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Disruptions in these processes can lead to speech and language disorders, including stuttering, which is characterized by prolongations, blocks, and repetitions of speech sounds. To date, almost 60 genome-wide significant loci have been associated with stuttering. Alas, most of these signals appear in non-coding regions of the genome and thus remain largely uncharacterized. In this study, we probed functionality by leveraging the largest genome-wide association studies (GWAS) of self-reported stuttering in individuals with European genetic ancestry (N case = 78,394, N control = 865,956). We performed transcriptome-wide association studies (TWAS), tested causal effects via Mendelian randomization (MR), and assessed neuroimaging features associated with stuttering. Stuttering was associated with the genetically regulated gene expression (GReX) of 2,875 significant gene-tissue pairs (236 independent signals). Many of these GReX genes were enriched for neurological processes, including synapse organization and nervous system development, and 12 genes were independently supported in a clinically ascertained stuttering cohort. Our MR analysis identified 150 unique causal stuttering genes (53 distinct signals). Additionally, our neuroimaging analysis identified stuttering-associated genetic signals functionally linked with basal ganglia, cerebellum, and superior longitudinal fasciculus neuroimaging features. Together, these findings characterize transcriptomic signatures of stuttering and illuminate the neurological mechanisms driving this complex trait.<\/jats:p>","DOI":"10.64898\/2026.08.11.26359888","type":"posted-content","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:15:17Z","timestamp":1786706117000},"source":"Crossref","is-referenced-by-count":1,"title":["Functionally Oriented Genetic Analyses Reveal Potential Transcriptomic and Neurological Mechanisms of Stuttering"],"prefix":"10.64898","author":[{"given":"Alyssa C.","family":"Scartozzi","sequence":"first","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah G.","family":"Polikowsky","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Baker","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Highland","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Petty","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Lin","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"23andMe Research Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin M.","family":"Jones","sequence":"additional","affiliation":[{"name":"Hearing and Speech Sciences, Vanderbilt University, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Gamazon","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad D.","family":"Huff","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J.","family":"Cox","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly Jo","family":"Kraft","sequence":"additional","affiliation":[{"name":"Communication Sciences and Disorders, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dillon G.","family":"Pruett","sequence":"additional","affiliation":[{"name":"School of Communication Science and Disorders, Florida State University, Tallahassee, FL 32301"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Below","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081802300708000_2026.08.11.26359888v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfludis.2012.11.002"},{"key":"2026081802300708000_2026.08.11.26359888v1.2","unstructured":"Bloodstein O , Ratner NB . 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