{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:40:56Z","timestamp":1760060456898,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)","award":["NRF-2017R1C1B2012084"],"award-info":[{"award-number":["NRF-2017R1C1B2012084"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoporosis is a common disease characterized by a reduction in bone mineral density (BMD), leading to an increased risk of pathological fractures and even mortality. Although menopause is a major risk factor, osteoporosis can also occur in premenopausal women. The aim of this study was to identify genetic variants associated with the development of osteoporosis in Korean premenopausal women. Subjects were recruited from the Anseong and Ansan cohorts of the Korean Genome and Epidemiology Study (KoGES). Clinical and epidemiological characteristics were assessed, and participants were classified based on BMD values measured at the distal radius and mid-shaft tibia. Individuals with confounding risk factors such as low body weight, smoking, high alcohol consumption, steroid\/hormone therapy, or relevant medical history were excluded. A total of 247 healthy controls and 57 osteoporosis patients were included. Genotyping was performed using the Illumina Infinium HumanExome BeadChip and the Affymetrix Axiom Exome Array. Data were analyzed using the SNP and Variation Suite and PLINK, with quality control thresholds set at MAF \u2265 0.05 and HWE p \u2265 0.01. Functional annotation and protein structure predictions were performed using PolyPhen-2, SIFT, and PROVEAN. Genome-wide association analyses identified 113 single-nucleotide polymorphisms (SNPs) in 69 genes significantly associated with osteoporosis (p &lt; 0.05) in both platforms, with 18 SNPs showing high cross-platform consistency (p &lt; 0.01). Several of these genes were implicated in bone metabolism (e.g., ESRRG, PECAM1, COL6A5), vitamin D metabolism (e.g., NADSYN1, EFTUD1), skeletal muscle function (e.g., PACSIN2, ESRRG), and reproductive processes (e.g., CPEB1, EFCAB6, ASXL3). Notably, the CPEB1 rs783540 SNP exhibited the strongest association (p &lt; 0.001) in both analyses. Our findings suggest that genetic polymorphisms in pathways related to bone metabolism, vitamin D signaling, muscle\u2013bone interaction, and reproductive hormone regulation may contribute to the development of osteoporosis in Korean premenopausal women. These results provide a genetic basis for early identification of at-risk individuals and warrant further functional studies to elucidate the underlying mechanisms.<\/jats:p>","DOI":"10.3390\/ijms26178177","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T15:57:47Z","timestamp":1755878267000},"page":"8177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome-Wide Association Study of Osteoporosis Risk in Korean Pre-Menopausal Women: The Korean Genome and Epidemiology Study"],"prefix":"10.3390","volume":"26","author":[{"given":"Su Kang","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Laboratory Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seoung-Jin","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2075-3136","authenticated-orcid":false,"given":"Gyutae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Radiology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1992-5188","authenticated-orcid":false,"given":"Ju Yeon","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, College of Dentistry, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-2304","authenticated-orcid":false,"given":"Sang Wook","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1007\/s00198-003-1483-3","article-title":"The association between osteoporotic fractures and health-related quality of life as measured by the Health Utilities Index in the Canadian Multicentre Osteoporosis Study (CaMos)","volume":"14","author":"Adachi","year":"2003","journal-title":"Osteoporos. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1136\/bmj.294.6568.329","article-title":"Osteoporosis: Cause and management","volume":"294","author":"Smith","year":"1987","journal-title":"Br. Med. J. (Clin. Res. Ed.)"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1359\/jbmr.2002.17.7.1273","article-title":"Genetic and environmental determinants of peak bone mass in young men and women","volume":"17","author":"McGuigan","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.jmii.2018.08.017","article-title":"Monitoring early developed low bone mineral density in HIV-infected patients by intact parathyroid hormone and circulating fibroblast growth factor 23","volume":"52","author":"Chen","year":"2019","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_5","first-page":"2317","article-title":"Graves\u2019 disease and bone metabolism","volume":"64","author":"Sato","year":"2006","journal-title":"Nihon. Rinsho."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e007914","DOI":"10.1136\/bmjopen-2015-007914","article-title":"Association between alcohol consumption and Korean young women\u2019s bone health: A cross sectional study from the 2008 to 2011 Korea National Health and Nutrition Examination Survey","volume":"5","author":"Seo","year":"2015","journal-title":"BMJ Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ando.2018.04.016","article-title":"Bone and glucocorticoids","volume":"79","author":"Briot","year":"2018","journal-title":"Ann. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/art.1780380110","article-title":"Environmental and genetic factors affecting bone mass. Similarity of bone density among members of healthy families","volume":"38","author":"Jouanny","year":"1995","journal-title":"Arthritis Rheum."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1080\/13697137.2018.1554643","article-title":"Association of VDR and OPG gene polymorphism with osteoporosis risk in Chinese postmenopausal women","volume":"22","author":"Wu","year":"2019","journal-title":"Climacteric"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mondockova, V., Adamkovicova, M., Lukacova, M., Grosskopf, B., Babosova, R., Galbavy, D., Martiniakova, M., and Omelka, R. (2018). The estrogen receptor 1 gene affects bone mineral density and osteoporosis treatment efficiency in Slovak postmenopausal women. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0684-8"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.5603\/GP.2016.0014","article-title":"The RANKL\/RANK\/OPG signal trail: Significance of genetic polymorphisms in the etiology of postmenopausal osteoporosis","volume":"87","author":"Wolski","year":"2016","journal-title":"Ginekol. Pol."},{"key":"ref_12","first-page":"2.14.1","article-title":"Quality Control for the Illumina HumanExome BeadChip","volume":"90","author":"Igo","year":"2016","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mizrahi-Man, O., Woehrmann, M.H., Webster, T.A., Gollub, J., Bivol, A., Keeble, S.M., Aull, K.H., Mittal, A., Roter, A.H., and Wong, B.A. (2022). Novel genotyping algorithms for rare variants significantly improve the accuracy of Applied Biosystems Axiom array genotyping calls: Retrospective evaluation of UK Biobank array data. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0277680"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.bone.2010.03.017","article-title":"Prevalence and risk factors of osteoporosis in Korea: A community-based cohort study with lumbar spine and hip bone mineral density","volume":"47","author":"Shin","year":"2010","journal-title":"Bone"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"572","DOI":"10.2188\/jea.JE20150267","article-title":"Underweight Young Women Without Later Weight Gain Are at High Risk for Osteopenia After Midlife: The KOBE Study","volume":"26","author":"Tatsumi","year":"2016","journal-title":"J. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1172\/JCI11066","article-title":"Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha","volume":"106","author":"Cenci","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_17","first-page":"1522","article-title":"Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: A population-based study","volume":"82","author":"Khosla","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","first-page":"176","article-title":"Evidence of an age-related decrease in intestinal responsiveness to vitamin D: Relationship between serum 1,25-dihydroxyvitamin D3 and intestinal vitamin D receptor concentrations in normal women","volume":"75","author":"Ebeling","year":"1992","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1210\/jcem-67-4-644","article-title":"The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects","volume":"67","author":"Lips","year":"1988","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105S","DOI":"10.1016\/S8756-3282(98)00014-3","article-title":"Perspective on the impact of weightlessness on calcium and bone metabolism","volume":"22","author":"Holick","year":"1998","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/nm1096-1132","article-title":"Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta","volume":"2","author":"Hughes","year":"1996","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.bone.2008.02.017","article-title":"Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: A key mechanism in osteoporosis","volume":"43","author":"Grimaldi","year":"2008","journal-title":"Bone"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1055\/s-0033-1363265","article-title":"Estrogen withdrawal from osteoblasts and osteocytes causes increased mineralization and apoptosis","volume":"46","author":"Brennan","year":"2014","journal-title":"Horm. Metab. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1359\/jbmr.091014","article-title":"Association with replication between estrogen-related receptor gamma (ESRRgamma) polymorphisms and bone phenotypes in women of European ancestry","volume":"25","author":"Elfassihi","year":"2010","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cardelli, M., and Aubin, J.E. (2014). ERRgamma is not required for skeletal development but is a RUNX2-dependent negative regulator of postnatal bone formation in male mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109592"},{"key":"ref_26","first-page":"793","article-title":"Netrin-4 Promotes Differentiation and Migration of Osteoblasts","volume":"31","author":"Enoki","year":"2017","journal-title":"Vivo"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1016\/j.febslet.2014.05.009","article-title":"Netrin-4 derived from murine vascular endothelial cells inhibits osteoclast differentiation in vitro and prevents bone loss in vivo","volume":"588","author":"Enoki","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.bone.2008.08.107","article-title":"Role of iron metabolism and oxidative damage in postmenopausal bone loss","volume":"43","author":"Cristofaro","year":"2008","journal-title":"Bone"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3858\/emm.2010.42.5.039","article-title":"Genetic association of angiogenesis- and hypoxia-related gene polymorphisms with osteonecrosis of the femoral head","volume":"42","author":"Hong","year":"2010","journal-title":"Exp. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Swanberg, M., McGuigan, F.E., Ivaska, K.K., Gerdhem, P., and Akesson, K. (2012). Polymorphisms in the inflammatory genes CIITA, CLEC16A and IFNG influence BMD, bone loss and fracture in elderly women. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047964"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.4049\/jimmunol.0802398","article-title":"Bone marrow monocyte PECAM-1 deficiency elicits increased osteoclastogenesis resulting in trabecular bone loss","volume":"182","author":"Wu","year":"2009","journal-title":"J. Immunol."},{"key":"ref_32","first-page":"335","article-title":"N-CAM is not required for initiation of secondary chondrogenesis: The role of N-CAM in skeletal condensation and differentiation","volume":"43","author":"Fang","year":"1999","journal-title":"Int. J. Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1210\/en.2007-0215","article-title":"Overexpression of gamma-glutamyltransferase in transgenic mice accelerates bone resorption and causes osteoporosis","volume":"148","author":"Hiramatsu","year":"2007","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Moriwaki, S., Into, T., Suzuki, K., Miyauchi, M., Takata, T., Shibayama, K., and Niida, S. (2016). gamma-Glutamyltranspeptidase is an endogenous activator of Toll-like receptor 4-mediated osteoclastogenesis. Sci. Rep., 6.","DOI":"10.1038\/srep35930"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10464","DOI":"10.1038\/ncomms10464","article-title":"Joint mouse-human phenome-wide association to test gene function and disease risk","volume":"7","author":"Wang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_36","first-page":"1383","article-title":"Circulating microRNAs, miR-10b-5p, miR-328-3p, miR-100 and let-7, are associated with osteoblast differentiation in osteoporosis","volume":"11","author":"Chen","year":"2018","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tang, F., Zhang, R., He, Y., Zou, M., Guo, L., and Xi, T. (2012). MicroRNA-125b induces metastasis by targeting STARD13 in MCF-7 and MDA-MB-231 breast cancer cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035435"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Foucan, L., Velayoudom-Cephise, F.L., Larifla, L., Armand, C., Deloumeaux, J., Fagour, C., Plumasseau, J., Portlis, M.L., Liu, L., and Bonnet, F. (2013). Polymorphisms in GC and NADSYN1 Genes are associated with vitamin D status and metabolic profile in Non-diabetic adults. BMC Endocr. Disord., 13.","DOI":"10.1186\/1472-6823-13-36"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1016\/j.clnu.2017.10.024","article-title":"Vitamin D pathway gene polymorphisms influenced vitamin D level among pregnant women","volume":"37 Pt A","author":"Shao","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1002\/jcb.25129","article-title":"Gene Signatures of 1,25-Dihydroxyvitamin D3 Exposure in Normal and Transformed Mammary Cells","volume":"116","author":"Simmons","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jsbmb.2015.10.012","article-title":"Identification of vitamin D(3) target genes in human breast cancer tissue","volume":"164","author":"Sheng","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00223-018-0503-4","article-title":"Association Between the Decline in Muscle Health and the Decline in Bone Health in Older Individuals from the SarcoPhAge Cohort","volume":"104","author":"Locquet","year":"2019","journal-title":"Calcif. Tissue Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"551","DOI":"10.12965\/jer.1836268.134","article-title":"Role of exercise in age-related sarcopenia","volume":"14","author":"Yoo","year":"2018","journal-title":"J. Exerc. Rehabil."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"277","DOI":"10.5114\/biolsport.2018.77828","article-title":"Intensity-dependent gene expression after aerobic exercise in endurance-trained skeletal muscle","volume":"35","author":"Popov","year":"2018","journal-title":"Biol. Sport."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.1210\/jcem.84.10.6122","article-title":"Selective androgen receptor modulators (SARMs): A novel approach to androgen therapy for the new millennium","volume":"84","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_46","first-page":"247","article-title":"DJBP: A novel DJ-1-binding protein, negatively regulates the androgen receptor by recruiting histone deacetylase complex, and DJ-1 antagonizes this inhibition by abrogation of this complex","volume":"1","author":"Niki","year":"2003","journal-title":"Mol. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"baw030","DOI":"10.1093\/database\/baw030","article-title":"Genic insights from integrated human proteomics in GeneCards","volume":"2016","author":"Fishilevich","year":"2016","journal-title":"Database"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1210\/en.2018-00246","article-title":"Whole-Exome Sequencing Identifies Novel Recurrent Somatic Mutations in Sporadic Parathyroid Adenomas","volume":"159","author":"Wei","year":"2018","journal-title":"Endocrinology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.biopsych.2018.01.002","article-title":"Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder","volume":"84","author":"Quartier","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S1043-2760(02)00592-1","article-title":"To ERR in the estrogen pathway","volume":"13","author":"Giguere","year":"2002","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1158\/1078-0432.CCR-07-0224","article-title":"Identification of NTN4, TRA1, and STC2 as prognostic markers in breast cancer in a screen for signal sequence encoding proteins","volume":"13","author":"Esseghir","year":"2007","journal-title":"Clin. Cancer Res. An. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1600-0463.2008.00015.x","article-title":"Expression of CPEB, GAPDH and U6snRNA in cervical and ovarian tissue during cancer development","volume":"117","author":"Hansen","year":"2009","journal-title":"APMIS"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1242\/jcs.179218","article-title":"DAZL and CPEB1 regulate mRNA translation synergistically during oocyte maturation","volume":"129","author":"Liu","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1210\/jc.2016-1291","article-title":"Deletion of CPEB1 Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency","volume":"101","author":"Hyon","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.18632\/aging.101449","article-title":"Repeated superovulation increases the risk of osteoporosis and cardiovascular diseases by accelerating ovarian aging in mice","volume":"10","author":"Zhang","year":"2018","journal-title":"Aging"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.7754\/Clin.Lab.2024.240541","article-title":"Identification of Potential Biomarkers Associated with Spermatogenesis in Azoospermia","volume":"70","author":"Li","year":"2024","journal-title":"Clin. Lab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1592\/phco.29.3.305","article-title":"Osteoporosis risk in premenopausal women","volume":"29","author":"Vondracek","year":"2009","journal-title":"Pharmacotherapy"},{"key":"ref_58","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_59","doi-asserted-by":"crossref","unstructured":"Wang, S., Dvorkin, D., and Da, Y. (2012). SNPEVG: A graphical tool for GWAS graphing with mouse clicks. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-319"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nprot.2015.123","article-title":"SIFT missense predictions for genomes","volume":"11","author":"Vaser","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:24Z","timestamp":1760034864000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":62,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178177"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178177","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,8,22]]}}}