{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T09:48:09Z","timestamp":1791884889235,"version":"4.3.4"},"reference-count":45,"publisher":"Cambridge University Press (CUP)","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/www.cambridge.org\/core\/terms"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Twin Res Hum Genet"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Attention-deficit\/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder. Current pharmacological treatments have limitations, highlighting the need for new therapeutic targets. Using two-sample Mendelian randomization with cis-expression quantitative trait loci from the eQTLGen Consortium (31,684 individuals), we performed genomewide analysis against ADHD genomewide association study summary statistics from European ancestry (20,183 cases; 35,191 controls) and FinnGen R10 (2,788 cases; 405,153 controls). Genetic instruments were selected at\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 5 \u00d7 10\n                    <jats:sup>\u22128<\/jats:sup>\n                    with\n                    <jats:italic>F<\/jats:italic>\n                    -statistic &gt; 10 and linkage disequilibrium clumping (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    &lt; .001). Mendelian randomization estimates were derived using inverse-variance weighted, weighted-median, and Mendelian randomization-Egger methods, with leave-one-out sensitivity analysis. Colocalization was performed to distinguish causality from linkage disequilibrium. From 5430 genes with valid instruments, we identified 10 ADHD-associated genes (inverse-variance weighted\n                    <jats:italic>p<\/jats:italic>\n                    &lt; .01, consistent direction across methods): four risk-increasing genes (\n                    <jats:italic>RRAGD, DTX2, HMOX1, AGAP3<\/jats:italic>\n                    ) and six protective genes (\n                    <jats:italic>NUCKS1, CPSF1, MAU2, CLDN5, CYP4F12, ATP6V1E2<\/jats:italic>\n                    ).\n                    <jats:italic>MAU2<\/jats:italic>\n                    demonstrated strong colocalization support (posterior probability for hypothesis 4 &gt; .6). Pathway enrichment highlighted mechanistic target of rapamycin signaling as a priority mechanism. Computational in silico drug prioritization nominated candidate compounds (e.g., selenium, ketoconazole) predicted to modulate these targets. This study identifies genetically supported therapeutic targets for ADHD.\n                    <jats:italic>MAU2<\/jats:italic>\n                    emerged as the most promising causal locus. Rapamycin signaling represents a key mechanistic pathway. Several repositioned candidates (e.g., selenium, ketoconazole) warrant further experimental evaluation as potential leads. These findings provide a hypothesis-generating foundation for drug target prioritization, and require functional confirmation in CNS models and clinical validation before therapeutic relevance can be established.\n                  <\/jats:p>","DOI":"10.1017\/thg.2026.10106","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T09:22:26Z","timestamp":1791883346000},"page":"1-10","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":0,"title":["Identifying Potential Drug Targets for Treating ADHD From a Genetic Perspective: A Mendelian Randomization Study"],"prefix":"10.1017","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2512-8471","authenticated-orcid":false,"given":"Pei","family":"Pei","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00j2a7k55","id-type":"ROR","asserted-by":"publisher"}],"name":"Jiaxing University Affiliated Second Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Lu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00j2a7k55","id-type":"ROR","asserted-by":"publisher"}],"name":"Jiaxing University Affiliated Second Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00j2a7k55","id-type":"ROR","asserted-by":"publisher"}],"name":"Jiaxing University Affiliated Second Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Zhao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00j2a7k55","id-type":"ROR","asserted-by":"publisher"}],"name":"Jiaxing University Affiliated Second Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiannan","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00j2a7k55","id-type":"ROR","asserted-by":"publisher"}],"name":"Jiaxing University Affiliated Second Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"S1832427426101066_ref18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04965-x"},{"key":"S1832427426101066_ref39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16969-0"},{"key":"S1832427426101066_ref45","unstructured":"World Health Organization. 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