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The Val allele of the functional Val158Met polymorphism of the catechol\u2010O\u2010methyltransferase (<jats:italic><jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content><\/jats:italic>) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory\u2010related prefrontal activity. This functional magnetic resonance imaging (<jats:styled-content style=\"fixed-case\">fMRI<\/jats:styled-content>) study investigated for the first time whether the <jats:italic><jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content><\/jats:italic> Val158Met genotype modulates prefrontal activity during spatial working memory in <jats:styled-content style=\"fixed-case\">BD<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sixty\u2010four outpatients with <jats:styled-content style=\"fixed-case\">BD<\/jats:styled-content> in full or partial remission were stratified according to <jats:italic><jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content><\/jats:italic> Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n\u2010back working memory task during <jats:styled-content style=\"fixed-case\">fMRI<\/jats:styled-content> and the Cambridge Neuropsychological Test Automated Battery (<jats:styled-content style=\"fixed-case\">CANTAB<\/jats:styled-content>) Spatial Working Memory test outside the scanner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During high working memory load (2\u2010back vs 1\u2010back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dl<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content>) (<jats:italic>P<\/jats:italic>=.016). Exploratory whole\u2010brain analysis revealed a bilateral decrease in working memory\u2010related dl<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during <jats:styled-content style=\"fixed-case\">fMRI<\/jats:styled-content>. Outside the <jats:styled-content style=\"fixed-case\">MRI<\/jats:styled-content> scanner, Val carriers performed worse in the <jats:styled-content style=\"fixed-case\">CANTAB<\/jats:styled-content> Spatial Working Memory task than Met homozygotes (<jats:italic>P<\/jats:italic>\u2264.006), with deficits being most pronounced in Val homozygotes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The association between Val allelic load, dl<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> activity and <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> impairment points to a putative role of aberrant <jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> dopamine tonus in the cognitive impairments in <jats:styled-content style=\"fixed-case\">BD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bdi.12497","type":"journal-article","created":{"date-parts":[[2017,5,24]],"date-time":"2017-05-24T00:50:33Z","timestamp":1495587033000},"page":"214-224","source":"Crossref","is-referenced-by-count":38,"title":["The catechol\u2010O\u2010methyltransferase (<i>COMT<\/i>) Val158Met genotype modulates working memory\u2010related dorsolateral prefrontal response and performance in bipolar disorder"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2572-1384","authenticated-orcid":false,"given":"KW","family":"Miskowiak","sequence":"first","affiliation":[{"name":"Copenhagen Affective Disorder Research Centre Psychiatric Centre Copenhagen Copenhagen University Hospital  Rigshospitalet Denmark"},{"name":"Danish Research Centre for Magnetic Resonance Centre for Functional and Diagnostic Imaging and Research Hvidovre Hospital University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7781-8853","authenticated-orcid":false,"given":"HL","family":"Kj\u00e6rstad","sequence":"additional","affiliation":[{"name":"Copenhagen Affective Disorder Research Centre Psychiatric Centre Copenhagen Copenhagen University Hospital  Rigshospitalet Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MM","family":"St\u00f8ttrup","sequence":"additional","affiliation":[{"name":"Copenhagen Affective Disorder Research Centre Psychiatric Centre Copenhagen Copenhagen University Hospital  Rigshospitalet Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AM","family":"Svendsen","sequence":"additional","affiliation":[{"name":"Mental Health Centre Copenhagen Capital Region of Denmark  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"KM","family":"Demant","sequence":"additional","affiliation":[{"name":"Copenhagen Affective Disorder Research Centre Psychiatric Centre Copenhagen Copenhagen University Hospital  Rigshospitalet Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LK","family":"Hoeffding","sequence":"additional","affiliation":[{"name":"Institute of Biological Psychiatry MHC Sct. 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