentrations in elderly Lebanese individuals (n = 199) through a whole-exome-based genome-wide association study. Novel genomic loci displaying suggestive evidence of association with 25-hydroxyvitamin D levels were identified in our study, including rs141064014 in the MGAM (p-value of 4.40 \u00d7 10\u22126) and rs7036592 in PHF2 (p-value of 8.43 \u00d7 10\u22126). A meta-analysis of the Lebanese data and the largest European genome-wide association study confirmed consistency replication of numerous variants, including rs2725405 in SLC38A10 (p-value of 3.73 \u00d7 10\u22128). Although the polygenic risk score model derived from European populations exhibited lower performance than European estimations, it still effectively predicted vitamin D deficiency among our cohort. Our discoveries offer novel perspectives on the genetic mechanisms underlying vitamin D deficiency among elderly Middle Eastern populations, facilitating the development of personalized approaches for more effective management of vitamin D deficiency. Additionally, we demonstrated that whole-exome-based genome-wide association study is an effective method for identifying genetic components associated with phenotypes.<\/jats:p>","DOI":"10.3390\/nu15143216","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T04:27:13Z","timestamp":1689827233000},"page":"3216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Genetic Architecture of Vitamin D Deficiency among an Elderly Lebanese Middle Eastern Population: An Exome-Wide Association Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2737-0565","authenticated-orcid":false,"given":"Nagham Nafiz","family":"Hendi","sequence":"first","affiliation":[{"name":"Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Chakhtoura","sequence":"additional","affiliation":[{"name":"Calcium Metabolism & Osteoporosis Program, American University of Beirut Medical Center, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1505-6360","authenticated-orcid":false,"given":"Yasser","family":"Al-Sarraj","sequence":"additional","affiliation":[{"name":"Qatar Genome Program (QGP), Qatar Foundation Research, Development and Innovation, Qatar Foundation (QF), Doha P.O. Box 5825, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dania Saleh","family":"Basha","sequence":"additional","affiliation":[{"name":"Calcium Metabolism & Osteoporosis Program, American University of Beirut Medical Center, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5916-5983","authenticated-orcid":false,"given":"Omar","family":"Albagha","sequence":"additional","affiliation":[{"name":"Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada El-Hajj","family":"Fuleihan","sequence":"additional","affiliation":[{"name":"Calcium Metabolism & Osteoporosis Program, American University of Beirut Medical Center, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-5279","authenticated-orcid":false,"given":"Georges","family":"Nemer","sequence":"additional","affiliation":[{"name":"Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"},{"name":"Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ruiz-Garcia, A., Pallares-Carratala, V., Turegano-Yedro, M., Torres, F., Sapena, V., Martin-Gorgojo, A., and Martin-Moreno, J.M. (2023). Vitamin D Supplementation and Its Impact on Mortality and Cardiovascular Outcomes: Systematic Review and Meta-Analysis of 80 Randomized Clinical Trials. Nutrients, 15.","DOI":"10.3390\/nu15081810"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"BSR20190369","DOI":"10.1042\/BSR20190369","article-title":"Meta-analysis of randomized controlled trials on vitamin D supplement and cancer incidence and mortality","volume":"39","author":"Zhang","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1002\/jbmr.3122","article-title":"Impact of Calcium and Two Doses of Vitamin D on Bone Metabolism in the Elderly: A Randomized Controlled Trial","volume":"32","author":"Rahme","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cashman, K.D., Ritz, C., Kiely, M., and Odin, C. (2017). Improved Dietary Guidelines for Vitamin D: Application of Individual Participant Data (IPD)-Level Meta-Regression Analyses. Nutrients, 9.","DOI":"10.3390\/nu9050469"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3390\/medicina55070368","article-title":"Is Vitamin D Supplementation Useful for Weight Loss Programs? A systematic review and meta-analysis of randomized controlled trials","volume":"55","author":"Perna","year":"2019","journal-title":"Medicina"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1007\/s10519-019-09954-x","article-title":"Half the Genetic Variance in Vitamin D Concentration is Shared with Skin Colour and Sun Exposure Genes","volume":"49","author":"Mitchell","year":"2019","journal-title":"Behav. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/s41430-022-01218-y","article-title":"Variability in response to vitamin D supplementation according to vitamin D metabolism related gene polymorphisms in healthy adults","volume":"77","author":"Ammar","year":"2023","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1039\/c8pp00320c","article-title":"Pigment genes not skin pigmentation affect UVB-induced vitamin D","volume":"18","author":"Datta","year":"2019","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.jsbmb.2006.12.053","article-title":"A genome-wide linkage scan for 25-OH-D(3) and 1,25-(OH)2-D3 serum levels in asthma families","volume":"103","author":"Wjst","year":"2007","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.ajhg.2020.01.017","article-title":"Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci","volume":"106","author":"Manousaki","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1038\/s41588-021-00956-2","article-title":"Author Correction: Genetics of 35 blood and urine biomarkers in the UK Biobank","volume":"53","author":"Tanigawa","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1038\/s41467-020-15421-7","article-title":"Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration","volume":"11","author":"Revez","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/s41467-017-02662-2","article-title":"Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels","volume":"9","author":"Jiang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/S2213-8587(17)30357-1","article-title":"Effect of vitamin D supplementation on non-skeletal disorders: A systematic review of meta-analyses and randomised trials","volume":"5","author":"Autier","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1530\/EJE-18-0736","article-title":"Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: A position statement of the European Calcified Tissue Society","volume":"180","author":"Lips","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.bonr.2018.03.004","article-title":"Vitamin D in the Middle East and North Africa","volume":"8","author":"Chakhtoura","year":"2018","journal-title":"Bone Rep."},{"key":"ref_17","first-page":"e14881","article-title":"Prevalence and Predictors of Vitamin D Inadequacy: A Sample of 2,547 Patients in a Mediterranean Country","volume":"13","author":"Salman","year":"2021","journal-title":"Cureus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100005","DOI":"10.1016\/j.xgen.2021.100005","article-title":"Sequencing-based genome-wide association studies reporting standards","volume":"1","author":"McMahon","year":"2021","journal-title":"Cell Genom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1111\/biom.13214","article-title":"Operating characteristics of the rank-based inverse normal transformation for quantitative trait analysis in genome-wide association studies","volume":"76","author":"McCaw","year":"2020","journal-title":"Biometrics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1101\/gr.9.8.677","article-title":"dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation","volume":"9","author":"Sherry","year":"1999","journal-title":"Genome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: Rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"Zhou","year":"2018","journal-title":"Nat Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","article-title":"LocusZoom: Regional visualization of genome-wide association scan results","volume":"26","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41588-021-00783-5","article-title":"The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation","volume":"53","author":"Lambert","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1002\/humu.24298","article-title":"Annotating and prioritizing genomic variants using the Ensembl Variant Effect Predictor\u2014A tutorial","volume":"43","author":"Hunt","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/s41467-018-03751-6","article-title":"Massive mining of publicly available RNA-seq data from human and mouse","volume":"9","author":"Lachmann","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0140-6736(10)60588-0","article-title":"Common genetic determinants of vitamin D insufficiency: A genome-wide association study","volume":"376","author":"Wang","year":"2010","journal-title":"Lancet"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s40246-021-00350-3","article-title":"Identification of subgroups along the glycolysis-cholesterol synthesis axis and the development of an associated prognostic risk model","volume":"15","author":"Zhang","year":"2021","journal-title":"Hum. Genom."},{"key":"ref_34","first-page":"e14349","article-title":"Sucrase-Isomaltase Deficiency Causing Persistent Bloating and Diarrhea in an Adult Female","volume":"13","author":"Chiruvella","year":"2021","journal-title":"Cureus"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.2337\/db12-0628","article-title":"Epigenetic regulation of adipogenesis by PHF2 histone demethylase","volume":"62","author":"Okuno","year":"2013","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10398","DOI":"10.1038\/s41598-022-13660-w","article-title":"HIF-1alpha-mediated augmentation of miRNA-18b-5p facilitates proliferation and metastasis in osteosarcoma through attenuation PHF2","volume":"12","author":"Luo","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.4161\/cc.11.6.19508","article-title":"Vitamin D has wide regulatory effects on histone demethylase genes","volume":"11","author":"Pereira","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.11005\/jbm.2019.26.1.3","article-title":"The Function of the Vitamin D Receptor and a Possible Role of Enhancer RNA in Epigenomic Regulation of Target Genes: Implications for Bone Metabolism","volume":"26","author":"Sawatsubashi","year":"2019","journal-title":"J. Bone Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/cr.2014.127","article-title":"Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation","volume":"24","author":"Kim","year":"2014","journal-title":"Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"854397","DOI":"10.3389\/fcell.2022.854397","article-title":"SLC38A10 Regulate Glutamate Homeostasis and Modulate the AKT\/TSC2\/mTOR Pathway in Mouse Primary Cortex Cells","volume":"10","author":"Tripathi","year":"2022","journal-title":"Front Cell Dev. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.ajhg.2022.05.014","article-title":"Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits","volume":"109","author":"Patel","year":"2022","journal-title":"Am. J. Hum. Genet."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/14\/3216\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:15:26Z","timestamp":1760127326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/14\/3216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,20]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["nu15143216"],"URL":"https:\/\/doi.org\/10.3390\/nu15143216","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,20]]}}}