{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T14:53:57Z","timestamp":1789829637694,"version":"4.0.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Insomnia, a common clinical disorder, significantly impacts the physical and mental well-being of patients. Currently, available hypnotic medications are unsatisfactory due to adverse reactions and dependency, necessitating the identification of new drug targets for the treatment of insomnia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we utilized 734 plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis, with insomnia as the outcome variable, to identify potential drug targets for insomnia. Additionally, we validated our results externally using other datasets. Sensitivity analyses entailed reverse Mendelian randomization analysis, Bayesian co-localization analysis, and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mendelian randomization analysis indicated that elevated levels of TGFBI (OR = 1.01; 95% CI, 1.01\u20131.02) and PAM ((OR = 1.01; 95% CI, 1.01\u20131.02) in plasma are associated with an increased risk of insomnia, with external validation supporting these findings. Moreover, there was no evidence of reverse causality for these two proteins. Co-localization analysis confirmed that PAM (coloc.abf-PPH4 = 0.823) shared the same variant with insomnia, further substantiating its potential role as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of insomnia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Overall, our findings suggested that elevated plasma levels of TGFBI and PAM are connected with an increased risk of insomnia and might be promising therapeutic targets, particularly PAM. However, further exploration is necessary to fully understand the underlying mechanisms involved.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2024.1380321","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T04:43:45Z","timestamp":1714020225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of potential drug targets for insomnia by Mendelian randomization analysis based on plasma proteomics"],"prefix":"10.3389","volume":"15","author":[{"given":"Ni","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangyuan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimeng","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1212\/CON.0000000000000879","article-title":"Insomnia","volume":"26","author":"Perez","year":"2020","journal-title":"Continuum (Minneap Minn)"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1016\/j.biopsych.2006.05.039","article-title":"Sleep problems, comorbid mental disorders, and role functioning in the National Comorbidity Survey Replication","volume":"60","author":"Roth","year":"2006","journal-title":"Biol Psychiatry"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.sleep.2005.08.008","article-title":"Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors","volume":"7","author":"Morin","year":"2006","journal-title":"Sleep Med"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1177\/070674371105600905","article-title":"Prevalence of insomnia and its treatment in Canada","volume":"56","author":"Morin","year":"2011","journal-title":"Can J Psychiatr"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.sleep.2009.07.008","article-title":"Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the international classification of sleep disorders (ICSD)","volume":"10","author":"Ohayon","year":"2009","journal-title":"Sleep Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/J.JSMC.2022.02.008","article-title":"The effects of insomnia and sleep loss on cardiovascular disease","volume":"17","author":"Khan","year":"2022","journal-title":"Sleep Med Clin"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"101583","DOI":"10.1016\/J.SMRV.2021.101583","article-title":"Sleep and anxiety: from mechanisms to interventions","volume":"61","author":"Chellappa","year":"2022","journal-title":"Sleep Med Rev"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/S11325-014-1059-9","article-title":"Plasma neuropeptide Y levels in Chinese patients with primary insomnia","volume":"19","author":"Huang","year":"2015","journal-title":"Sleep Breath"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e12876","DOI":"10.1111\/jsr.12876","article-title":"Does insomnia predict a high risk of cancer? 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