{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:14:28Z","timestamp":1775736868468,"version":"3.50.1"},"reference-count":59,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH\/NEI","doi-asserted-by":"publisher","award":["1K08EY031800-01"],"award-info":[{"award-number":["1K08EY031800-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH\/NEI","doi-asserted-by":"publisher","award":["UL1TR0012-05"],"award-info":[{"award-number":["UL1TR0012-05"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["1K08EY031800-01"],"award-info":[{"award-number":["1K08EY031800-01"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR0012-05"],"award-info":[{"award-number":["UL1TR0012-05"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41\u201371% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients\u2019 glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System\u2019s pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and\/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p &lt; 10\u22123) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p &lt; 10\u22123) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer\u2019s disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62\u20135.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 \u00d7 10\u20136) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11\u20130.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47\u201358%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes\/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.<\/jats:p>","DOI":"10.3390\/ijms24065636","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:50:45Z","timestamp":1678938645000},"page":"5636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence"],"prefix":"10.3390","volume":"24","author":[{"given":"Julie L.","family":"Barr","sequence":"first","affiliation":[{"name":"Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Feehan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Cerner Enviza, an Oracle Company, Kansas City, MO 64117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1203-1782","authenticated-orcid":false,"given":"Casey","family":"Tak","sequence":"additional","affiliation":[{"name":"Departments of Pharmacotherapy and Internal Medicine, University of Utah Health, Salt Lake City, UT 8413, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3802-3868","authenticated-orcid":false,"given":"Leah A.","family":"Owen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA"},{"name":"Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA"},{"name":"Department of Obstetrics and Gynecology, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"Finley","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parker A.","family":"Cromwell","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8274-8511","authenticated-orcid":false,"given":"John H.","family":"Lillvis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3399-9028","authenticated-orcid":false,"given":"Patrice M.","family":"Hicks","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Au","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1102-3999","authenticated-orcid":false,"given":"Michael H.","family":"Farkas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asher","family":"Weiner","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew L.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra F.","family":"Sieminski","sequence":"additional","affiliation":[{"name":"Cerner Enviza, an Oracle Company, Kansas City, MO 64117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Sherva","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9543-1898","authenticated-orcid":false,"given":"Mark A.","family":"Munger","sequence":"additional","affiliation":[{"name":"Departments of Pharmacotherapy and Internal Medicine, University of Utah Health, Salt Lake City, UT 8413, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murray H.","family":"Brilliant","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3731-142X","authenticated-orcid":false,"given":"Margaret M.","family":"DeAngelis","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA"},{"name":"Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA"},{"name":"Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA"},{"name":"Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Genetics, Genomics and Bioinformatics Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, 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J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.ajo.2011.06.004","article-title":"An Assessment of the Health and Economic Burdens of Glaucoma","volume":"152","author":"Varma","year":"2011","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13762","DOI":"10.1038\/s41598-021-92971-w","article-title":"Prevalence of primary open angle glaucoma in the last 20 years: A meta-analysis and systematic review","volume":"11","author":"Zhang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e218348","DOI":"10.1001\/jamanetworkopen.2021.8348","article-title":"Racial and Ethnic Disparities in Primary Open-Angle Glaucoma Clinical Trials: A Systematic Review and Meta-Analysis","volume":"4","author":"Allison","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/08820538.2022.2152702","article-title":"Racial Disparities Affecting Black Patients in Glaucoma Diagnosis And Management","volume":"38","author":"Wu","year":"2022","journal-title":"Semin. Ophthalmol."},{"key":"ref_8","first-page":"49","article-title":"Racial Disparities in Glaucoma: From Epidemiology to Pathophysiology","volume":"119","author":"Siegfried","year":"2022","journal-title":"Mo. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1001\/archopht.120.6.701","article-title":"The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma","volume":"120","author":"Kass","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1001\/archopht.120.10.1268","article-title":"Reduction of Intraocular Pressure and Glaucoma Progression: Results from the Early Manifest Glaucoma Trial","volume":"120","author":"Heijl","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1016\/j.ophtha.2011.05.013","article-title":"The Relationship between Glaucoma Medication Adherence, Eye Drop Technique, and Visual Field Defect Severity","volume":"118","author":"Sleath","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"410","DOI":"10.5301\/EJO.2010.6112","article-title":"Do Adherence Rates and Glaucomatous Visual Field Progression Correlate?","volume":"21","author":"Rossi","year":"2011","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_13","first-page":"87","article-title":"Health-related Quality of Life in Patients with Cataract and Glaucoma","volume":"9","author":"Lee","year":"2000","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_14","first-page":"393","article-title":"Compliance Barriers in Glaucoma: A Systematic Classification","volume":"12","author":"Tsai","year":"2003","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Court, R., Leisegang, R., Stewart, A., Sunpath, H., Murphy, R., Winternheimer, P., Ally, M., and Maartens, G. (2014). Short term adherence tool predicts failure on second line protease inhibitor-based antiretroviral therapy: An observational cohort study. BMC Infect. Dis., 14.","DOI":"10.1186\/s12879-014-0664-3"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e014435","DOI":"10.1136\/bmjopen-2016-014435","article-title":"Factors predicting self-reported medication low adherence in a large sample of adults in the US general population: A cross-sectional study","volume":"7","author":"Feehan","year":"2017","journal-title":"BMJ Open"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Feehan, M., Munger, M.A., Cooper, D.K., Hess, K.T., Durante, R., Jones, G.J., Montuoro, J., Morrison, M.A., Clegg, D., and Crandall, A.S. (2016). Adherence to Glaucoma Medications Over 12 Months in Two US Community Pharmacy Chains. J. Clin. Med., 5.","DOI":"10.3390\/jcm5090079"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.ophtha.2019.09.041","article-title":"Cost-Utility Analysis of Glaucoma Medication Adherence","volume":"127","author":"Salman","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fernandez-Lazaro, C.I., Garc\u00eda-Gonz\u00e1lez, J.M., Adams, D.P., Fernandez-Lazaro, D., Mielgo-Ayuso, J., Caballero-Garcia, A., Racionero, F.M., C\u00f3rdova, A., and Miron-Canelo, J.A. (2019). Adherence to treatment and related factors among patients with chronic conditions in primary care: A cross-sectional study. BMC Fam. Pract., 20.","DOI":"10.1186\/s12875-019-1019-3"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/vop.12843","article-title":"Medical anti-glaucoma therapy: Beyond the drop","volume":"24","author":"Miller","year":"2020","journal-title":"Vet. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.5808\/GI.2014.12.3.121","article-title":"Genome-Wide Association Study of Medication Adherence in Chronic Diseases in the Korean Population","volume":"12","author":"Seo","year":"2014","journal-title":"Genom. Inform."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/cpt.2557","article-title":"The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms","volume":"111","author":"Niemi","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ajo.2022.05.007","article-title":"Adverse Effects and Safety in Glaucoma Patients: Agreement on Clinical Trial Outcomes for Reports on Eye Drops (ASGARD)\u2014A Delphi Consensus Statement","volume":"241","author":"Thein","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"DiBonaventura, M., Gabriel, S., Dupclay, L., Gupta, S., and Kim, E. (2012). A patient perspective of the impact of medication side effects on adherence: Results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry, 12.","DOI":"10.1186\/1471-244X-12-20"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e857","DOI":"10.4088\/JCP.15f10150","article-title":"Understanding Relative Risk, Odds Ratio, and Related Terms: As Simple as It Can Get","volume":"76","author":"Andrade","year":"2015","journal-title":"J. Clin. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"bax028","DOI":"10.1093\/database\/bax028","article-title":"GeneHancer: Genome-wide integration of enhancers and target genes in GeneCards","volume":"2017","author":"Fishilevich","year":"2017","journal-title":"Database"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.cr.7290105","article-title":"MAPK signal pathways in the regulation of cell proliferation in mammalian cells","volume":"12","author":"Zhang","year":"2002","journal-title":"Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.neubiorev.2021.10.009","article-title":"ERK\/MAPK signalling in the developing brain: Perturbations and consequences","volume":"131","author":"Iroegbu","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1038\/s41380-018-0313-0","article-title":"Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci","volume":"25","author":"Erzurumluoglu","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/mp.2017.77","article-title":"Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability","volume":"23","author":"Duncan","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1017\/S0033291714002165","article-title":"The heritability of alcohol use disorders: A meta-analysis of twin and adoption studies","volume":"45","author":"Verhulst","year":"2015","journal-title":"Psychol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1038\/s41467-018-04445-9","article-title":"CREB controls cortical circuit plasticity and functional recovery after stroke","volume":"9","author":"Caracciolo","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1038\/nn.2405","article-title":"CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala","volume":"12","author":"Zhou","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nn1661","article-title":"CREB modulates excitability of nucleus accumbens neurons","volume":"9","author":"Dong","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16064","DOI":"10.1038\/srep16064","article-title":"Mitofilin and CHCHD6 physically interact with Sam50 to sustain cristae structure","volume":"5","author":"Ding","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s00401-022-02499-0","article-title":"A CHCHD6\u2013APP axis connects amyloid and mitochondrial pathology in Alzheimer\u2019s disease","volume":"144","author":"Shang","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/13816810.2020.1737951","article-title":"Association of VIPR2 and ZMAT4 with high myopia","volume":"41","author":"Cheong","year":"2020","journal-title":"Ophthalmic Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9884155","DOI":"10.1155\/2022\/9884155","article-title":"Research on the Expression Level of Matrin-Type Zinc Finger Protein 4 Gene in T Cells of Thyroid Carcinoma Tissue","volume":"2022","author":"Zhang","year":"2022","journal-title":"Contrast Media Mol. Imaging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1080\/09286586.2021.1958350","article-title":"Gene-environment Interaction in Spherical Equivalent and Myopia: An Evidence-based Review","volume":"29","author":"Zhang","year":"2022","journal-title":"Ophthalmic Epidemiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1517\/17425255.2012.685237","article-title":"Role of CAR and PXR in xenobiotic sensing and metabolism","volume":"8","author":"Wang","year":"2012","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Pant, A., Maiti, T.K., Mahajan, D., and Das, B. (2022). Human Gut Microbiota and Drug Metabolism. Microb. Ecol., 1\u201315.","DOI":"10.1007\/s00248-022-02081-x"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1021\/tx100020p","article-title":"Xenobiotic Metabolism: A View through the Metabolometer","volume":"23","author":"Patterson","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Pot\u0119ga, A. (2022). Glutathione-Mediated Conjugation of Anticancer Drugs: An Overview of Reaction Mechanisms and Biological Significance for Drug Detoxification and Bioactivation. Molecules, 27.","DOI":"10.3390\/molecules27165252"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1001\/jamaophthalmol.2022.0055","article-title":"Racial and Ethnic Disparities in Cost-Related Barriers to Medication Adherence Among Patients with Glaucoma Enrolled in the National Institutes of Health All of Us Research Program","volume":"140","author":"Delavar","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1517\/17410541.2.1.49","article-title":"Marshfield Clinic Personalized Medicine Research Project (PMRP): Design, methods and recruitment for a large population-based biobank","volume":"2","author":"McCarty","year":"2005","journal-title":"Pers. Med."},{"key":"ref_46","unstructured":"Pharmacy Times (2023, March 03). Do You Know the Difference Between These Adherence Measures?. Available online: https:\/\/www.pharmacytimes.com\/view\/do-you-know-the-difference-between-these-adherence-measures."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/jcpt.12316","article-title":"Adherence to controller asthma medications: 6-month prevalence across a US community pharmacy chain","volume":"40","author":"Feehan","year":"2015","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"Fritsche","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng1847","article-title":"Principal components analysis corrects for stratification in genome-wide association studies","volume":"38","author":"Price","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Johnson, R.C., Nelson, G.W., Troyer, J.L., Lautenberger, J.A., Kessing, B.D., Winkler, C.A., and O\u2019Brien, S.J. (2010). Accounting for multiple comparisons in a genome-wide association study (GWAS). BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-724"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/ejhg.2015.269","article-title":"The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants","volume":"24","author":"Fadista","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_53","unstructured":"Two-Sample Z-Score Power Calculation (2023, March 06). Statistics Kindgom. Available online: https:\/\/www.statskingdom.com\/32test_power_t_z.html."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1093\/bioinformatics\/btn653","article-title":"SNPnexus: A web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms","volume":"25","author":"Chelala","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","article-title":"GCTA: A Tool for Genome-wide Complex Trait Analysis","volume":"88","author":"Yang","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10519-013-9584-z","article-title":"Three Mutually Informative Ways to Understand the Genetic Relationships Among Behavioral Disinhibition, Alcohol Use, Drug Use, Nicotine Use\/Dependence, and Their Co-occurrence: Twin Biometry, GCTA, and Genome-Wide Scoring","volume":"43","author":"Vrieze","year":"2013","journal-title":"Behav. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13024-021-00452-5","article-title":"Protective genes and pathways in Alzheimer\u2019s disease: Moving towards precision interventions","volume":"16","author":"Seto","year":"2021","journal-title":"Mol. Neurodegener."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5636\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:55:58Z","timestamp":1760122558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5636"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,15]]},"references-count":59,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065636"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065636","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,15]]}}}