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Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. <jats:italic>MARK4<\/jats:italic> (which encodes microtubule affinity-regulating kinase 4) and <jats:italic>PPP1R37<\/jats:italic> (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. <jats:italic>EGFLAM<\/jats:italic> (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD.<\/jats:p>","DOI":"10.1038\/s41398-023-02532-0","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T04:01:48Z","timestamp":1688097708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression"],"prefix":"10.1038","volume":"13","author":[{"given":"Rafae A.","family":"Wathra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1594-666X","authenticated-orcid":false,"given":"Xiaoyu","family":"Men","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar S. 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TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. Dr. Rajji also received for an investigator-initiated study in-kind equipment support from Newronika, and in-kind research online accounts from Scientific Brain Training Pro, and participated in 2021 and 2022 in an advisory activity for Biogen Canada Inc. Dr. Rajji is also an inventor on the United States Provisional Patent No. 17\/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. BHM is supported in part by the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received during the past five years research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past five years, he has been an unpaid consultant to Myriad Neuroscience. JFK receipt of medication supplies for investigator-initiated studies from Pfizer and Indivior. Service on scientific advisory board of Aifred Health with potential for equity. He has served as a scientific advisor for Biogen. CFR has received research support from the NIH, PCORI, the Center for Medicare and Medicaid Services, the American Foundation for Suicide Prevention, the Brain and Behavior Research Foundation, and the Commonwealth of Pennsylvania. Bristol Meyers Squib and Pfizer have provided pharmaceutical supplies for his NIH sponsored research. EJL receives research support from the US National Institute of Health (NIH), the Patient-Centered Outcomes Research Institute (PCORI), McKnight Brain Research Foundation, Takeda, Lundbeck, and consulting fees (past) from Janssen and Jazz Pharmaceuticals. ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc and industry-initiated trials through Magnus Inc. He also currently serves on the scientific advisory board for Brainsway Inc. His work has been supported by the National Institutes of Mental Health (NIMH), the Canadian Institutes of Health Research (CIHR), Brain Canada and the Temerty Family, Grant and Kreutzcamp Family Foundations. DMB receives research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health \u2013 US (NIH), Weston Brain Institute, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He receives in-kind equipment support from Magventure for two investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"234"}}